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Background: In patients complaining common symptoms such as chest/abdominal/back pain or syncope, acute aortic syndromes (AAS) are rare underlying causes. AAS diagnosis requires urgent advanced aortic imaging (AAI), mostly computed tomography angiography. However, patient selection for AAI poses conflicting risks of misdiagnosis and overtesting., Objectives: We assessed the safety and efficiency of a diagnostic protocol integrating clinical data with point-of-care ultrasound (POCUS) and d-dimer (single/age-adjusted cutoff), to select patients for AAI., Methods: This prospective study involved 12 Emergency Departments from 5 countries. POCUS findings were integrated with a guideline-compliant clinical score, to define the integrated pre-test probability (iPTP) of AAS. If iPTP was high, urgent AAI was requested. If iPTP was low and d-dimer was negative, AAS was ruled out. Patients were followed for 30 days, to adjudicate outcomes., Results: Within 1979 enrolled patients, 176 (9 %) had an AAS. POCUS led to net reclassification improvement of 20 % (24 %/-4 % for events/non-events, P < 0.001) over clinical score alone. Median time to AAS diagnosis was 60 min if POCUS was positive vs 118 if negative (P = 0.042). Within 941 patients satisfying rule-out criteria, the 30-day incidence of AAS was 0 % (95 % CI, 0-0.41 %); without POCUS, 2 AAS were potentially missed. Protocol rule-out efficiency was 48 % (95 % CI, 46-50 %) and AAI was averted in 41 % of patients. Using age-adjusted d-dimer, rule-out efficiency was 54 % (difference 6 %, 95 % CI, 4-9 %, vs standard cutoff)., Conclusions: The integrated algorithm allowed rapid triage of high-probability patients, while providing safe and efficient rule-out of AAS. Age-adjusted d-dimer maximized efficiency., Clinical Trial Registration: Clinicaltrials.gov, NCT04430400., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

In settings where access to expert echocardiography is limited, focused echocardiography, combined with artificial intelligence (AI)-supported analysis, may improve diagnosis and monitoring of left ventricular hypertrophy (LVH). Sixteen nurses/nurse-assistants without prior experience in echocardiography underwent a 2-day hands-on intensive training to learn how to assess parasternal long axis views (PLAX) using an inexpensive hand-held ultrasound device in Lesotho, Southern Africa. Loops were stored on a cloud-drive, analyzed using deep learning algorithms at the University Hospital Basel, and afterwards confirmed by a board-certified cardiologist. The nurses/nurse-assistants obtained 756 echocardiograms. Of the 754 uploaded image files, 628 (83.3%) were evaluable by deep learning algorithms. Of those, results of 514/628 (81.9%) were confirmed by a cardiologist. Of the 126 not evaluable by the AI algorithm, 46 (36.5%) were manually evaluable. Overall, 660 (87.5%) uploaded files were evaluable and confirmed. Following short-term training of nursing cadres, a high proportion of obtained PLAX was evaluable using AI-supported analysis. This could be a basis for AI- and telemedical support in hard-to-reach areas with minimal resources., (© 2024. The Author(s).)

Aims: Tachycardia-induced cardiomyopathy (TCM) represents a partially reversible type of cardiomyopathy (CM) that is often underdiagnosed and cardiac chamber remodelling in TCM remains incompletely understood. We aim to explore differences in the dimensions of the left ventricle and functional recovery in patients with TCM compared with patients with other forms of CM., Methods and Results: We identified patients with reduced ejection fraction (≤50%) and/or atrial fibrillation or flutter with a left ventricular ejection fraction that improved from baseline (≥15% in left ventricular ejection fraction at follow-up or normalization of cardiac function with at least 10% improvement). Patients were then divided into two groups: (A) TCM patients and (B) patients with other forms of CM (controls). Two hundred thirty-eight patients were included (31% female, 70 years median age), 127 patients had TCM, and 111 had other forms of CM. Patients with TCM did not significantly improve indexed left ventricular volume (LVEDVI) after treatment (60 [45, 84] mL/m 2 versus 56 [45, 70] mL/m 2 , P = ns) compared with controls (67 [54, 81] mL/m 2 versus 52 [42, 69] mL/m 2 , P < 0.001). Patients with TCM patients had significantly worse fractional shortening at baseline than controls (15.5 [12, 23] vs. 20 [13, 30], P = 0.01) and higher indexed left atrial volume (LAVI) at baseline than controls (48 [37, 58] vs. 41 [33, 51], P = 0.01) that remained dilated at follow-up (follow-up LAVI 41 [33, 52] mL/m 2 ). Good predictors of TCM were: normal LVEDVI (LVEDVI < 58 mL/m 2 (M) and < 52 mL/m 2 (F)) (odds ratio [OR] 5.2; 95% confidence interval [CI] 2.2-13.3, P < 0.001), fractional shortening < 30% (OR 3.5; 95% CI 1.4-9.2, P = 0.009), LAVI >40 mL/m 2 (OR 3.4; 95% CI 1.6-7.3, P = 0.001) and normal wall thickness left ventricle (OR 3.2; 95% CI 1.4-7.8, P = 0.008). 54% of patients with TCM demonstrated diastolic dysfunction at follow-up, without differences from controls (54% vs. 43%, P = ns). 21% of patients with TCM showed persistent heart failure symptoms at follow-up compared with 4.5% of controls, P = 0.004., Conclusions: TCM patients have a specific pattern of functional recovery with persistent remodelling of the left atria and left ventricle. Several echocardiographic parameters might help identify TCM before treatment., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Hypertensive heart disease (HHD) develops in response to the chronic exposure of the left ventricle and left atrium to elevated systemic blood pressure. Left ventricular structural changes include hypertrophy and interstitial fibrosis that in turn lead to functional changes including diastolic dysfunction and impaired left atrial and LV mechanical function. Ultimately, these changes can lead to heart failure with a preserved (HFpEF) or reduced (HFrEF) ejection fraction. This review will outline the clinical evaluation of a patient with hypertension and/or suspected HHD, with a particular emphasis on the role and recent advances of multimodality imaging in both diagnosis and differential diagnosis.

Background: While renal function has been observed to inversely correlate with clinical outcome in other cardiomyopathies, its prognostic significance in patients with left ventricular non-compaction cardiomyopathy (LVNC) has not been investigated. The aim of this study was to determine the prognostic value of renal function in LVNC patients., Methods: Patients with isolated LVNC as diagnosed by echocardiography and/or magnetic resonance imaging in 4 Swiss centers were retrospectively analyzed for this study. Values for creatinine, urea, and estimated glomerular filtration rate (eGFR) as assessed by the CKD-EPI 2009 formula were collected and analyzed by a Cox regression model for the occurrence of a composite endpoint (death or heart transplantation)., Results: During the median observation period of 7.4 years 23 patients reached the endpoint. The ageand gender-corrected hazard ratios (HR) for death or heart transplantation were: 1.9 (95% confidence interval [CI] 1.4-2.6) for each increase over baseline creatinine level of 30 μmol/L (p < 0.001), 1.6 (95% CI 1.2-2.2) for each increase over baseline urea level of 5 mmol/L (p = 0.004), and 3.6 (95% CI 1.9-6.9) for each decrease below baseline eGFR level of 30 mL/min (p ≤ 0.001). The HR (log2) for every doubling of creatinine was 7.7 (95% CI 3-19.8; p < 0.001), for every doubling of urea 2.5 (95% CI 1.5-4.3; p < 0.001), and for every bisection of eGFR 5.3 (95% CI 2.4-11.6; p < 0.001)., Conclusions: This study provides evidence that in patients with LVNC impairment in renal function is associated with an increased risk of death and heart transplantation suggesting that kidney function assessment should be standard in risk assessment of LVNC patients.

Introduction: Atrial fibrillation (AF) adversely impacts right ventricular (RV) and right atrial (RA) structure and function. There are limited data on these changes after electrical cardioversion (ECV) and the relative contribution of heart rate to evaluate the immediate (1-2 h) and short-term (4-6 weeks) changes in right cardiac chamber dimensions and RV function after ECV in patients with persistent AF., Methods: Right cardiac chamber dimensions and RV function were measured in 64 patients using transthoracic echocardiography 1-2 h before, immediately after, and 4-6 weeks after ECV. Associations between changes in right-heart measures and rhythm status at follow-up were assessed using linear regression models., Results: For patients who remained in sinus rhythm 4-6 weeks after ECV (n = 48), median fractional area change (FAC) at baseline, immediately after ECV, and 4-6 weeks after ECV were 39 (Q1:35, Q3:42) %, 42 (Q1:39, Q3:46) %, 46 (Q1:43, Q3:49) % (p &lt; 0.01); median tricuspid annular plane systolic excursion (TAPSE) values at the same time points were 18 (Q1:17, Q3:20) mm, 20 (Q1:18, Q3:23) mm, and 24 (Q1:22, Q3:26) mm (p &lt; 0.01), respectively. There was no significant difference in RV end systolic area and RA volume index before and after ECV. However, RV end systolic area and RA volume index decreased significantly after 4-6 weeks from a median of 10 (Q1:8, Q3:13) cm2 to 8 (Q1:7, Q3:10) cm2 (p &lt; 0.01), and from a median of 30 (Q1:24, Q3:36) mL/m2 to 24 (Q1:20, Q3:27) mL/m2 (p &lt; 0.01). Changes in TAPSE were significantly associated with sinus rhythm at follow-up (p = 0.027), changes in FAC showed a strong trend to association with sinus rhythm (p = 0.053), and this was not true for RA measures (p = 0.64)., Conclusions: Among AF patients who remained in sinus rhythm after ECV, RV function improved immediately after ECV with further improvement at 4-6 weeks following sinus rhythm restoration., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

The authors determined the effect of the GLP-1 receptor agonist liraglutide on endothelial surface expression of vascular cell adhesion molecule (VCAM)-1 in murine apolipoprotein E knockout atherosclerosis. Contrast-enhanced ultrasound molecular imaging using microbubbles targeted to VCAM-1 and control microbubbles showed a 3-fold increase in endothelial surface VCAM-1 signal in vehicle-treated animals, whereas in the liraglutide-treated animals the signal ratio remained around 1 throughout the study. Liraglutide had no influence on low-density lipoprotein cholesterol or glycated hemoglobin, but reduced TNF-α, IL-1β, MCP-1, and OPN. Aortic plaque lesion area and luminal VCAM-1 expression on immunohistology were reduced under liraglutide treatment., Competing Interests: This work is supported by grants 310030-169905 and 310030-197673 from the Swiss national Science Foundation and from the Swiss Heart Foundation to Dr Kaufmann. This work was funded in part by Novo Nordisk A/S, Bagsværd, Denmark. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Aims: Microvascular inflammation plays an important role in the pathogenesis of diastolic dysfunction (DD) and metabolic heart disease. NOX1 is expressed in vascular and immune cells and has been implicated in the vascular pathology of metabolic disease. However, its contribution to metabolic heart disease is less understood., Methods and Results: NOX1-deficient mice (KO) and male wild-type (WT) littermates were fed a high-fat high-sucrose diet (HFHS) and injected streptozotocin (75 mg/kg i.p.) or control diet (CTD) and sodium citrate. Despite similar weight gain and increase in fasting blood glucose and insulin, only WT-HFHS but not KO-HFHS mice developed concentric cardiac hypertrophy and elevated left ventricular filling pressure. This was associated with increased endothelial adhesion molecule expression, accumulation of Mac-2-, IL-1β-, and NLRP3-positive cells and nitrosative stress in WT-HFHS but not KO-HFHS hearts. Nox1 mRNA was solidly expressed in CD45+ immune cells isolated from healthy mouse hearts but was negligible in cardiac CD31+ endothelial cells. However, in vitro, Nox1 expression increased in response to lipopolysaccharide (LPS) in endothelial cells and contributed to LPS-induced upregulation of Icam-1. Nox1 was also upregulated in mouse bone marrow-derived macrophages in response to LPS. In peripheral monocytes from age- and sex-matched symptomatic patients with and without DD, NOX1 was significantly higher in patients with DD compared to those without DD., Conclusions: NOX1 mediates endothelial activation and contributes to myocardial inflammation and remodelling in metabolic disease in mice. Given its high expression in monocytes of humans with DD, NOX1 may represent a potential target to mitigate heart disease associated with DD., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Patients developing perioperative myocardial infarction/injury (PMI) have a high mortality. PMI work-up and therapy remain poorly defined. This prospective multicenter study included high-risk patients undergoing major non-cardiac surgery within a systematic PMI screening and clinical response program. The frequency of cardiovascular imaging during PMI work-up and its yield for possible type 1 myocardial infarction (T1MI) was assessed. Automated PMI detection triggered evaluation by the treating physician/cardiologist, who determined selection/timing of cardiovascular imaging. T1M1 was considered with the presence of a new wall motion abnormality within 30 days in transthoracic echocardiography (TTE), a new scar or ischemia within 90 days in myocardial perfusion imaging (MPI), and Ambrose-Type II or complex lesions within 7 days of PMI in coronary angiography (CA). In patients with PMI, 21% (268/1269) underwent at least one cardiac imaging modality. TTE was used in 13% (163/1269), MPI in 3% (37/1269), and CA in 5% (68/1269). Cardiology consultation was associated with higher use of cardiovascular imaging (27% versus 13%). Signs indicative of T1MI were found in 8% of TTE, 46% of MPI, and 63% of CA. Most patients with PMI did not undergo any cardiovascular imaging within their PMI work-up. If performed, MPI and CA showed high yield for signs indicative of T1MI.Trial registration: https://clinicaltrials.gov/ct2/show/NCT02573532 ., (© 2022. The Author(s).)

Biomarkers may help to improve our knowledge about the complex pathophysiology of atrial fibrillation (AF). In this study we sought to identify significant changes in biomarkers and clinical measures in patients with and without AF recurrence after electrical cardioversion. We measured 21 conventional and new biomarkers before and 30 days after electrical cardioversion and assessed the associations of changes in biomarker levels with rhythm status at follow-up. Significant between-group changes were observed for bone morphogenetic protein 10 (BMP10), N-terminal pro-B-type natriuretic peptide (NT-proBNP) and total bilirubin. Their respective changes were - 10.4%, - 62.0% and - 25.6% in patients with sinus rhythm, and 3.1%, 1.1% and - 9.4% in patients with recurrent AF, for a between-group difference of - 13.5% (95% confidence interval [CI] - 19.3% to - 7.6%; P < 0.001), - 63.1% (95% CI - 76.6% to - 49.6%; P < 0.001) and - 16.3% (95% CI - 27.9% to - 4.7%; P = 0.007). In multivariable models, the reductions of BMP10 and NT-proBNP were significantly associated with follow-up rhythm status (β coefficient per 1 - SD decrease, - 3.85; 95% CI - 6.34 to - 1.35; P = 0.003 for BMP10 and - 5.84; 95% CI - 10.22 to - 1.47; P = 0.009 for NT-proBNP. In conclusion, changes in BMP10 und NT-proBNP levels were independently associated with rhythm status after cardioversion, suggesting that these markers may be dependent on the actual heart rhythm., (© 2022. The Author(s).)

Previous mouse studies have shown the increased presence of platelets in the myocardium during early stages of myocarditis and their selective detection by MRI. Here, we aimed to depict early myocarditis using molecular contrast-enhanced ultrasound of activated platelets, and to evaluate the impact of a P2Y 12 receptor platelet inhibition. Experimental autoimmune myocarditis was induced in BALB/c mice by subcutaneous injection of porcine cardiac myosin and complete Freund adjuvant (CFA). Activated platelets were targeted with microbubbles (MB) coupled to a single-chain antibody that binds to the "ligand-induced binding sites" of the GPIIb/IIIa-receptor (=LIBS-MB). Alongside myocarditis induction, a group of mice received a daily dose of 100 g prasugrel for 1 month. Mice injected with myosin and CFA had a significantly deteriorated ejection fraction and histological inflammation on day 28 compared to mice only injected with myosin. Platelets infiltrated the myocardium before reduction in ejection fraction could be detected by echocardiography. No selective binding of the LIBS-MB contrast agent could be detected by either ultrasound or histology. Prasugrel therapy preserved ejection fraction and significantly reduced platelet aggregates in the myocardium compared to mice without prasugrel therapy. Therefore, P2Y 12 inhibition could be a promising early therapeutic target in myocarditis, requiring further investigation.

Clinical translation of ultrasound molecular imaging will depend on the development of binders that can easily be generated, manufactured and coupled, and that are compatible with in vivo use. We describe targeted microbubbles (MBs) using designed ankyrin repeat proteins (DARPins) as a novel class of such translatable binders. Candidate DARPin binders for vascular cell adhesion molecule 1, an endothelial cell adhesion molecule involved in inflammatory processes, were selected using ribosome display and coupled to MBs. Flow-chamber assays of five MBs carrying high-affinity binders showed selective retention on endothelial cells activated by tumor necrosis factor-α for two binders compared with a MB carrying a control DARPin. In vivo ultrasound molecular imaging in a murine hind-limb inflammation model demonstrated up to a fourfold signal enhancement for three of the five MBs versus control. However, there was no correlation between results from flow-chamber assays and in vivo imaging. Thus, we conclude that ultrasound molecular imaging of inflammation using DARPin binders is feasible per se, but that screening of candidates cannot be accomplished with flow-chamber assays as used in our study., Competing Interests: Conflict of interest disclosure A.P. is a co-founder of and shareholder in Molecular Partners AG, which is developing DARPins for therapeutic purposes. For the remaining authors, no conflicts of interest are declared., (Copyright © 2021. Published by Elsevier Inc.)

Background: Both loop diuretics (LDs) and congestion have been related to worse heart failure (HF) outcome. The relationship between the cause and effect is unknown. The aim of this study was to investigate the interaction between congestion, diuretic use and HF outcome., Methods: Six hundred and twenty-two chronic HF patients from TIME-CHF were studied. Congestion was measured by means of a clinical congestion index (CCI). Loop diuretic dose was considered at baseline and month 6. Treatment intensification was defined as the increase in LD dose over 6 months or loop diuretic and thiazide or thiazide-like diuretic co-administration. The end-points were survival and HF hospitalisation-free survival., Results: High-LD dose at baseline and month 6 (≥ 80 mg of furosemide per day) was not identified as an independent predictor of outcome. CCI at baseline remained independently associated with impaired survival [hazard ratio (HR) 1.34, (95% confidence interval) (95% CI) (1.20-1.50), p < 0.001] and HF hospitalisation-free survival [HR 1.09, 95% CI (1.02-1.17), p = 0.015]. CCI at month 6 was independently associated with HF hospitalisation-free survival [HR 1.24, 95% CI (1.11-1.38), p < 0.001]. Treatment intensification was independently associated with survival [HR 1.75, 95% CI (1.19-1.38), p = 0.004] and HF hospitalisation-free survival [HR 1.69, 95% CI (1.22-2.35), p = 0.002]. Patients undergoing treatment intensification resulting in decongestion had better outcome than patients with persistent (worsening) congestion despite LD dose up-titration (p < 0.001)., Conclusion: Intensification of pharmacological decongestion but not the actual LD dose was related to poor outcome in chronic HF. If treatment intensification translated into clinical decongestion, outcome was better than in case of persistent or worsening congestion., (© 2020. Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: The natural course of atrial fibrillation (AF) is not well defined. We aimed to investigate the change in AF burden over time and its associated risk factors among AF patients., Methods: Fifty-four participants with recently documented paroxysmal or persistent AF were enrolled. Main exclusion criteria were permanent AF or previous catheter ablation for AF. AF burden was calculated as time in AF divided by total recording time using yearly continuous 7-day Holter-ECG recordings. A relative change ≥10% or an absolute change >0.5% in AF burden between two yearly Holter-ECG recordings was considered significant., Results: Mean age was 67 years, 72% were men. The proportion of patients with no recorded AF increased from 53.7% at baseline to 78.6% ( p =0.1) after 4 years of follow-up. In 7-day Holter-ECG recordings performed after baseline, 23.7% of participants had a decrease and 23.7% an increase in AF burden. In separate mixed effect models, AF burden over time was associated with prior stroke ( β 42.59, 95% CI (23.40; 61.77); p < 0.0001), BNP ( β 0.05, CI (0.02; 0.09); p =0.005) end-diastolic ( β 0.49, CI (0.23; 0.74); p =0.0003) as well as end-systolic ( β 0.25, CI (0.05; 0.46); p =0.02) left atrial volume, left atrial ejection fraction ( β -0.43, CI (-0.76;-0.10); p =0.01), E -wave ( β 36.67, CI (12.96; 60.38); p =0.003), and deceleration time ( β -0.1, CI (-0.16; -0.05); p =0.002). In a multivariable model, a history of prior stroke ( β 29.87, CI (2.61; 57.13); p =0.03) and BNP levels ( β 0.05, CI (0.01; 0.08); p =0.007) remained significantly associated with AF burden., Conclusions: Few patients with paroxysmal or persistent AF have AF episodes on yearly 7-day Holter-ECG recordings, and AF progression is rare. AF burden was independently associated with a history of prior stroke and BNP levels., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Philipp Krisai et al.)

Ultrasound molecular imaging has been developed in the past two decades with the goal of non-invasively imaging disease phenotypes on a cellular level not depicted on anatomic imaging. Such techniques already play a role in pre-clinical research for the assessment of disease mechanisms and drug effects, and are thought to in the future contribute to earlier diagnosis of disease, assessment of therapeutic effects and patient-tailored therapy in the clinical field. In this review, we first describe the chemical composition and structure as well as the in vivo behavior of the ultrasound contrast agents that have been developed for molecular imaging. We then discuss the strategies that are used for targeting of contrast agents to specific cellular targets and protocols used for imaging. Next we describe pre-clinical data on imaging of thrombosis, atherosclerosis and microvascular inflammation and in oncology, including the pathophysiological principles underlying the selection of targets in each area. Where applicable, we also discuss efforts that are currently underway for translation of this technique into the clinical arena., (Copyright © 2020. Published by Elsevier Inc.)

Background: The risk of adverse events in patients with left ventricular non-compaction cardiomyopathy (LVNC) is substantial. Information on prognostic factors, however, is limited. This study was designed to assess the prognostic value of right ventricular (RV) size and function in LVNC patients., Methods: Cox regression analyses were used to determine the association of indexed RV end-diastolic area (RV-EDAI), indexed end-diastolic diameter (RV-EDDI), fractional area change (FAC), and tricuspid annular systolic excursion (TAPSE) with the occurrence of death or heart transplantation (composite endpoint)., Results: Out of 127 patients (53.2 ± 17.8 years; 61% males, median follow-up time was 7.7 years), 17 patients reached the endpoint. In a univariate analysis, RV-EDAI was the strongest predictor of outcome [HR 1.48 (1.24-1.77) per cm 2 /m 2 ; p < 0.0001]. FAC was predictive as well [HR 1.44 (1.16-1.83) per 5% decrease; p = 0.0009], while TAPSE was not (p=ns). RV-EDAI remained an independent predictor in a bivariable analysis with indexed left ventricular ED volume [HR 1.41 (1.18-1.70) per cm 2 /m 2 ; p = 0.0002], while analysis of FAC and left ventricular ejection fraction demonstrated that FAC was not independent [HR 1.20 (0.98-1.52); per 5% decrease; p = 0.0721]. RV-EDAI 11.5 cm 2 /m 2 was the best cut-off value for separating patients in terms of outcome. Patients with RV-EDAI >11.5 cm 2 /m 2 had a survival rate of 18.5% over 12 years as compared to 93.8% in patients with RV-EDAI <11.5 cm 2 /m 2 (p < 0.0001)., Conclusion: Increased end-diastolic RV size and decreased systolic RV function are predictors of adverse outcome in patients with LVNC. Patients with RV-EDAI >11.5 cm 2 /m 2 exhibit a significantly lower survival than those <11.5 cm 2 /m 2 ., (Copyright © 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Objective: The prognostic value of left atrial (LA) dimensions may differ between patients with and without atrial fibrillation (AF)., Methods: MEDLINE and EMBASE were searched for studies that investigated the association between LA echocardiographic parameters measured by transthoracic echocardiography and cardiovascular outcomes in patients with or without AF. Data were independently abstracted by two reviewers and pooled using random-effects meta-analysis. The primary outcome was incident stroke or thromboembolic events. Secondary outcomes were heart failure, all-cause mortality and major adverse cardiac events (MACE)., Results: Twenty-three studies of patients with AF (14 939 patients) and 68 studies of patients without AF (50 720 patients) in this systematic review. Increasing LA diameter was significantly associated with stroke and thromboembolic events in patients without AF (risk ratio (RR) 1.38, 95% CI 1.02 to 1.87; p=0.03), but not in patients with AF (RR 1.02, 95% CI 0.98 to 1.07; p=0.27; p for difference=0.05). Increasing LA diameter index was significantly associated with MACE in patients with AF (RR 1.13, 95% CI 1.09 to 1.17; p<0.001) and in patients without AF (RR 2.98, 95% CI 1.90 to 4.66; p<0.001), with stronger effects in non-AF populations (p for difference <0.001). Greater LA volume index was significantly associated with the risk of MACE in patients with AF (RR 1.01, 95% CI 1.00 to 1.02; p=0.03) and in non-AF populations (RR 1.08, 95% CI 1.05 to 1.10; p<0.001), the association being stronger in individuals without AF (p for difference <0.001)., Conclusions: Larger LA parameters were associated with various adverse cardiovascular events. Many of these associations were stronger in individuals without AF, highlighting the potential importance of LA myopathy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: This study aimed to investigate the prevalence and management of left atrial (LA) thrombi detected by transesophageal echocardiography (TEE) in patients with atrial fibrillation undergoing pulmonary vein isolation (PVI)., Background: Little data are available on LA thrombi before PVI., Methods: All patients scheduled for PVI between April 2010 and April 2018 undergoing pre-procedural TEE were analyzed. Management of LA thrombus was at the discretion of the treating physician., Results: In this study, 1,753 pre-procedural TEE from 1,358 patients (mean age 61 ± 10 years, 28% female) were included. Anticoagulation was used in 86% of all TEE (51% with direct oral anticoagulants [DOAC], 35% with vitamin K antagonists [VKA]). Thrombi were found in 11 TEE (0.6%), all in the LA appendage. Of the 11 patients with a thrombus, 5 (46%) had paroxysmal atrial fibrillation, 2 (18%) had a CHA 2 DS 2 -VASc (Congestive Heart Failure, Hypertension, Age ≥75 Years, Diabetes Mellitus, Prior Stroke or Transient Ischemic Attack or Thromboembolism, Vascular Disease, Age 65 to 74 Years, Sex) score of 1, and 5 (46%) were in sinus rhythm at the time of TEE. Of the 8 patients (72%) on anticoagulation therapy, 5 were treated with DOAC and 3 with VKA. Starting anticoagulation (n = 3), switching to VKA with a target international normalized ratio of 2.5 to 3 (n = 3), or switching to a DOAC (n = 1) or a different DOAC (n = 4) resulted in thrombus resolution in 9 of 11 patients (82%)., Conclusions: In patients with atrial fibrillation scheduled for PVI, LA thrombi are rare and present in <1%. Thrombi were found in patients on VKA and DOAC, in low-risk patients, and despite sinus rhythm. Thrombus resolution was achieved in the majority of patients by changing the anticoagulation regimen., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objective: Contrast-enhanced ultrasound molecular imaging (CEUMI) of endothelial expression of VCAM (vascular cell adhesion molecule)-1 could improve risk stratification for atherosclerosis. The microbubble contrast agents developed for preclinical studies are not suitable for clinical translation. Our aim was to characterize and validate a microbubble contrast agent using a clinically translatable single-variable domain immunoglobulin (nanobody) ligand. Approach and Results: Microbubble with a nanobody targeting VCAM-1 (MB cAbVcam1-5 ) and microbubble with a control nanobody (MB VHH2E7 ) were prepared and characterized in vitro. Attachment efficiency to VCAM-1 under continuous and pulsatile flow was investigated using activated murine endothelial cells. In vivo CEUMI of the aorta was performed in atherosclerotic double knockout and wild-type mice after injection of MB cAbVcam1-5 and MB VHH2E7 . Ex vivo CEUMI of human endarterectomy specimens was performed in a closed-loop circulation model. The surface density of the nanobody ligand was 3.5×10 5 per microbubble. Compared with MB VHH2E7 , MB cAbVcam1-5 showed increased attachment under continuous flow with increasing shear stress of 1-8 dynes/cm 2 while under pulsatile flow attachment occurred at higher shear stress. CEUMI in double knockout mice showed signal enhancement for MB cAbVcam1-5 in early ( P =0.0003 versus MB VHH2E7 ) and late atherosclerosis ( P =0.007 versus MB VHH2E7 ); in wild-type mice, there were no differences between MB cAbVcam1-5 and MB VHH2E7 . CEUMI in human endarterectomy specimens showed a 100% increase in signal for MB cAbVcam1-5 versus MB VHH2E7 (20.6±27.7 versus 9.6±14.7, P =0.0156)., Conclusions: CEUMI of the expression of VCAM-1 is feasible in murine models of atherosclerosis and on human tissue using a clinically translatable microbubble bearing a VCAM-1 targeted nanobody.

Background: Myocarditis can lead to myocyte loss and myocardial fibrosis resulting in dilated cardiomyopathy (DCMP). Currently employed methods for assessing the risk for development of DCMP are inaccurate or rely on invasive myocardial biopsies. We hypothesized that molecular imaging of tissue inflammation with contrast enhanced ultrasound during peak inflammation in myocarditis could predict development of fibrosis and impaired left ventricular function., Methods and Results: Experimental autoimmune myocarditis (EAM) was induced in Balbc mice by injection of the α-myosin heavy chain peptide. Contrast enhanced ultrasound (CEU) using microbubbles targeted to leukocytes (MBLc), to CD4+ lymphocytes (MBCD4), and to the endothelial cell adhesion molecule P-selectin (MBPSel) was performed during the expected EAM peak inflammatory activity 21 days after induction. High resolution ultrasound, invasive hemodynamic measurements and fibrosis quantification were done 63 days after EAM assessment. All tested microbubbles correlated to fibrosis (MBLc spearman r 0.28, p 0.047, MBCD4 r 0.44, p 0.01, MBPSel r 0.73, p 0.02), however, correlations were weak overall and the spread of data was considerable. Also, targeted CEU data on day 21 did not correlate to hemodynamic and functional data on day 63., Conclusions: Ultrasound molecular imaging using targeted microbubbles during the peak inflammatory activity of myocarditis correlates weakly with later development of fibrosis but not with hemodynamic or left ventricular functional parameters., Competing Interests: The authors have declared that no competing interests exist.

Background: The relationship between longitudinal clinical congestion pattern and heart failure outcome is uncertain. This study was designed to assess the prevalence of congestion over time and to investigate its impact on outcome in chronic heart failure., Methods: A total of 588 patients with chronic heart failure older than 60 years of age with New York Heart Association (NYHA) functional class ≥II from the TIME-CHF study were included. The endpoints for this study were survival and hospitalization-free heart failure survival. Orthopnea, NYHA ≥III, paroxysmal nocturnal dyspnea, hepatomegaly, peripheral pitting edema, jugular venous distension, and rales were repeatedly investigated and related to outcomes. These congestion-related signs and symptoms were used to design a 7-item Clinical Congestion Index., Results: Sixty-one percent of patients had a Clinical Congestion Index ≥3 at baseline, which decreased to 18% at month 18. During the median [interquartile range] follow-up of 27.2 [14.3-39.8] months, 17%, 27%, and 47% of patients with baseline Clinical Congestion Index of 0, 1-2, and ≥3 at inclusion, respectively, died (P <.001). Clinical Congestion Index was identified as an independent predictor of mortality at all visits (P <.05) except month 6 and reduced hospitalization-free heart failure survival (P <.05). Successful decongestion was related to better outcome as compared to persistent congestion or partial decongestion (log-rank P <0.001)., Conclusions: The extent of congestion as assessed by means of clinical signs and symptoms decreased over time with intensified treatment, but it remained present or relapsed in a substantial number of patients with heart failure and was associated with poor outcome. This highlights the importance of appropriate decongestion in chronic heart failure., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Constitutive JAK2 signaling is central to myeloproliferative neoplasm (MPN) pathogenesis and results in activation of STAT, PI3K/AKT, and MEK/ERK signaling. However, the therapeutic efficacy of current JAK2 inhibitors is limited. We investigated the role of MEK/ERK signaling in MPN cell survival in the setting of JAK inhibition. Type I and II JAK2 inhibition suppressed MEK/ERK activation in MPN cell lines in vitro, but not in Jak2V617F and MPLW515L mouse models in vivo. JAK2 inhibition ex vivo inhibited MEK/ERK signaling, suggesting that cell-extrinsic factors maintain ERK activation in vivo. We identified PDGFRα as an activated kinase that remains activated upon JAK2 inhibition in vivo, and PDGF-AA/PDGF-BB production persisted in the setting of JAK inhibition. PDGF-BB maintained ERK activation in the presence of ruxolitinib, consistent with its function as a ligand-induced bypass for ERK activation. Combined JAK/MEK inhibition suppressed MEK/ERK activation in Jak2V617F and MPLW515L mice with increased efficacy and reversal of fibrosis to an extent not seen with JAK inhibitors. This demonstrates that compensatory ERK activation limits the efficacy of JAK2 inhibition and dual JAK/MEK inhibition provides an opportunity for improved therapeutic efficacy in MPNs and in other malignancies driven by aberrant JAK-STAT signaling.

Background and Purpose: The aim was to assess the feasibility and safety of fast-track hospitalizations in a selected cohort of patients with stroke., Methods: Patients hospitalized at the Stroke Center of the University Hospital Basel, Switzerland, with an acute ischaemic stroke confirmed on magnetic resonance diffusion-weighted imaging were included. Neurological deficits of the included patients were non-disabling, i.e. not interfering with activities of daily living and compatible with a direct discharge home. Patients with premorbid disability were excluded. All patients were admitted to the Stroke Center for ≥24 h. Two study groups were compared - fast-track hospitalizations (≤72 h) and long-term hospitalizations (>72 h). The primary end-point was a composite of any unplanned rehospitalization for any reason within 3 months since hospital discharge and a modified Rankin Scale 3-6 at 3 months. Adjustment for confounders was done using the inverse probability of treatment weights (IPTW)., Results: Amongst the 521 patients who met the inclusion criteria, fast-track hospitalizations were performed in 79 patients (15%). In the fast-track group, seven patients (8.9%) met the primary end-point, compared to 37 (8.4%) in the long-term group [odds ratio (OR) 1.06, 95% confidence interval (CI) 0.42-2.34, P = 0.88]. After weighting for IPTW, the odds of the primary end-point remained similar between the two arms (OR IPTW 1.27, 95% CI 0.51-3.16, P = 0.61). The costs of fast-track hospitalizations were lower, on average, by $4994., Conclusions: Fast-track hospitalizations including a full workup proved to be feasible, showed no increased risk and were less expensive than long-term hospitalizations., (© 2018 EAN.)

Background: Whether the clinical presentation and in particular prevalence of symptoms and signs of heart failure (HF) is different in elderly versus younger patients and in those with reduced (HFrEF) versus preserved (HFpEF) left ventricular ejection fraction (LVEF) is a matter of ongoing debate., Aims: To compare detailed clinical characteristics of these important subgroups and to develop a prediction rule for the differentiation of HFpEF and HFrEF based on clinical parameters., Methods: The analysis was based on the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF) comprising 622 patients ≥60 years with HF including the whole LVEF spectrum., Results: In the groups ≥75 years and with HFpEF typical symptoms and clinical signs of HF were more prevalent as compared to those <75 years or with HFrEF, respectively. The burden of comorbidities was higher in the older age group. HFrEF could not be differentiated from HFpEF by symptom history and clinical examination alone. However, a combination of age, presence of pulmonary rales, systolic blood pressure, cause of heart failure, osteoporosis, current smoking, NT-proBNP, haemoglobin, QRS width and heart rhythm allowed to identify HFrEF versus HFpEF with a sensitivity of 81% and specificity of 90% (c-statistics 0.91)., Conclusions: More symptoms and signs of HF were present both in the older age group and in patients with HFpEF. HFpEF versus HFrEF could be differentiated by a set of simple clinical, laboratory and ECG parameters but not by symptom history and physical examination alone., (Copyright © 2018 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Background: Changes in left ventricular (LV) torsion have been related to LV geometry in patients with concomitant long-standing myocardial disease or pulmonary hypertension (PH). We evaluated the effect of acute high altitude-induced isolated PH on LV geometry, volumes, systolic function, and torsional mechanics., Methods: Twenty-three volunteers were prospectively studied at low altitude and after the second (D3) and third night (D4) at high altitude (4,559 m). LV ejection fraction, multidirectional strains and torsion, LV volumes, sphericity, and eccentricity were derived by speckle-tracking on three-dimensional echocardiographic data sets. Pulmonary pressure was estimated from the transtricuspid pressure gradient (TRPG), LV preload from end-diastolic LV volume, and transmitral over mitral annular E velocity (E/e')., Results: At high altitude, oxygen saturation decreased by 15%-20%, heart rate and cardiac index increased by 15%-20%, and TRPG increased from 21 ± 2 to 37 ± 9 mm Hg (P < .01). LV volumes, preload, ejection fraction, multidirectional strains, and sphericity remained unaffected, but diastolic (1.04 ± 0.07 to 1.09 ± 0.09 on D3/D4, P < .05) and systolic (1.00 ± 0.06 to 1.08 ± 0.1 [D3] and 1.06 ± 0.07 [D4], P < .05) eccentricity slightly increased, indicating mild septal flattening. LV torsion decreased from 2.14 ± 0.85 to 1.34 ± 0.68 (P < .05) and 1.65 ± 0.54 (P = .08) degrees/cm on D3/D4, respectively. Changes in torsion showed a weak inverse relationship to changes in systolic (r = -0.369, P = .013) and diastolic (r = -0.329, P = .032) eccentricity but not to changes in TRPG, heart rate or preload., Conclusions: High-altitude exposure was associated with mild septal flattening of the LV and reduced ventricular torsion at unchanged global LV function and preload, suggesting a relation between LV geometry and torsional mechanics., (Copyright © 2017 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Activated platelets are amongst the most attractive imaging targets in atherosclerosis due to their important role in early processes of atherogenesis and thrombus formation. We developed a molecular intravascular ultrasound (IVUS) approach to detect activated platelets ex vivo on the surface of human plaques, using an IVUS system applied in clinical routine., Methods: Human carotid endarterectomy specimens were obtained directly from the operating room and exposed to artificial arterial flow conditions for incubation with the contrast agent. This consists of microbubbles (MB), which are linked to an antibody against the ligand induced binding site (LIBS) of the activated platelet glycoprotein IIb/IIa, and a sialyl Lewis polymer (SL), which mediates binding to selectins (LIBS-SL-MB). IVUS was performed pre and post incubation with LIBS-SL-MB and after rinsing with PBS. In comparison, IVUS was performed pre and post incubation with MBs linked to an unspecific control antibody and a dysfunctional polymer (control-MB). All imaging results were correlated to histology findings., Results: IVUS imaging showed a high signal enhancement after administration of LIBS-SL-MB. After rinsing with PBS, the signal enhancement remained stable. Immunofluorescence and immunohistochemistry confirmed significant binding of microbubbles to thrombi on the plaque surface. Moreover, thrombus size and number of bound MBs correlated well., Conclusions: LIBS-SL-MB allows ex vivo IVUS imaging of even small numbers of activated platelets on the surface of human carotid endarterectomy specimens. This diagnostic approach could deliver valuable additional information for risk stratification of atherosclerotic plaques, especially since we apply a clinically well-established IVUS imaging system., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Delivery of genetically modified cells overexpressing Vascular Endothelial Growth Factor (VEGF) is a promising approach to induce therapeutic angiogenesis in ischemic tissues. The effect of the protein is strictly modulated by its interaction with the components of the extracellular matrix. Its therapeutic potential depends on a sustained but controlled release at the microenvironmental level in order to avoid the formation of abnormal blood vessels. In this study, it is hypothesized that the composition of the scaffold plays a key role in modulating the binding, hence the therapeutic effect, of the VEGF released by 3D-cell constructs. It is found that collagen sponges, which poorly bind VEGF, prevent the formation of localized hot spots of excessive concentration, therefore, precluding the development of aberrant angiogenesis despite uncontrolled expression by a genetically engineered population of adipose tissue-derived stromal cells. On the contrary, after seeding on VEGF-binding egg-white scaffolds, the same cell population caused aberrantly enlarged vascular structures after 14 d. Collagen-based engineered tissues also induced a safe and efficient angiogenesis in both the patch itself and the underlying myocardium in rat models. These findings open new perspectives on the control and the delivery of proangiogenic stimuli, and are fundamental for the vascularization of engineered tissues/organs., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Aims: While the conditions of heart failure (HF) with reduced (HFrEF, LVEF < 40%) and preserved (HFpEF, LVEF ≥ 50%) left ventricular ejection fraction (LVEF) are well characterized, it is unknown whether patients with HF and mid-range LVEF (HFmrEF, LVEF 40-49%) have to be regarded as a separate clinical entity. The aim of this study was to characterize these three populations and to compare outcome and response to therapy., Methods and Results: The analysis was based on the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF) comprising a population with established HF including the whole spectrum of LVEF. Of the 622 patients, 108 (17%) were classified as having HFmrEF. This group was in general found to be 'intermediate' regarding clinical characteristics with a comparable and high burden of comorbidities and equally impaired quality of life but was more likely to have coronary artery disease as compared with the HFpEF group. During a median follow-up of 794 days, mortality was 39.7% without significant differences between groups. N-terminal pro-B-type natriuretic peptide (NT-proBNP)-guided as compared with standard therapy resulted in improved survival free of HF hospitalizations in HFrEF and HFmrEF, but not in HFpEF., Conclusion: Although the 'intermediate' clinical profile of HFmrEF between HFrEF and HFpEF would support the conclusion that HFmrEF is a distinct clinical entity, we hypothesize that HFmrEF has to be categorized as HFrEF because of the high prevalence of coronary artery disease and the similar benefit of NT-proBNP-guided therapy in HFrEF and HFmrEF, in contrast to HFpEF., (© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.)

Successful recanalization of chronic total occlusions (CTO) has been associated with improved survival. Data on outcomes in patients with left ventricular (LV) systolic dysfunction undergoing percutaneous coronary intervention for CTO, however, are scarce. Between January 2005 and December 2013, a total of 2,002 consecutive patients undergoing elective CTO percutaneous coronary intervention at a tertiary care center were divided into patients with (LV ejection fraction ≤ 40%) and without (LV ejection fraction > 40%) LV systolic dysfunction as defined by transthoracic echocardiography. The primary end point was all-cause mortality. Median follow-up was 2.6 (1.1 to 3.1) years. A total of 348 (17.4%) patients had LV dysfunction. All-cause mortality was higher in patients with LV dysfunction (30.2%) than in those with normal LV function (8.2%, p <0.001), and associations remained significant after adjustment for baseline differences (adjusted hazard ratio [HR] 3.39, 95% confidence interval [CI] 2.57 to 4.47, p <0.001). Successful CTO recanalization was independently associated with reduced all-cause mortality, with similar relative risk reductions in both the preserved (6.6% vs 16.9%, adjusted HR 0.48, 95% CI 0.34 to 0.70, p <0.001) and the reduced LV function groups (26.2% vs 45.2%, adjusted HR 0.63, 95% CI 0.41 to 0.98, p = 0.04, interaction p = 0.28). In conclusion, irrespective of LV function, successful CTO recanalization is associated with a clear survival benefit., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Platelets can be found on the surface of inflamed and ruptured atherosclerotic plaques. Thus, targeting of activated platelets may allow for molecular imaging of vulnerable atherosclerotic lesions. We here investigated microbubbles (MB) functionalized with the selectin ligand sialyl Lewis a individually (MB sLea ) or dually with sLe a and an antibody targeting ligand-induced binding sites of the activated GPIIb/IIIa receptor (MB Dual ). Assessed by in vitro flow chamber, targeted MB exhibited increased adhesion to platelets as compared to MB Control . While MB sLea rolled slowly on the platelets' surface, MB Dual enhanced the percentage of firm adhesion. In vivo, MB were investigated by ultrasound in a model of ferric chloride induced non-occlusive carotid artery thrombosis. MB sLea and MB Dual revealed a higher ultrasound mean acoustic intensity than MB Control (p < 0.05), however MB Dual demonstrated no additional increase in mean signal intensity as compared to MB sLea . The degree of carotid artery stenosis on histology correlated well with the ultrasound acoustic intensity of targeted MB (p < 0.05). While dual targeting of MB using fast binding carbohydrate polymers and specific antibodies is a promising strategy to support adhesion to activated platelets under arterial shear stress, these advantages seem not readily translatable to in vivo models.

Arenaviruses such as Lassa virus (LASV) cause hemorrhagic fever. Terminal shock is associated with a systemic cytokine storm, but the mechanisms are ill defined. Here we used HLA-A2-expressing mice infected with a monkey-pathogenic strain of lymphocytic choriomeningitis virus (LCMV-WE), a close relative of LASV, to investigate the pathophysiology of arenavirus hemorrhagic fever (AHF). AHF manifested as pleural effusions, edematous skin swelling, and serum albumin loss, culminating in hypovolemic shock. A characteristic cytokine storm included numerous pro-inflammatory cytokines and nitric oxide (NO) metabolites. Edema formation and terminal shock were abrogated in mice lacking inducible nitric oxide synthase (iNOS), although the cytokine storm persisted. iNOS was upregulated in the liver in a T cell- and interferon-γ (IFN-γ)-dependent fashion. Accordingly, blockade of IFN-γ or depletion of T cells repressed hepatic iNOS and prevented disease despite unchecked high-level viremia. We identify the IFN-γ-iNOS axis as an essential and potentially druggable molecular pathway to AHF-induced shock., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: The risk of adverse events in patients with left ventricular non-compaction cardiomyopathy (LVNC) is substantial. This study was designed to determine the prognostic value of NT-proBNP, left ventricular ejection fraction (LVEF), NYHA class, and exercise capacity in LVNC patients., Methods: Cox regression analyses were performed for evaluating the prognostic value of NT-proBNP, LVEF, NYHA class, and exercise capacity on the occurrence of death or heart transplantation. 153 patients were included., Results: During 1013 person-years (longest follow-up 18.5years) 23 patients (15%) died or underwent heart transplantation. We observed a significant relationship of NT-proBNP (adjusted HR 2.44, 95% CI 1.45-4.09, for every NT-proBNP doubling, p=0.0007) and LVEF (adjusted HR for age 60years: 2.68, 95% CI 1.62-4.41, p=0.0001) with the risk of death or heart transplantation. Combined covariate analysis indicated a strong influence of NT-proBNP (adjusted 2.89, 95% CI 1.33-6.26, p=0.007), whereas LVEF was no longer significant (adjusted HR 0.82, 95% CI 0.42-1.67, p=0.66) demonstrating a favorable prognostic power of NT-proBNP over LVEF. An increase in NYHA class was associated with a worse outcome, and exercise capacity revealed a trend in the same direction. For all the abovementioned analyses, similar results were obtained when assessing the values at first presentation., Conclusion: This study provides evidence that an increase in NT-proBNP is a strong predictor of outcome in patients with LVNC. The prognostic power of NT-proBNP is at least as good as that of LVEF, indicating that routine NT-proBNP measurement may improve risk assessment in LVNC., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Arrhythmia recurrence after atrial fibrillation (AF) ablation remains high and requires repeat interventions in a substantial number of patients. We assessed the value of conventional and 3-D echocardiography to predict AF recurrence., Methods and Results: Consecutive patients undergoing AF ablation by means of pulmonary vein isolation were included in a prospective registry. Echocardiograms were obtained prior to the ablation procedure, and analyzed offline in a standardized manner, including 3-D left atrial (LA) volumetry and determination of LA function and sphericity. The primary endpoint, AF recurrence (>30 seconds) between 3 to 12 months after AF ablation, was independently adjudicated. We included 276 patients (73% male, mean age 59.9 ± 9.9 years). Paroxysmal and persistent AF were present in 178 (64%) and 98 (36%) patients, respectively. Mean left ventricular ejection fraction and indexed LA volume in 3-D (LAVI) were 52 ± 12% and 42 ± 13 mL/m 2 , respectively. AF recurrence was observed in 110 (40%) patients after a single procedure. Median (interquartile range) time to AF recurrence was 123 (92; 236) days. In multivariable Cox regression models, the only predictors for AF recurrence were the minimal, maximal, and indexed 3-D LA volumes, P = 0.024, P = 0.016, and P = 0.014, respectively. Quartile specific analysis of 3-D LAVI showed an HR of 1.885 (95%CI 1.066-3.334; P for trend = 0.015) for the highest compared to the lowest quartile., Conclusion: Our results show the important role of LA volume for the long-term freedom from arrhythmia after AF ablation. These data also highlight the potential of 3-D echocardiography in this context and may facilitate patient selection for AF ablation., (© 2017 Wiley Periodicals, Inc.)

Premature atherosclerosis and thrombotic complications are major causes of morbidity and mortality in patients with systemic lupus erythematosus (SLE). However, the high incidence of these complications cannot be explained by traditional risk factors alone, suggesting direct effects of an activated immune system on hemostasis. The unexpected nucleotide sequence homology between SLE patient-derived autoantibodies against complement C1q (Fab anti-C1q) and von Willebrand factor (VWF) led us to investigate a potential interaction between the complement and hemostatic systems on the level of initiating molecules. VWF was found to bind to surface-bound C1q under static conditions. The binding could specifically be inhibited by Fab anti-C1q and C1q-derived peptides. Under shear stress the C1q-VWF interaction was enhanced, resembling the binding of VWF to collagen I. Additionally, we could show that C1q-VWF complexes induced platelet rolling and firm adhesion. Furthermore, we observed VWF binding to C1q-positive apoptotic microparticles and cholesterol crystals, as well as increased VWF deposition in C1q-positive glomeruli of SLE patients compared with control nephropathy. We show, to our knowledge for the first time, binding of VWF to C1q and thus a direct interaction between starter molecules of hemostasis and the classical pathway of complement. This direct interaction might contribute to the pathogenic mechanisms in complement-mediated, inflammatory diseases., (Copyright © 2016 by The American Association of Immunologists, Inc.)

Pastoral systems are important producers and repositories of livestock diversity. Pastoralists use variability in their livestock resources to manage high levels of environmental variability in economically advantageous ways. In pastoral systems, human-animal-environment interactions are the basis of production and the key to higher productivity and efficiency. In other words, pastoralists manage a production system that exploits variability and keeps production costs low. When differentiating, characterising and evaluating pastoral breeds, this context-specific, functional dimension of diversity in livestock resources needs to be considered. The interaction of animals with their environment is determined not only by morphological and physiological traits but also by experience and socially learned behaviour. This high proportion of non-genetic components determining the performance of livestock means that current models for analysing livestock diversity and performance, which are based on genetic inheritance, have limited ability to describe pastoral performance. There is a need for methodological innovations to evaluate pastoral breeds and animals, since comparisons based on performance 'under optimal conditions' are irrelevant within this production system. Such innovations must acknowledge that livestock or breed performance is governed by complex human-animal-environment interactions, and varies through time and space due to the mobile and seasonal nature of the pastoral system. Pastoralists' breeding concepts and selection strategies seem to be geared towards improving their animals' capability to exploit variability, by - among other things - enhancing within-breed diversity. In-depth studies of these concepts and strategies could contribute considerably towards developing methodological innovations for the characterisation and evaluation of pastoral livestock resources.

Introduction: Left atrial (LA) enlargement is an important risk factor for incident stroke and a key determinant for the success of rhythm control strategies in patients with atrial fibrillation (AF). However, factors associated with LA volume in AF patients remain poorly understood., Methods: Patients with paroxysmal or persistent AF were enrolled in this study. Real time 3-D echocardiography was performed in all participants and analyzed offline in a standardized manner. We performed stepwise backward linear regression analyses using a broad set of clinical parameters to determine independent correlates for 3-D LA volume., Results: We included 210 patients (70.9% male, mean age 61±11years). Paroxysmal and persistent AF were present in 95 (45%) and 115 (55%) patients, respectively. Overall, 115 (55%) had hypertension, 11 (5%) had diabetes, and 18 (9%) had ischemic heart disease. Mean indexed LA volume was 36±12ml/m2. In multivariable models, significant associations were found for female sex (β coefficient -10.51 (95% confidence interval (CI) -17.85;-3.16), p = 0.0053), undergoing cardioversion (β 11.95 (CI 5.15; 18.74), p = 0.0006), diabetes (β 14.23 (CI 2.36; 26.10), p = 0.019), body surface area (BSA) (β 34.21 (CI 19.30; 49.12), p<0.0001), glomerular filtration rate (β -0.21 (CI -0.36; -0.06), p = 0.0064) and plasma levels of NT-pro brain natriuretic peptide (NT-proBNP) (β 6.79 (CI 4.05; 9.52), p<0.0001), but not age (p = 0.59) or hypertension (p = 0.42). Our final model explained 52% of the LA volume variability., Conclusions: In patients with AF, the most important correlates with LA volume are sex, BSA, diabetes, renal function and NT-proBNP, but not age or hypertension. These results may help to refine rhythm control strategies in AF patients., Competing Interests: The authors have declared that no competing interests exist.

Background: Cardiac tests for diagnosing myocarditis lack sensitivity or specificity. We hypothesized that contrast-enhanced ultrasound molecular imaging could detect myocardial inflammation and the recruitment of specific cellular subsets of the inflammatory response in murine myocarditis., Methods and Results: Microbubbles (MB) bearing antibodies targeting lymphocyte CD4 (MBCD4), endothelial P-selectin (MBPSel), or isotype control antibody (MBIso) and MB with a negative electric charge for targeting of leukocytes (MBLc) were prepared. Attachment of MBCD4 was validated in vitro using murine spleen CD4+ T cells. Twenty-eight mice were studied after the induction of autoimmune myocarditis by immunization with α-myosin-peptide; 20 mice served as controls. Contrast-enhanced ultrasound molecular imaging of the heart was performed. Left ventricular function was assessed by conventional and deformation echocardiography, and myocarditis severity graded on histology. Animals were grouped into no myocarditis, moderate myocarditis, and severe myocarditis. In vitro, attachment of MBCD4 to CD4+ T cells was significantly greater than of MBIso. Of the left ventricular ejection fraction or strain and strain rate readouts, only longitudinal strain was significantly different from control animals in severe myocarditis. In contrast, contrast-enhanced ultrasound molecular imaging showed increased signals for all targeted MB versus MBIso both in moderate and severe myocarditis, and MBCD4 signal correlated with CD4+ T-lymphocyte infiltration in the myocardium., Conclusions: Contrast-enhanced ultrasound molecular imaging can detect endothelial inflammation and leukocyte infiltration in myocarditis in the absence of a detectable decline in left ventricular performance by functional imaging. In particular, imaging of CD4+ T cells involved in autoimmune responses could be helpful in diagnosing myocarditis., (© 2016 American Heart Association, Inc.)

Background: Treatment to restore sinus rhythm among patients with atrial fibrillation (AF) has limited long-term success rates. Gene expression profiling may provide new insights into AF pathophysiology., Objective: To identify biomarkers and improve our understanding of AF pathophysiology by comparing whole blood gene expression before and after electrical cardioversion (ECV)., Methods: In 46 patients with persistent AF that underwent ECV, whole blood samples were collected 1-2 hours before and 4 to 6 weeks after successful cardioversion. The paired samples were sent for microarray and plasma biomarker comparison., Results: Of 13,942 genes tested, expression of SLC25A20 and PDK4 had the strongest associations with AF. Post-cardioversion, SLC25A20 and PDK4 expression decreased by 0.8 (CI 0.7-0.8, p = 2.0x10-6) and 0.7 (CI 0.6-0.8, p = 3.0x10-5) fold respectively. Median N-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations decreased from 127.7 pg/mL to 44.9 pg/mL (p = 2.3x10-13) after cardioversion. AF discrimination models combining NT-proBNP and gene expression (NT-proBNP + SLC25A20 area under the curve = 0.88, NT-proBNP + PDK4 AUC = 0.86) had greater discriminative capacity as compared with NT-proBNP alone (AUC = 0.82). Moreover, a model including NT-proBNP, SLC25A20 and PDK4 significantly improved AF discrimination as compared with other models (AUC = 0.87, Net Reclassification Index >0.56, p<5.8x10-3). We validated the association between SLC25A20 and PDK4 with AF in an independent sample of 17 patients., Conclusion: This study demonstrates that SLC25A20, PDK4, and NT-proBNP have incremental utility as biomarkers discriminating AF from sinus rhythm. Elevated SLC25A20 and PDK4 expression during AF indicates an important role for energy metabolism in AF.

Introduction: The advent of electroanatomical mapping (EAM) systems for pulmonary vein isolation (PVI) has dramatically decreased radiation exposure. However, the need for some fluoroscopy remains for obtaining left atrial (LA) access. The aim was to test the feasibility of fluoroscopy-free PVI in patients with atrial fibrillation (AF) and a patent foramen ovale (PFO) guided solely by an EAM system., Methods: Consecutive patients with AF undergoing PVI and documented PFO were studied. An EAM-guided approach without fluoroscopy and ultrasound was used. After completing the map of the right atrium, the superior vena cava and the coronary sinus, a catheter pull-down to the PFO was performed allowing LA access. The map of the LA and subsequent PVI was also performed without fluoroscopy., Results: 30 patients [age 61±12 years, 73% male, ejection fraction 0.64 (0.53-0.65), LA size in parasternal long axis 38±7 mm] undergoing PVI were included. The time required for right atrial mapping including transseptal crossing was 9±4 minutes. Total procedure time was 127±37 minutes. Fluoroscopy-free PVI was feasible in 26/30 (87%) patients. In four patients, fluoroscopy was needed to access (n = 3) or to re-access (n = 1) the LA. In these four patients, total fluoroscopy time was 5±3 min and the DAP was 14.9±13.4 Gy*cm2. Single-procedure success rate was 80% (24/30) after a median follow-up of 12 months., Conclusion: In patients with a documented PFO, completely fluoroscopy-free PVI is feasible in the vast majority of cases.