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left1256030Cahalane, R.M.1, O’Brien, J.2, Kavanagh, E.3, Moloney, T.3, O’Connor, E,4 and Walsh, M.T.1 1Biomaterials Cluster, Bernal Institute, University of Limerick (UL). 2Department of Radiology, University Hospital Limerick (UHL). 3Department of Vascular Surgery, UHL. 4Department of Biological Sciences, UL.email: rachel.cahalane@ul.ie00Cahalane, R.M.1, O’Brien, J.2, Kavanagh, E.3, Moloney, T.3, O’Connor, E,4 and Walsh, M.T.1 1Biomaterials Cluster, Bernal Institute, University of Limerick (UL). 2Department of Radiology, University Hospital Limerick (UHL). 3Department of Vascular Surgery, UHL. 4Department of Biological Sciences, UL.email: rachel.cahalane@ul.iecenter1003935Towards Improving the diagnosis and treatment of Carotid Arterial Disease00Towards Improving the diagnosis and treatment of Carotid Arterial DiseaseIntroductionCardiovascular disease is the leading cause of death worldwide. Atheroprone regions include the coronary and carotid arteries, which lead to myocardial and cerebral infarctions, respectively. Calcified deposits are present in over 70% of these atherosclerotic plaques. The current gold standard of calcification quantification in vivo is the Computed Tomography (CT) coronary Agatston Calcium Score (ACS)1. The ACS is a powerful predictor of future cardiac events. However, it has not yet been validated for similar use in the carotid arteries to predict strokes. It is also uncertain how the ACS correlates with calcification morphology, a critical factor in plaque stability. Confirmation of the calcification characteristics associated with cerebrovascular symptoms is required to identify high-risk carotid plaques. Additionally, the active formation of calcification2 presents a unique opportunity to investigate the utility of blood-based biomarkers in vulnerable plaque diagnosis. Finally, calcification is associated with increased intervention failure and the occurrence of procedural complications. Full consideration of tissue mechanics is required to predict device-tissue interaction and there is much variation in published properties of atherosclerotic calcification3. Consequently, endarterectomy remains the leading choice of treatment for carotid arterial disease. Therefore, the purpose of this study is to accumulate the aforementioned knowledge, towards improving our methods of high-risk carotid plaque identification and treatment, ultimately optimizing patient outcomes. Materials and methodsConsenting patients undergoing standard carotid endarterectomy procedures were enrolled in this study (n=38). Fasting venous bloods and excised plaque samples were collected pre- and post-operatively, respectively. Cerebrovascular symptoms were classified by clinicians as either stroke (n=8), transient ischemic attack (TIA) (n=26) or asymptomatic (n=4). High-resolution micro-CT was performed on the ex vivo plaques, simultaneously identifying the internal calcified deposits and quantifying their radiographic densities. Image post-processing methodologies determine the calcification volume and calcified particle distributions. Image scaling replicates clinically relevant CT resolutions and Agatston calcium score (ACS) approximations are thus calculated. Chemiluminescent immunoassays quantify the circulating blood levels of dephospho-uncarboxylated Matrix Gla-Protein (dp-ucMGP). Nanoindentation measurements were obtained using a Berkovich tip on a cross section of calcification. The elastic modulus is calculated from the unloading curve using the Oliver and Pharr methodology. results and DiscussionThe Agatston calcium score (ACS) positively correlates with carotid calcification volume fractions (r2=0.98), but not calcified particle measurements (r2<0.5)4, rationalizing its ability to identify high-risk patients but not high-risk plaques5. The ratio of number of calcified particles to total calcification volume (mm3) (Calcified Particle Index)4 is increased in symptomatic patients at high-resolution CT (p=0.188). The fraction of low-density calcification (130-199 Houndfield Units) is statistically significantly increased in symptomatic patients at low-resolution CT (p<0.05) (Fig.1A), supporting recent findings6. Patients with multiple atherosclerotic regions appear to have higher circulating dp-ucMGP levels. However, there are no strong correlations between dp-ucMGP and any carotid calcification measurements (r2<0.4) (Fig.1B). This indicates that circulating biomarkers may reflect overall patient calcification rather than individual plaque calcification. There is a strong association between radiographic density and elastic modulus of calcification (p<0.0005) (Fig.1C)7. The elastic modulus of fully calcified carotid tissue is similar to human bone (17-25GPa)7, as previously predicted3. Figure 1: (A) Carotid calcium scoring using micro-CT and clinical CT resolutions. (B) Circulating dp-ucMGP levels versus plaque locations and carotid-specific calcification measurements. (C) Nanoindentation of carotid calcification based on radiographic density groups. ConclusionIn this study we have combined techniques to enhance our understanding of the diagnosis and treatment of carotid arterial disease. Quantification of clinical CT low-density calcification in carotid arteries could identify patients at risk of stroke. Blood biomarkers, while appealing, appear to be reflective of global patient atherosclerotic calcification, rather than plaque-calcification. The mechanical properties of carotid calcifications are similar to bone, affording computational models and manufacturers with accurate material properties to revise medical device design and treatment approaches.References1Agatston (et al.), JACC, 15:827-832, 1990. 2Doherty (et al.), PNAS, 100:11201-11206, 2003. 3Ebenstein (et al.), JBMR - Part A, 91:1028-1037, 2009. 4Cahalane (et al.), JCCT, [epub], 2019. 5Mauriello (et al.), Atherosclerosis, 229:124-129, 2013. 6Criqui (et al.), JAMA, 15:271-278, 2014. 7Cahalane (et al.), Acta Biomaterilia, 80:228-236, 2018. ................
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