Implementing focused echocardiography and AI-supported analysis in a population-based survey in Lesotho: implications for community-based cardiovascular disease care models.

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.

Right Heart Structure and Function after Electrical Cardioversion for Atrial Fibrillation.

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 < 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 < 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 < 0.01), and from a median of 30 (Q1:24, Q3:36) mL/m2 to 24 (Q1:20, Q3:27) mL/m2 (p < 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.

Echocardiographic pattern of left ventricular function recovery in tachycardia-induced cardiomyopathy patients.

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/m2 versus 56 [45, 70] mL/m2 , P = ns) compared with controls (67 [54, 81] mL/m2 versus 52 [42, 69] mL/m2 , 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/m2 ). Good predictors of TCM were: normal LVEDVI (LVEDVI < 58 mL/m2 (M) and < 52 mL/m2 (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/m2 (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.

Hypertensive Heart Disease-The Imaging Perspective.

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.

Liraglutide Lowers Endothelial Vascular Cell Adhesion Molecule-1 in Murine Atherosclerosis Independent of Glucose Levels.

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-1ß, MCP-1, and OPN. Aortic plaque lesion area and luminal VCAM-1 expression on immunohistology were reduced under liraglutide treatment.

Renal dysfunction and outcome in left ventricular non-compaction.

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.

Cardiovascular imaging following perioperative myocardial infarction/injury.

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 .

Biomarkers associated with rhythm status after cardioversion in patients with atrial fibrillation.

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 (ß 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.

NOX1 mediates metabolic heart disease in mice and is upregulated in monocytes of humans with diastolic dysfunction.

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-1ß-, 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.

P2Y12 Inhibition in Murine Myocarditis Results in Reduced Platelet Infiltration and Preserved Ejection Fraction.

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 P2Y12 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, P2Y12 inhibition could be a promising early therapeutic target in myocarditis, requiring further investigation.

Designed Ankyrin Repeat Proteins as Novel Binders for Ultrasound Molecular Imaging.

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.

Intensification of pharmacological decongestion but not the actual daily loop diuretic dose predicts worse chronic heart failure outcome: insights from TIME-CHF.

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.

Change in Atrial Fibrillation Burden over Time in Patients with Nonpermanent Atrial Fibrillation.

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 (ß 42.59, 95% CI (23.40; 61.77); p < 0.0001), BNP (ß 0.05, CI (0.02; 0.09); p=0.005) end-diastolic (ß 0.49, CI (0.23; 0.74); p=0.0003) as well as end-systolic (ß 0.25, CI (0.05; 0.46); p=0.02) left atrial volume, left atrial ejection fraction (ß -0.43, CI (-0.76;-0.10); p=0.01), E-wave (ß 36.67, CI (12.96; 60.38); p=0.003), and deceleration time (ß -0.1, CI (-0.16; -0.05); p=0.002). In a multivariable model, a history of prior stroke (ß 29.87, CI (2.61; 57.13); p=0.03) and BNP levels (ß 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.

Seeing the Invisible-Ultrasound Molecular Imaging.

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.

Right ventricle and outcome in left ventricular non-compaction cardiomyopathy.

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 ±â€¯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 cm2/m2; 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 cm2/m2; 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 cm2/m2 was the best cut-off value for separating patients in terms of outcome. Patients with RV-EDAI >11.5 cm2/m2 had a survival rate of 18.5% over 12 years as compared to 93.8% in patients with RV-EDAI <11.5 cm2/m2 (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 cm2/m2 exhibit a significantly lower survival than those <11.5 cm2/m2.

Prevalence and Management of Atrial Thrombi in Patients With Atrial Fibrillation Before Pulmonary Vein Isolation.

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 CHA2DS2-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.

Non-invasive contrast enhanced ultrasound molecular imaging of inflammation in autoimmune myocarditis for prediction of left ventricular fibrosis and remodeling.

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.

Ultrasound Molecular Imaging of Atherosclerosis With Nanobodies: Translatable Microbubble Targeting Murine and Human VCAM (Vascular Cell Adhesion Molecule) 1.

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 (MBcAbVcam1-5) and microbubble with a control nanobody (MBVHH2E7) 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 MBcAbVcam1-5 and MBVHH2E7. Ex vivo CEUMI of human endarterectomy specimens was performed in a closed-loop circulation model. The surface density of the nanobody ligand was 3.5×105 per microbubble. Compared with MBVHH2E7, MBcAbVcam1-5 showed increased attachment under continuous flow with increasing shear stress of 1-8 dynes/cm2 while under pulsatile flow attachment occurred at higher shear stress. CEUMI in double knockout mice showed signal enhancement for MBcAbVcam1-5 in early (P=0.0003 versus MBVHH2E7) and late atherosclerosis (P=0.007 versus MBVHH2E7); in wild-type mice, there were no differences between MBcAbVcam1-5 and MBVHH2E7. CEUMI in human endarterectomy specimens showed a 100% increase in signal for MBcAbVcam1-5versus MBVHH2E7 (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.

Left atrial dimension and cardiovascular outcomes in patients with and without atrial fibrillation: a systematic review and meta-analysis.

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.