579 Pre-operative computed tomography evaluation of suprarenal aortic burden predicts post-procedural acute kidney injury after transcatheter aortic valve replacement: the spread-AKI study

Aims Acute kidney injury (AKI) is a potential complication of transcatheter aortic valve replacement (TAVR). Athero-embolization linked to catheter manipulation in the supra-renal aorta is a possible pathogenetic mechanism of AKI after TAVR. We sought to determine the impact of supra-renal aortic atheroma burden (AB) on AKI, and the potential role of pre-operative multislice computed tomography (PO-MSCT) in evaluating the supra-renal aortic atherosclerosis and the pre-operative risk of AKI. Methods and results We collected PO-MSCT, as well as baseline, procedural, and post-procedural characteristics of 222 consecutive patients who underwent TAVR from January 2018 to December 2020 at a single, high-volume, Italian centre. PO-MSCT was performed using a dedicated TAVR protocol with an ECG-triggered high-pitch spiral acquisition. The non-contrast aortic valve calcium score (AV-CS) was calculated by a dedicated software. Angiographic data were analysed on a dedicated 3D workstation. Bidimensional measurements, total renal volume (TRV), and presence of significant (≥50%) renal artery stenosis (RAS) were recorded. The supra-renal AB was quantified using a ‘plaque analysis’ module that automatically segments the entire aortic root, from the sino-tubular junction to the renal arteries, by drawing a centreline across the aortic lumen and delineating the inner and outer vessel walls (including the plaque). Manual correction was applied. A set of Hounsfield unit (HU) intensity ranges were defined and mapped to a color overlay to visualize the various elements of atherosclerotic lesion by using the plaque density classification of the Society of Cardiovascular Computed Tomography (necrotic core, fibro-fatty, fibrous, and calcified plaque); calcified plaque were subcategorized on a voxel-level basis into three strata: low- (351–700 HU), mid- (701–1000 HU), and high-calcium (>1000 HU, termed 1K plaque). Post-procedural complications were defined according to Valve Academic Research Consortium (VARC-3) criteria. Mean age was 83.3 ± 5.7 years, and 95 (42.8%) patients were males. AKI occurred in 67/222 (30.2%). Patients who developed AKI had higher supra-renal AB (17.6 ± 5.1% vs. 13.9 ± 4.3%, P < 0.001), TRV indexed for body surface area (TRVBSA; 153.7 ± 43.1 vs. 134.9 ± 38.7, P = 0.002), mid-calcium plaque (2.2 ± 1.5% vs. 1.3 ± 1.1%, P < 0.001), 1K plaque (5.4 ± 3.7% vs. 2.4 ± 2.4%, P < 0.001) and suffered more post-procedural major/life-threatening (severe) bleedings [9/67 (13.4%) vs. 5/155 (3.2%), P = 0.004], whereas there was no difference in AV-CS (P = 0.691) and RAS (P = 0.077). Multivariate logistic regression analysis adjusted for other univariate predictors (male sex, baseline eGFR, baseline ejection fraction, baseline mean aortic gradient, and RAS) showed percent supra-renal AB (HR: 1.15, 95% CI: 1.06–1.26, P = 0.002), mid-to-high calcium plaque (HR: 5.67, 95% CI: 2.49–13.77, P < 0.001), severe bleedings (HR: 4.93, 95% CI: 1.09–24.69, P = 0.043), and TRVBSA (HR: 1.015, 95% CI: 1.01–1.02, P = 0.021) as independent predictors of AKI. Finally, a 3-knots spline curve analysis identified percent of supra-renal AB > 15.0% as the optimal threshold to predict an increased risk of AKI. Conclusions Suprarenal AB is associated with the occurrence of AKI, and this association is strengthened as the percentage of calcified plaque increases. Quantitative and qualitative pre-operative MSCT assessment of aortic atherosclerosis may help in early identification of patients at high-risk for AKI who could benefit from higher peri-operative surveillance.

Effects from the induction of heat shock proteins in a murine model due to progression of aortic atherosclerosis

Heat shock proteins (HSPs) are molecular chaperones that repair denatured proteins. The relationship between HSPs and various diseases has been extensively studied. However, the relationship between HSPs and atherosclerosis remains unclear. In this study, we induced the expression of HSPs and analyzed the effects on the development/progression of atherosclerosis in vivo. Remarkably, when HSPs were induced in apolipoprotein E deficient (ApoE−/−) mice prior to the formation of atheromas, the progression of atherosclerosis was inhibited; the short-term induction of HSPs significantly decreased the mRNA expression of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) in the aorta. In contrast, the induction of HSPs after the formation of atheromas promoted the progression of atherosclerosis. In fact, the short-term induction of HSPs, after the formation of atheromas, significantly increased the mRNA expression of tumor necrosis factor-alpha, and interleukin 6 in the aorta. Of note, the induction of HSPs also promoted the formation of macrophage-derived foam cells. Overall, these results indicate that HSPs exerts different effects in the context of aortic atherosclerosis, depending on its degree of progression. Therefore, the induction and inhibition of HSPs should be considered for the prevention and treatment of atherosclerosis, respectively.

Nicotinamide Prevents Apolipoprotein B-Containing Lipoprotein Oxidation, Inflammation and Atherosclerosis in Apolipoprotein E-Deficient Mice

The potential of nicotinamide (NAM) to prevent atherosclerosis has not yet been examined. This study investigated the effect of NAM supplementation on the development of atherosclerosis in a mouse model of the disease. The development of aortic atherosclerosis was significantly reduced (NAM low dose: 45%; NAM high dose: 55%) in NAM-treated, apolipoprotein (Apo)E-deficient mice challenged with a Western diet for 4 weeks. NAM administration significantly increased (1.8-fold) the plasma concentration of proatherogenic ApoB-containing lipoproteins in NAM high-dose (HD)-treated mice compared with untreated mice. However, isolated ApoB-containing lipoproteins from NAM HD mice were less prone to oxidation than those of untreated mice. This result was consistent with the decreased (1.5-fold) concentration of oxidized low-density lipoproteins in this group. Immunohistochemical staining of aortas from NAM-treated mice showed significantly increased levels of IL-10 (NAM low-dose (LD): 1.3-fold; NAM HD: 1.2-fold), concomitant with a significant decrease in the relative expression of TNFα (NAM LD: −44%; NAM HD: −57%). An improved anti-inflammatory pattern was reproduced in macrophages cultured in the presence of NAM. Thus, dietary NAM supplementation in ApoE-deficient mice prevented the development of atherosclerosis and improved protection against ApoB-containing lipoprotein oxidation and aortic inflammation.

Regional Variation in Genetic Control of Atherosclerosis in Hyperlipidemic Mice

Atherosclerosis is a polygenic disorder that often affects multiple arteries. Carotid arteries are common sites for evaluating subclinical atherosclerosis, and aortic root is the standard site for quantifying atherosclerosis in mice. We compared genetic control of atherosclerosis between the two sites in the same cohort derived from two phenotypically divergent Apoe-null (Apoe−/−) mouse strains. Female F2 mice were generated from C57BL/6 (B6) and C3H/He (C3H) Apoe−/− mice and fed 12 weeks of Western diet. Atherosclerotic lesions in carotid bifurcation and aortic root and plasma levels of fasting lipids and glucose were measured. 153 genetic markers across the genome were typed. All F2 mice developed aortic atherosclerosis, while 1/5 formed no or little carotid lesions. Genome-wide scans revealed 3 significant loci on chromosome (Chr) 1, Chr15, 6 suggestive loci for aortic atherosclerosis, 2 significant loci on Chr6, Chr12, and 6 suggestive loci for carotid atherosclerosis. Only 2 loci for aortic lesions showed colocalization with loci for carotid lesions. Carotid lesion sizes were moderately correlated with aortic lesion sizes (r = 0.303; P = 4.6E-6), but they showed slight or no association with plasma HDL, non-HDL cholesterol, triglyceride, or glucose levels among F2 mice. Bioinformatics analyses prioritized Cryge as a likely causal gene for Ath30, Cdh6 and Dnah5 as causal genes for Ath22. Our data demonstrate vascular site-specific effects of genetic factors on atherosclerosis in the same animals and highlight the need to extend studies of atherosclerosis to sites beyond aortas of mice.