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Objective: First-phase ejection fraction (EF1) is a novel measure of early left ventricular systolic dysfunction. We investigated determinants of EF1 and its prognostic value in aortic stenosis.Methods: EF1 was measured retrospectively in participants of an echocardiography/cardiovascular magnetic resonance cohort study which recruited patients with aortic stenosis (peak aortic velocity of ≥2 m/s) between 2012 and 2014. Linear regression models were constructed to examine variables associated with EF1. Cox proportional hazards were used to determine the prognostic power of EF1 for aortic valve replacement (AVR, performed as part of clinical care in accordance with international guidelines) or death.Results: Total follow-up of the 149 participants (69.8% male, 70 (65-76) years, mean gradient 33 (21-42) mm Hg) was 238 029 person-days. Sixty-seven participants (45%) had a low baseline EF1 (<25%) despite normal ejection fraction (67% (62%-71%)). Patients with low EF1 had more severe aortic stenosis (mean gradient 39 (34-45) mm Hg vs 24 (16-35) mm Hg, p<0.001) and more myocardial fibrosis (indexed extracellular volume (iECV) (24.2 (19.6-28.7) mL/m2 vs 20.6 (16.8-24.3) mL/m2, p=0.002; late gadolinium enhancement (LGE) prevalence 52% vs 20%, p<0.001). Zva, iECV and infarct LGE were independent predictors of EF1. EF1 improved post-AVR (n=57 with post-AVR EF1 available, baseline 16 (12-24) vs follow-up 27% (22%-31%); p<0.001). Low baseline EF1 was an independent predictor of AVR/death (HR 5.6, 95% CI 3.4 to 9.4), driven by AVR.Conclusion: EF1 quantifies early, potentially reversible systolic dysfunction in aortic stenosis, is associated with global afterload and myocardial fibrosis, and is an independent predictor of AVR. [ABSTRACT FROM AUTHOR]

Objectives: Intraplaque angiogenesis and inflammation are key promoters of atherosclerosis and are mediated by the alpha-V beta-3 (αvβ3) integrin pathway. We investigated the applicability of the αvβ3-integrin receptor-selective positron emission tomography (PET) radiotracer 18F-fluciclatide in assessing human aortic atherosclerosis.Methods: Vascular 18F-fluciclatide binding was evaluated using ex vivo analysis of carotid endarterectomy samples with autoradiography and immunohistochemistry, and in vivo kinetic modelling following radiotracer administration. Forty-six subjects with a spectrum of atherosclerotic disease categorised as stable (n=27) or unstable (n=19; recent myocardial infarction) underwent PET and CT imaging of the thorax after administration of 229 (IQR 217-237) MBq 18F-fluciclatide. Thoracic aortic 18F-fluciclatide uptake was quantified on fused PET-CT images and corrected for blood-pool activity using the maximum tissue-to-background ratio (TBRmax). Aortic atherosclerotic burden was quantified by CT wall thickness, plaque volume and calcium scoring.Results: 18F-Fluciclatide uptake co-localised with regions of increased αvβ3 integrin expression, and markers of inflammation and angiogenesis. 18F-Fluciclatide vascular uptake was confirmed in vivo using kinetic modelling, and on static imaging correlated with measures of aortic atherosclerotic burden: wall thickness (r=0.57, p=0.001), total plaque volume (r=0.56, p=0.001) and aortic CT calcium score (r=0.37, p=0.01). Patients with recent myocardial infarction had greater aortic 18F-fluciclatide uptake than those with stable disease (TBRmax 1.29 vs 1.21, p=0.02).Conclusions: In vivo expression of αvβ3 integrin in human aortic atheroma is associated with plaque burden and is increased in patients with recent myocardial infarction. Quantification of αvβ3 integrin expression with 18F-fluciclatide PET has potential to assess plaque vulnerability and disease activity in atherosclerosis. [ABSTRACT FROM AUTHOR]

Objectives: Macrophages play a central role in the cellular inflammatory response to myocardial infarction (MI) and predict subsequent clinical outcomes. We aimed to assess temporal changes in cellular inflammation and tissue oedema in patients with acute MI using ultrasmallsuperparamagnetic particles of iron oxide (USPIO)-enhanced MRI.Methods: Thirty-one patients were recruited following acute MI and followed up for 3 months with repeated T2 and USPIO-enhanced T2*-mapping MRI. Regions of interest were categorised into infarct, peri-infarct and remote myocardial zones, and compared with control tissues.Results: Following a single dose, USPIO enhancement was detected in the myocardium until 24 hours (p<0.0001). Histology confirmed colocalisation of iron and macrophages within the infarcted, but not the non-infarcted, myocardium. Following repeated doses, USPIO uptake in the infarct zone peaked at days 2-3, and greater USPIO uptake was detected in the infarct zone compared with remote myocardium until days 10-16 (p<0.05). In contrast, T2-defined myocardial oedema peaked at days 3-9 and remained increased in the infarct zone throughout the 3-month follow-up period (p<0.01).Conclusion: Myocardial macrophage activity can be detected using USPIO-enhanced MRI in the first 2 weeks following acute MI. This observed pattern of cellular inflammation is distinct, and provides complementary information to the more prolonged myocardial oedema detectable using T2 mapping. This imaging technique holds promise as a non-invasive method of assessing and monitoring myocardial cellular inflammation with potential application to diagnosis, risk stratification and assessment of novel anti-inflammatory therapeutic interventions.Trial Registration Number: Trial registration number: 14663. Registered on UK Clinical Research Network (http://public.ukcrn.org.uk) and also ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT02319278?term=DECIFER&rank=2). [ABSTRACT FROM AUTHOR]

Objective: Maladaptive repair contributes towards the development of heart failure following myocardial infarction (MI). The αvβ3 integrin receptor is a key mediator and determinant of cardiac repair. We aimed to establish whether αvβ3 integrin expression determines myocardial recovery following MI.Methods: 18F-Fluciclatide (a novel αvβ3-selective radiotracer) positron emission tomography (PET) and CT imaging and gadolinium-enhanced MRI (CMR) were performed in 21 patients 2 weeks after ST-segment elevation MI (anterior, n=16; lateral, n=4; inferior, n=1). CMR was repeated 9 months after MI. 7 stable patients with chronic total occlusion (CTO) of a major coronary vessel and nine healthy volunteers underwent a single PET/CT and CMR.Results: 18F-Fluciclatide uptake was increased at sites of acute infarction compared with remote myocardium (tissue-to-background ratio (TBRmean) 1.34±0.22 vs 0.85±0.17; p<0.001) and myocardium of healthy volunteers (TBRmean 1.34±0.22 vs 0.70±0.03; p<0.001). There was no 18F-fluciclatide uptake at sites of established prior infarction in patients with CTO, with activity similar to the myocardium of healthy volunteers (TBRmean 0.71±0.06 vs 0.70±0.03, p=0.83). 18F-Fluciclatide uptake occurred at sites of regional wall hypokinesia (wall motion index≥1 vs 0; TBRmean 0.93±0.31 vs 0.80±0.26 respectively, p<0.001) and subendocardial infarction. Importantly, although there was no correlation with infarct size (r=0.03, p=0.90) or inflammation (C reactive protein, r=-0.20, p=0.38), 18F-fluciclatide uptake was increased in segments displaying functional recovery (TBRmean 0.95±0.33 vs 0.81±0.27, p=0.002) and associated with increase in probability of regional recovery.Conclusion: 18F-Fluciclatide uptake is increased at sites of recent MI acting as a biomarker of cardiac repair and predicting regions of recovery.Trial Registration Number: NCT01813045; Post-results. [ABSTRACT FROM AUTHOR]

Background--Combined positron emission tomography (PET) and computed tomography (CT) can assess both anatomy and biology of carotid atherosclerosis. We sought to assess whether 18F-fluoride or 18F-fluorodeoxyglucose can identify culprit and high-risk carotid plaque. Methods and Results--We performed 18F-fluoride and 18F-fluorodeoxyglucose PET/CT in 26 patients after recent transient ischemic attack or minor ischemic stroke: 18 patients with culprit carotid stenosis awaiting carotid endarterectomy and 8 controls without culprit carotid atheroma. We compared standardized uptake values in the clinically adjudicated culprit to the contralateral asymptomatic artery, and assessed the relationship between radiotracer uptake and plaque phenotype or predicted cardiovascular risk (ASSIGN score [Assessing Cardiovascular Risk Using SIGN Guidelines to Assign Preventive Treatment]). We also performed micro PET/CT and histological analysis of excised plaque. On histological and micro PET/CT analysis, 18F-fluoride selectively highlighted microcalcification. Carotid 18F-fluoride uptake was increased in clinically adjudicated culprit plaques compared with asymptomatic contralateral plaques (log10standardized uptake valuemean 0.29±0.10 versus 0.23±0.11, P=0.001) and compared with control patients (log10standardized uptake valuemean 0.29±0.10 versus 0.12±0.11, P=0.001). 18F-Fluoride uptake correlated with high-risk plaque features (remodeling index [r=0.53, P=0.003], plaque burden [r=0.51, P=0.004]), and predicted cardiovascular risk [r=0.65, P=0.002]). Carotid 18F-fluorodeoxyglucose uptake appeared to be increased in 7 of 16 culprit plaques, but no overall differences in uptake were observed in culprit versus contralateral plaques or control patients. However, 18F-fluorodeoxyglucose did correlate with predicted cardiovascular risk (r=0.53, P=0.019), but not with plaque phenotype. Conclusions--18F-Fluoride PET/CT highlights culprit and phenotypically high-risk carotid plaque. This has the potential to improve risk stratification and selection of patients who may benefit from intervention. [ABSTRACT FROM AUTHOR]

Background--18F-Fluoride positron emission tomography (PET) and computed tomography (CT) can measure disease activity and progression in aortic stenosis. Our objectives were to optimize the methodology, analysis, and scan-rescan reproducibility of aortic valve 18F-fluoride PET-CT imaging. Methods and Results--Fifteen patients with aortic stenosis underwent repeated 18F-fluoride PET-CT. We compared nongated PET and noncontrast CT, with a modified approach that incorporated contrast CT and ECG-gated PET. We explored a range of image analysis techniques, including estimation of blood-pool activity at differing vascular sites and a most diseased segment approach. Contrast-enhanced ECG-gated PET-CT permitted localization of 18F-fluoride uptake to individual valve leaflets. Uptake was most commonly observed at sites of maximal mechanical stress: the leaflet tips and the commissures. Scan-rescan reproducibility was markedly improved using enhanced analysis techniques leading to a reduction in percentage error from «63% to «10% (tissue to background ratio MDS mean of 1.55, bias -0.05, limits of agreement -0·20 to +0·11). Conclusions--Optimized 18F-fluoride PET-CT allows reproducible localization of calcification activity to different regions of the aortic valve leaflet and commonly to areas of increased mechanical stress. This technique holds major promise in improving our understanding of the pathophysiology of aortic stenosis and as a biomarker end point in clinical trials of novel therapies. [ABSTRACT FROM AUTHOR]

Valvular heart disease is a major cause of morbidity and mortality, and with an aging population, its prevalence is increasing. Here, we review the evolving use of positron emission tomography/computed tomography in valvular heart disease, with particular focus on calcific aortic stenosis and infective endocarditis. In principle, the activity of any pathological process can be studied, as long as an appropriate radiotracer can be developed. We will review some of the early data using established tracers in the above and other conditions, providing discussion as to the future research and clinical roles of these techniques. Furthermore, we will discuss the potential impact of novel tracers that are currently under development or testing in preclinical models. It is hoped that such advanced imaging might improve the diagnosis, treatment and outlook for patients with valvular heart disease. [ABSTRACT FROM AUTHOR]

Background: Lipoprotein(a) [Lp(a)], a major carrier of oxidized phospholipids (OxPL), is associated with an increased incidence of aortic stenosis (AS). However, it remains unclear whether elevated Lp(a) and OxPL drive disease progression and are therefore targets for therapeutic intervention., Objectives: This study investigated whether Lp(a) and OxPL on apolipoprotein B-100 (OxPL-apoB) levels are associated with disease activity, disease progression, and clinical events in AS patients, along with the mechanisms underlying any associations., Methods: This study combined 2 prospective cohorts and measured Lp(a) and OxPL-apoB levels in patients with AS (V max >2.0 m/s), who underwent baseline 18 F-sodium fluoride ( 18 F-NaF) positron emission tomography (PET), repeat computed tomography calcium scoring, and repeat echocardiography. In vitro studies investigated the effects of Lp(a) and OxPL on valvular interstitial cells., Results: Overall, 145 patients were studied (68% men; age 70.3 ± 9.9 years). On baseline positron emission tomography, patients in the top Lp(a) tertile had increased valve calcification activity compared with those in lower tertiles (n = 79; 18 F-NaF tissue-to-background ratio of the most diseased segment: 2.16 vs. 1.97; p = 0.043). During follow-up, patients in the top Lp(a) tertile had increased progression of valvular computed tomography calcium score (n = 51; 309 AU/year [interquartile range: 142 to 483 AU/year] vs. 93 AU/year [interquartile range: 56 to 296 AU/year; p = 0.015), faster hemodynamic progression on echocardiography (n = 129; 0.23 ± 0.20 m/s/year vs. 0.14 ± 0.20 m/s/year] p = 0.019), and increased risk for aortic valve replacement and death (n = 145; hazard ratio: 1.87; 95% CI: 1.13 to 3.08; p = 0.014), compared with lower tertiles. Similar results were noted with OxPL-apoB. In vitro, Lp(a) induced osteogenic differentiation of valvular interstitial cells, mediated by OxPL and inhibited with the E06 monoclonal antibody against OxPL., Conclusions: In patients with AS, Lp(a) and OxPL drive valve calcification and disease progression. These findings suggest lowering Lp(a) or inactivating OxPL may slow AS progression and provide a rationale for clinical trials to test this hypothesis., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Mitral annular calcification (MAC) is associated with cardiovascular events and mitral valve dysfunction. However, the underlying pathophysiology remains incompletely understood. In this prospective longitudinal study, we used a multimodality approach including positron emission tomography, computed tomography, and echocardiography to investigate the pathophysiology of MAC and assess factors associated with disease activity and progression., Methods: A total of 104 patients (age 72±8 years, 30% women) with calcific aortic valve disease, therefore predisposed to MAC, underwent 18 F-sodium fluoride (calcification activity) and 18 F-Fluorodeoxyglucose (inflammation activity) positron emission tomography, computed tomography calcium scoring, and echocardiography. Sixty patients underwent repeat computed tomography and echocardiography after 2 years., Results: MAC (mitral annular calcium score >0) was present in 35 (33.7%) patients who had increased 18 F-fluoride (tissue-to-background ratio, 2.32 [95% CI, 1.81-3.27] versus 1.30 [1.22-1.49]; P<0.001) and 18 F-Fluorodeoxyglucose activity (tissue-to-background ratio, 1.44 [1.37-1.58] versus 1.17 [1.12-1.24]; P<0.001) compared with patients without MAC. MAC activity ( 18 F-fluoride uptake) was closely associated with the local calcium score and 18 F-Fluorodeoxyglucose uptake, as well as female sex and renal function. Similarly, MAC progression was closely associated with local factors, in particular, baseline MAC. Traditional cardiovascular risk factors and calcification activity in bone or remote atherosclerotic areas were not associated with disease activity nor progression., Conclusions: MAC is characterized by increased local calcification activity and inflammation. Baseline MAC burden was associated with disease activity and the rate of subsequent progression. This suggests a self-perpetuating cycle of calcification and inflammation that may be the target of future therapeutic interventions.

Objective: Maladaptive repair contributes towards the development of heart failure following myocardial infarction (MI). The α v β 3 integrin receptor is a key mediator and determinant of cardiac repair. We aimed to establish whether α v β 3 integrin expression determines myocardial recovery following MI., Methods: 18 F-Fluciclatide (a novel α v β 3 -selective radiotracer) positron emission tomography (PET) and CT imaging and gadolinium-enhanced MRI (CMR) were performed in 21 patients 2 weeks after ST-segment elevation MI (anterior, n=16; lateral, n=4; inferior, n=1). CMR was repeated 9 months after MI. 7 stable patients with chronic total occlusion (CTO) of a major coronary vessel and nine healthy volunteers underwent a single PET/CT and CMR., Results: 18 F-Fluciclatide uptake was increased at sites of acute infarction compared with remote myocardium (tissue-to-background ratio (TBR mean ) 1.34±0.22 vs 0.85±0.17; p<0.001) and myocardium of healthy volunteers (TBR mean 1.34±0.22 vs 0.70±0.03; p<0.001). There was no 18 F-fluciclatide uptake at sites of established prior infarction in patients with CTO, with activity similar to the myocardium of healthy volunteers (TBR mean 0.71±0.06 vs 0.70±0.03, p=0.83). 18 F-Fluciclatide uptake occurred at sites of regional wall hypokinesia (wall motion index≥1 vs 0; TBR mean 0.93±0.31 vs 0.80±0.26 respectively, p<0.001) and subendocardial infarction. Importantly, although there was no correlation with infarct size (r=0.03, p=0.90) or inflammation (C reactive protein, r=-0.20, p=0.38), 18 F-fluciclatide uptake was increased in segments displaying functional recovery (TBR mean 0.95±0.33 vs 0.81±0.27, p=0.002) and associated with increase in probability of regional recovery., Conclusion: 18 F-Fluciclatide uptake is increased at sites of recent MI acting as a biomarker of cardiac repair and predicting regions of recovery., Trial Registration Number: NCT01813045; Post-results., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Calcified aortic stenosis is a condition that affects the valve and the myocardium. As the valve narrows, left ventricular hypertrophy occurs initially as an adaptive mechanism to maintain cardiac output. Ultimately, the ventricle decompensates and patients transition towards heart failure and adverse events. Current guidelines recommend aortic valve replacement in patients with severe aortic stenosis and evidence of decompensation based on either symptoms or an impaired ejection fraction <50%. However, symptoms can be subjective and correlate only modestly with the severity of aortic stenosis whilst impaired ejection fraction is an advanced manifestation and often irreversible. In this review, the authors will discuss the pathophysiology of left ventricular hypertrophy and the transition to heart failure. Subsequently, the authors will examine novel biomarkers that may better identify the transition from hypertrophy to heart failure and therefore guide the optimal timing for aortic valve replacement.

Background: 18F-Sodium fluoride (18F-NaF) and 18F-fluorodeoxyglucose (18F-FDG) are promising novel biomarkers of disease activity in aortic stenosis. We compared 18F-NaF and 18F-FDG uptake with histological characterization of the aortic valve and assessed whether they predicted disease progression., Methods and Results: Thirty patients with aortic stenosis underwent combined positron emission and computed tomography using 18F-NaF and 18F-FDG radiotracers. In 12 patients undergoing aortic valve replacement surgery (10 for each tracer), radiotracer uptake (mean tissue/, Background: =0.65; P=0.04) and osteocalcin (r=0.68; P=0.03) immunohistochemistry. There was no significant correlation between 18F-FDG uptake and CD68 staining (r=-0.43; P=0.22). After 1 year, aortic valve calcification increased from 314 (193-540) to 365 (207-934) AU (P<0.01). Baseline 18F-NaF uptake correlated closely with the change in calcium score (r=0.66; P<0.01), and this improved further (r=0.75; P<0.01) when 18F-NaF uptake overlying computed tomography-defined macrocalcification was excluded. No significant correlation was noted between valvular 18F-FDG uptake and change in calcium score (r=-0.11; P=0.66)., Conclusions: 18F-NaF uptake identifies active tissue calcification and predicts disease progression in patients with calcific aortic stenosis., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01358513.

We present the case of a 68-year-old woman who presented in extremis with a secondary pneumothorax with a past history of severe idiopathic pulmonary fibrosis. Following insertion of a 32F intercostal drain, she developed a persistent broncho-pleural fistula and became dependent on negative-pressure wall-mounted suction to prevent respiratory compromise. She declined definitive surgical intervention and was therefore managed conservatively. After adhering to the wall-mounted suction method for 49 days, we obtained for use a portable digital thoracic drainage system previously used only in the cardiothoracic postoperative patient. This electronically delivered, negative-pressure drainage system induced radiographic improvement within 24 h, and allowed the patient to mobilise for the first time since admission. The patient was discharged home with the Thopaz drain in situ 8 weeks after placing it, and the drain was removed successfully with a resolved pneumothorax 20 weeks after her initial presentation.