In Vivo Aortic Valve Thermal Heterogeneity in Patients With Nonrheumatic Aortic Valve Stenosis

Toutouzas, Konstantinos; Drakopoulou, Maria; Synetos, Αndreas; Tsiamis, Eleftherios; Agrogiannis, George; Kavantzas, Nikolaos; Patsouris, E.; Iliopoulos, Dimitrios; Theodoropoulos, Stergios; Yacoub, Magdi H.; Stefanadis, Christodoulos

doi:10.1016/j.jacc.2008.04.057

Cited by 27 publications

(15 citation statements)

References 21 publications

(18 reference statements)

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“…17 Although correlations between 18F-FDG uptake and macrophage burden have previously been demonstrated in regions of aortic and carotid atheroma, 8 we were unable to replicate this with respect to the valve. There are several explanations for this discrepancy.…”

Section: Discussionmentioning

confidence: 64%

18F-Sodium Fluoride Uptake Is a Marker of Active Calcification and Disease Progression in Patients With Aortic Stenosis

Dweck¹,

Jenkins²,

Vesey

et al. 2014

Circ: Cardiovascular Imaging

213

126

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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 ratio) was compared with CD68 (inflammation), alkaline phosphatase, and osteocalcin (calcification) immunohistochemistry of the excised valve. In 18 patients (6 aortic sclerosis, 5 mild, and 7 moderate), aortic valve computed tomography calcium scoring was performed at baseline and after 1 year. Aortic valve 18F-NaF uptake correlated with both alkaline phosphatase ( r =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.

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Section: Discussionmentioning

confidence: 64%

18F-Sodium Fluoride Uptake Is a Marker of Active Calcification and Disease Progression in Patients With Aortic Stenosis

Dweck¹,

Jenkins²,

Vesey

et al. 2014

Circ: Cardiovascular Imaging

213

126

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“…Inflammatory cytokines, [25][26][27] reactive oxygen species, 28 growth factors, and osteogenic factors 29,30 have been observed in human diseased valves and are considered to play important roles in the development of AVS. Our results show that inflammatory cytokines (tumor necrosis factor-α, interleukin-1β, and interleukin-6) and transforming growth factor-β1 were upregulated 1 week after injury, and this was sustained until ≥4 weeks.…”

Section: 18mentioning

confidence: 99%

A Novel Mouse Model of Aortic Valve Stenosis Induced by Direct Wire Injury

Honda

Miyamoto

Watanabe

et al. 2014

ATVB

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Objective-The response-to-tissue-injury theory is currently the favorite paradigm to investigate valve pathology. To the best of our knowledge, there are currently no in vivo valve injury models. There are few calcific aortic valve stenosis (AVS) models that develop hemodynamically significant stenosis. Here, we investigated the effect of direct mechanical injury on aortic valves in vivo and developed a novel mouse model of calcific AVS. Approach and Results-Aortic valve injury was created by inserting and moving a spring guidewire under echocardiographic guidance into the left ventricle of male C57/BL6 mice via right common carotid artery. Serial echocardiographic measurements revealed that aortic velocity was increased 1 week after injury and persistently increased until 16 weeks after injury. AVS mice showed a higher heart weight/body weight ratio and decreased left ventricular fractioning shortening 4 weeks after injury, compared with sham mice. We found remarkable proliferation of valve leaflets 4 weeks after injury. Proliferative valves showed increased production of reactive oxygen species and expression of inflammatory cytokines and osteochondrogenic factors. Alizarin red staining showed valvular calcification 12 weeks after injury. Conclusions-We report a novel calcific AVS model to support the response-to-tissue-injury theory. This model may be a valuable tool for analyzing the mechanism of AVS and assessing therapeutic options. Materials and MethodsMaterials and Methods are available in the online-only Supplement. Results Aortic Valve InjuryThe surgical procedure time, including anesthesia, needed for aortic valve injury was 21.0±5.1 minutes. Seven of 132 mice died during the operation due to sudden cardiac arrest (5 mice) and bleeding (2 mice). In the sham group, 1 of 63 mice died as a result of bleeding. After aortic valve injury, 25 of 125 mice died during the next 16 weeks. Survival curves showed that 18.7% of mice with aortic valve injury died <4 weeks, whereas none in the sham-operated mice died ( Figure 2A). The causes of death after aortic valve injury were congestive heart failure with pleural effusion at autopsy (5) and unknown causes (20), most likely attributable to cardiac arrhythmia or heart failure without obvious effusion. Valve and Ventricular FunctionImmediately after injury, aortic regurgitation was not observed on 2-dimensional color Doppler and pulse-wave Doppler imaging, and aortic velocity did not increase. Mice with aortic valve injury had significantly higher aortic velocity and smaller aortic valve area compared with sham-operated mice 1 week after surgery. The elevated velocity persisted for 16 weeks without improvement. Left ventricular outflow tract velocity was not significantly increased at all time points. Left ventricular fractional shortening was significantly decreased 4 weeks after surgery, and left ventricular end-diastolic diameter was increased 8 weeks after injury (see Table). Heart weight/body weight ratio gradually increased ( Figure 2C). Additionally, real-t...

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“…3 Additional evidence amassed that AS, like CAD, was an active inflammatory process with active inflammatory cells present in the lesions, with increased heat in some AS plaques and increased circulatory C-reactive protein present in AS patients. 4,5 Inflammation marked by increased valve calcification also presaged rapid progression to severe disease. 6 However, there are significant differences between the atherosclerosis of CAD and the process of aortic valve calcification.…”

Section: Evolution Of the Pathogenesis Of Asmentioning

confidence: 99%

Introduction to Aortic Stenosis

Carabello

2013

Circulation Research

119

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Aortic stenosis is perhaps the most common of all valvular heart diseases in the developed nations of the world. Once primarily caused by rheumatic fever, the most common pathogenesis today is an active inflammatory process with some features that are similar to atherosclerosis. Because of this shift, the age at onset of severe obstruction has changed from the sixth decade 50 years ago to the eighth decade in most individuals today. The onset of symptoms remains a key determinant of outcome, although the later age at onset may make it difficult to discern if aortic stenosis or other age-related comorbidities is the cause of the symptoms. Once symptoms of aortic stenosis develop, life expectancy is shortened to ≈3 years unless the mechanical obstruction to left ventricular outflow is relieved by aortic valve replacement. Traditionally performed during cardiac surgery, aortic valve replacement now may be performed safely and effectively using transcatheter techniques, potentially revolutionizing the approach to this potentially fatal disease. (Circ Res. 2013;113:179-185.)

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In Vivo Aortic Valve Thermal Heterogeneity in Patients With Nonrheumatic Aortic Valve Stenosis

Abstract: Thermal heterogeneity is increased in AVS and correlates with inflammatory mononuclear cell infiltration, expression of pro-inflammatory cytokines and neoangiogenic factors.

Cited by 27 publications

References 21 publications

18F-Sodium Fluoride Uptake Is a Marker of Active Calcification and Disease Progression in Patients With Aortic Stenosis

18F-Sodium Fluoride Uptake Is a Marker of Active Calcification and Disease Progression in Patients With Aortic Stenosis

A Novel Mouse Model of Aortic Valve Stenosis Induced by Direct Wire Injury

Introduction to Aortic Stenosis

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