Valve Calcification Research Articles

Diagnosis of bicuspid aortic valves: CT vs. TTE.

Bicuspid aortic valfves (BAV) are a relatively common cardiac abnormality, with an associated risk of aortic stenosis, aortic regurgitation and aortopathy. First-line diagnosis is via transthoracic echocardiography (TTE), which may be impacted by valve calcification and operator variability. Electrocardiogram-gated computed tomography (CT) offers an alternative form of assessment. The aim of this systematic review and meta-analysis is to evaluate the diagnostic performance of TTE versus CT for BAV. Eligible studies were retrieved from inception through to March 2024 on OVID Medline, Embase and Cochrane Library. All primary studies regarding the diagnostic performance of TTE and/or CT with regards to BAV were included. The QUADAS-2 tool was utilized for quality assessment. Sensitivity and specificity data were statistically analyzed. Of 4698 records, 19 were eligible for inclusion, and 16 had sufficient data for inclusion in the meta-analysis. There was only data regarding TTE vs. retrospectively ECG-gated CT. There was a significant difference between the sensitivity of retrospectively ECG-gated cardiac CT (95.5% (95% CI: [91.3-97.5%]) and TTE (79.7%, 95% CI: [71.6-86.0%]) for identifying BAV. The specificity was high and not significantly different for both CT and TTE (96%, 95% CI: [92.5-98.2%] and 91.3%, 95% CI: [87.3-93.8%], respectively). Retrospectively ECG-gated CT demonstrates greater sensitivity for diagnosis of BAV compared to TTE. Both modalities are non-invasive and demonstrate good specificity for excluding BAV. Given that CT scans are easily accessible, they offer a reasonable second-line investigation for diagnosis of BAV when an initial TTE is inconclusive.

Pre-interventional renal artery calcification and survival after transcatheter aortic valve implantation.

The prognostic significance of renal artery calcification (RAC) is unknown in patients with severe aortic stenosis (AS) eligible for transcatheter aortic valve implantation (TAVI). RAC can be assessed by computed tomography (CT) performed during pre-interventional planning for TAVI. This study aimed at investigating the utility of RAC for predicting survival after TAVI. In this longitudinal cohort study, RAC volume was measured by CT in 268 consecutive patients with severe AS undergoing TAVI. Association of RAC with mortality was assessed using Cox regression analysis. RAC was evaluated as a binary parameter and in a supplementary analysis as a logarithmically transformed continuous variable. Over a median follow-up time of 9.6 years, 237 (88.4%) patients died, with 174 (73.4%) deaths attributable to a cardiovascular cause. RAC was highly prevalent (N = 150 (86.2%)) among patients suffering cardiovascular death. Competing risk cumulative incidence curves revealed a higher occurrence of cardiovascular death in patients with RAC (P-value = 0.008), while this was not the case for non-cardiovascular death (P-value = 0.71). RAC was independently associated with cardiovascular death (HR 1.61 [95% CI: 1.01-2.57]; P = 0.047) after adjustment for age, sex, cardiovascular risk factors, impaired renal function, and aortic valve calcification. The presence or absence of RAC rather than its volume was important in all the analyses. RAC is a strong and independent predictor of cardiovascular death in patients with severe AS undergoing TAVI. Given its favourable properties for event prediction, RAC may be considered valuable for prognostic assessment of TAVI patients.

Macrophages in Calcific Aortic Valve Disease: Paracrine and Juxtacrine Disease Drivers

A significant role in the pathogenesis of CAVD is played by innate immunity cells, such as macrophages. In stenotic valves, macrophages have enhanced inflammatory activity, and the population’s balance is shifted toward pro-inflammatory ones. Pro-inflammatory macrophages release cytokines, chemokines, and microRNA, which can directly affect the resident valvular cells and cause valve calcification. In CAVD patients, macrophages may have more pronounced pro-inflammatory properties, enhanced not only by paracrine signals but also by juxtacrine Notch signaling and epigenetic factors, which influence the maturation of macrophages’ progenitors. In this review, we observe the accumulated data on the involvement of macrophages in CAVD development via paracrine and juxtacrine interactions.

Oxidized Phospholipids and Calcific Aortic Valvular Disease

BackgroundOxidized phospholipids (OxPLs) are carried by apolipoprotein B-100–containing lipoproteins (OxPL-apoB) including lipoprotein(a) (Lp[a]). Both OxPL-apoB and Lp(a) have been associated with calcific aortic valve disease (CAVD). ObjectivesThis study aimed to evaluate the associations between OxPL-apoB, Lp(a) and the prevalence, incidence, and progression of CAVD. MethodsOxPL-apoB and Lp(a) were evaluated in MESA (Multi-Ethnic Study of Atherosclerosis) and a participant-level meta-analysis of 4 randomized trials of participants with established aortic stenosis (AS). In MESA, the association of OxPL-apoB and Lp(a) with aortic valve calcium (AVC) at baseline and 9.5 years was evaluated using multivariable ordinal regression models. In the meta-analysis, the association between OxPL-apoB and Lp(a) with AS progression (annualized change in peak aortic valve jet velocity) was evaluated using multivariable linear regression models. ResultsIn MESA, both OxPL-apoB and Lp(a) were associated with prevalent AVC (OR per SD: 1.19 [95% CI: 1.07-1.32] and 1.13 [95% CI: 1.01-1.27], respectively) with a significant interaction between the two (P < 0.01). Both OxPL-apoB and Lp(a) were associated with incident AVC at 9.5 years when evaluated individually (interaction P < 0.01). The OxPL-apoB∗Lp(a) interaction demonstrated higher odds of prevalent and incident AVC for OxPL-apoB with increasing Lp(a) levels. In the meta-analysis, when analyzed separately, both OxPL-apoB and Lp(a) were associated with faster increase in peak aortic valve jet velocity, but when evaluated together, only OxPL-apoB remained significant (ß: 0.07; 95% CI: 0.01-0.12). ConclusionsOxPL-apoB is a predictor of the presence, incidence, and progression of AVC and established AS, particularly in the setting of elevated Lp(a) levels, and may represent a novel therapeutic target for CAVD.

Elucidating common biomarkers and pathways of osteoporosis and aortic valve calcification: insights into new therapeutic targets

Background: Osteoporosis and aortic valve calcification, prevalent in the elderly, have unclear common mechanisms. This study aims to uncover them through bioinformatics analysis. Methods: Microarray data from GEO was analyzed for osteoporosis and aortic valve calcification. Differential expression analysis identified co-expressed genes. SVM-RFE and random forest selected key genes. GO and KEGG enrichment analyses were performed. Immunoinfiltration and GSEA analyses were subsequently performed. NetworkAnalyst analyzed microRNAs/TFs. HERB predicted drugs, and molecular docking assessed targeting potential. Results: Thirteen genes linked to osteoporosis and aortic valve calcification were identified. TNFSF11, KYNU, and HLA-DMB emerged as key genes. miRNAs, TFs, and drug predictions offered therapeutic insights. Molecular docking suggested 17-beta-estradiol and vitamin D3 as potential treatments. Conclusion: The study clarifies shared mechanisms of osteoporosis and aortic valve calcification, identifies biomarkers, and highlights TNFSF11, KYNU, and HLA-DMB. It also suggests 17-beta-estradiol and vitamin D3 as potential effective treatments.

Abstract 4140121: Lipoprotein(a) Local Sybthesis And Plasma Uptake Via MDFS5 in Human Calcified Valve

Background: High circulating levels of lipoprotein(a) [Lp(a)] are associated with increased risk of calcific aortic stenosis (CAS). Targeting Lp(a) metabolism holds promise for therapeutic interventions. However, the precise mechanisms by which Lp(a) accumulates on aortic valves still not fully understood. Hypothesis: Lp(a) could be synthesized in situ in human aortic valves under specific stimuli, such as calcification, in addition to being taken up from plasma via membrane receptors, including the newly identified receptor Major Facilitator Superfamily Domain Containing 5 (MFSD5). Methods: Immunohistochemistry was used to detect the Lp(a) and its receptor MFSD5 in human aortic valves from CAS patients or controls, which were non-CAS patients. Plasma Lp(a) levels were measured in individuals undergoing aortic valve resection. Human valvular interstitial cells (VICs) were cultured in procalcifying medium, with or without Lp(a) (10uM) for 14 and 21 days. Von-kossa or Alizarin Red staining were used to assess valve calcification. Expression of Lp(a) and MFSD5 was analyzed with quantitative RT-PCR and western blot. Results: Lp(a) was nearly absent in control valve site, whereas it was abundantly present in valve site from CAS patients (p＜0.05). The higher the level of Lp(a) detected, the greater the extent of calcification noted in valve site. The mRNA and protein levels of Lp(a) extracted from calcified human valves were significantly higher compared to controls. However, the concentration of plasma Lp(a) did not affect the expression of Lp(a) in valve site (p＞0.05). In vitro studies showed that Lp(a) mRNA was minimally detectable in normal VICs, but was significantly upregulated following exposure to procalcifying medium (p &lt; 0.05). Lp(a) incubation led to severer calcification than that induced by procalcifying medium alone (p &lt; 0.05). As MFSD5 was a newly identified receptor of Lp(a), we also test its expression. MDFS5 was increased in human calcified valve (p＜0.05) and calcified VICs (p＜0.05). These results showed that the Lp(a) in valve could be increased by either uptake from serum or by synthesized locally by proper stimuli. Conclusion: Our study has shown that the degree of aortic valve calcification is correlated with the level of Lp(a) in the valve site rather than in serum. We also verified MFSD5 was the receptor of Lp(a) on human valve. Targeting Lp(a) accumulation at the valve site may offer a more effective strategy for the prevention or treatment of CAS.

Abstract 4134841: A Diagnostic Pitfall: Subclavian Stenosis Mimicking Severe Aortic Stenosis on Echocardiography"

Background: Aortic stenosis (AS) is a common and serious valve disease in the elderly, often diagnosed using echocardiography. However, certain conditions can mimic AS, leading to diagnostic challenges. This case highlights the importance of a comprehensive vascular assessment in patients with atypical symptoms and echocardiographic findings suggestive of severe AS. Case Presentation: An 80-year-old female presented with progressive dizziness and double vision over the past few months. She reported a long-standing history of lower blood pressure in her right arm compared to her left. Her medical history was significant for HER2-positive intraductal breast cancer treated with neoadjuvant chemotherapy. An echocardiogram performed two months prior to presentation, using a Pedoff probe, indicated severe AS with a peak systolic velocity of 5.1 m/sec, a mean systolic gradient of 50 mm Hg, and an aortic valve area of 0.6 cm. Investigations: Given the discrepancy in blood pressure between her arms and the wide open aortic valve on the echo which dosen't corrleate with the doppler numbers, CTA neck and chest was performed, revealing a dense calcific plaque causing severe stenosis at the origin of the left subclavian artery. An angiogram confirmed &gt;75% stenosis of the left subclavian artery, which was treated with angioplasty and stent placement, resulting in &lt;10% residual stenosis. Outcome: Following the intervention, a repeat echocardiogram showed only mild calcification of the aortic valve with a mean gradient of 4 mm Hg, significantly lower than the previous findings. Discussion: This case underscores the potential for subclavian artery stenosis to mimic severe AS on echocardiography, particularly when using the Pedhoff probe. It highlights the need for clinicians to consider vascular anomalies in the differential diagnosis when echocardiographic doppler findings do not correlate with clinical symptoms or with the structural apperance of the valves. Conclusion: Comprehensive assessment and consideration of alternative diagnoses are crucial in patients with suspected severe AS, especially when using Doppler echocardiography. Awareness of the potential for subclavian artery stenosis to cause false-positive echocardiographic findings can prevent unnecessary interventions and guide appropriate management.

Abstract 4113301: A Rare Cause of Recurrent Heart Failure Exacerbations After Transcatheter Aortic Valve Replacement: Ventricular Septal Defect and Significant Paravalvular Leak

Introduction: Ventricular septal defects (VSD) have been reported in &lt;1% of cases following transcatheter aortic valve replacement (TAVR). A retrospective record review of VSD cases occurring after all TAVRs performed between January 2012 and September 2020 at one urban US tertiary hospital showed 0.37% incidence of these complications, mostly with small and restrictive VSD. Case Description: An 80-year-old woman with history of hypertension, HFpEF, and TAVR 8 months prior for severe aortic stenosis (AS) at an outside hospital presented with worsening dyspnea and peripheral edema over the past month. Blood pressure was 148/53mmHg, heartrate 83bpm, oxygen saturation 98% and auscultation revealed a harsh holosystolic murmur 4/6 loudest at left sternal border and bibasilar rales. Chest X-ray showed pulmonary edema and bilateral pleural effusions. NT-proBNP was 17,000pg/ml and troponin-I was negative. Echocardiogram showed EF55-60%, a membranous VSD, severe pulmonary hypertension, and moderate paravalvular leak (PVL). Coronary angiogram showed non-obstructive disease. Right heart catheterization confirmed significant left to right shunting. Treatment/Outcomes: Cardiothoracic surgery was consulted for multidisciplinary evaluation, and joint recommendation was for surgical aortic valve replacement and VSD closure which was successfully performed. One month follow-up echocardiogram showed normal aortic valve gradient without PVL and normal right ventricular pressure. Discussion/Conclusion: Numerous potential risks such as severe and uneven calcification of the native valve, an elliptic aortic annulus, excessive valve sizing, or elevated valve placement can lead to VSD. A recurrent element in many of these instances involves direct trauma to the septum caused by the implanted valve, exacerbated by subsequent annulus dilation. The presence of PVL is common post-TAVR and is an established independent prognostic factor, while VSD post-TAVR is uncommon, but may be associated with low implantation position relative to the aortic annulus or post-implantation balloon dilatation. Rarely, worsening VSD may require operative management. In this case, the improvement of heart failure symptoms and echocardiogram parameters after transthoracic surgery confirmed successful repair.

Abstract 4135059: Enhanced Expression of iNOS is Associated with Aortic Valve Stenosis in Patients Undergoing Hemodialysis

Background: Patients undergoing hemodialysis (HD) have a greater prevalence of aortic valve calcification and aortic valve stenosis (AS). High prevalence and rapid progression of AS have been reported in patients undergoing HD. However, the precise mechanism of the relationship between HD treatment and rapid development of AS is still unknown. Several findings suggest a pivotal role for oxidative stress in the progression and acceleration of atherosclerosis in patients undergoing HD. A considerable number of human diseases have an inflammatory component, and a key mediator of immune activation and inflammation is inducible nitric oxide synthase (iNOS). Overexpressed iNOS has been implicated in numerous pathogenetic processes, including coronary plaque destabilization. To elucidate the role of iNOS in the aortic valve of patients with AS, we studied its presence in aortic valve specimens from patients with AS undergoing HD. Methods: We enrolled 32 patients undergoing HD and 42 patients not undergoing HD who had severe AS and underwent AVR. Valve samples were analyzed immunohistochemically with antibodies against macrophages, microvessels, iNOS and 4-hydroxy-2-nonenal (4-HNE), an index of lipid peroxidation. Immunoreactivity was quantified with computer-aided polarimetry. Double immunostaining was also performed to identify cell types that stained positive for iNOS. Results: Quantitative analysis demonstrated that macrophage-, iNOS-, and 4-HNE-positive areas, as well as the number of microvessels, were significantly higher in patients with AS undergoing HD (macrophages, P &lt;0.001; microvessels, P &lt;0.05; 4-HNE, P &lt;0.05; iNOS , P &lt;0.001). iNOS-positive areas were positively correlated with 4-HNE-positive areas (R=0.71, P &lt;0.0001). Double immunostaining for both iNOS and macrophages identified iNOS-positive cells as macrophages. Conclusions: These findings indicate that accumulation of iNOS in macrophages may increase oxidative stress and contribute to the rapid progression of AS in patients undergoing HD.

Abstract 4140136: Aortic Valve Calcification Density Performs Better Compared to Absolute Aortic Valve Calcification in Aortic Stenosis Risk Stratification

Aortic valve calcification (AVC) scores can be used to stratify aortic stenosis (AS) severity. Current practice guidelines recommend use of absolute AVC scores without considering body surface area or aortic annulus size. We investigated whether size variation in aortic annular area should be considered in identifying optimal AVC cutoffs for patients with severe AS. This was a retrospective analysis of AS patients that underwent AVC assessment during 2018-2023. Outcomes were composite of valve intervention or all-cause mortality. AVC density was defined by dividing AVC by echo-derived left ventricular tract area. Receiver operator curve analysis determined optimal AVC density scores. Absolute AVC cutoffs of &gt;1200AU for females and &gt;2000AU for males were used to identify severe AS. The study included 749 patients (mean age 78 years, 46% female). Median CT-annulus area was larger for males compared with females (532mm 2 [Q1, Q3: 479, 582] vs. 413mm 2 [370, 458], p&lt;0.001). There was a strong association of absolute AVC with CT-annulus area for both males and females (Spearman coefficient: 0.87 and 0.83, p&lt;0.01 each) respectively (Figure 1). The optimal AVC density cutoffs for males and females were 427 and 326, respectively (accuracy 76%, sensitivity 83%, specificity 51%). Composite outcomes were better differentiated with AVC density (males: HR 2.48, 95% CI: 1.82-3.37, p&lt;0.001; females: HR 2.37 (1.71-3.28), p&lt;0.001) compared with absolute AVC scores (males: HR 1.81 (1.43-2.30), p&lt;0.001; females: HR 2.11 (1.62-2.74), p&lt;0.001) (Figure 2). AVC is strongly associated with CT-annulus area and risk stratification is improved with the use of AVC density compared with absolute AVC. This may be especially helpful in patients with extremes of annulus area sizes.

Abstract 4138348: Mechanical stress-mediated nuclear envelope damage promotes Aortic Valve Calcification through the ZBP1-RIPK3-NF-κB signaling axis

Methods and Results: We describe a comprehensive characterization of the AVICs nucleus landscape as determined by transmission electron microscopy (TEM) of samples obtained from CAVD patients. Turbulence led to nuclear envelope integrity lose in AVICs cultured in shear stress experiments, with three different fluid conditions [static (ST), laminar stress (LS), and oscillatory stress (OS)], indicated by Western blot and immunofluorescence (IF). Silencing lamin A/C (LMNA) through small interfering RNA (siRNA), accelerated nuclear envelope damage , as indicated by Western blot, qPCR, and immunofluorescence (IF). The formation of Z-DNA and its co-localization with Z-DNA binding protein (ZBP1) was observed due to the nuclear envelope damage by IF. Western blot, qPCR, IHC and IF confirmed Z-DNA-induced inflammation in AVICs through the ZBP1-RIPK3-NF-κB signaling pathway. ZBP1 and RIPK3 knockdown with siRNA markedly reduced the protein level of osteogenic markers alkaline phosphatase (ALP), runt-related transcription factor 2 (RUNX2), and bone morphogenetic protein 2 (BMP2) in VICs. In vivo, aortic valve disease was constructed by direct wire injury (DWI), and we showed that overexpression of LMNA by adeno-associated virus significantly decelerated the progression of aortic valve lesion induced by DWI in mice. Conclusion: Excessive mechanical stress can induce damage to the nuclear envelope of AVICs by causing cytoskeletal remodeling, initiating the formation of Z-DNA, and hastening the calcification process in AVICs and CAVD.

Abstract 4138340: Cav-1/FGF2 Axis Mediates Endothelial-Mesenchymal Transition Promoting Aortic Valve Calcification

Background: Calcific Aortic Valve Disease is a common cardiac condition with no effective medication available; severe cases require surgery. Endothelial-to-mesenchymal transition is a key pathological process, yet the genetic regulatory mechanisms involved remain unclear. Research Questions: Investigating the mechanism of Cav-1/FGF2 axis-mediated endothelial-mesenchymal transition in aortic valve calcification. Methods: Histopathology, immunohistochemical staining, and western blot analysis were performed on 5 non-calcified and 5 calcified aortic valves. Proteomic sequencing was conducted on these samples. Single-cell RNA sequencing on 3 calcified aortic valves focused on valve endothelial and interstitial cells to explore key genes and functions in EndoMT. In vivo and in vitro experiments, along with single-cell multi-omics sequencing, elucidated the role and mechanism of the Cav-1/FGF2 axis in EndoMT using endothelial cell-specific EndoMT knockout mouse models and cell models. Results: Proteomics and single-cell sequencing results indicated that Cav-1 is involved in the Endothelial-to-mesenchymal transition process in Calcific Aortic Valve Disease. Cav-1 plays a crucial role in the intermediate transition of EndoMT, interacting significantly with FGF2. Immunohistochemical staining showed high expression of Cav-1 in calcified aortic valves. In vitro experiments demonstrated that Cav-1 mediates Endothelial-to-mesenchymal transition in valve endothelial cells, promoting aortic valve calcification. Molecular docking analysis revealed potential direct interaction between Cav-1 and FGF2 proteins. Elevated Cav-1 gene expression increases the number of cell surface caveolae, enhancing cell surface area, which promotes FGF2 binding to its receptor and activates the TGF-beta receptor, both of which facilitate EndoMT through the Smad pathway. Conclusion(s): Activation of the Cav-1/FGF2 axis promotes endothelial-mesenchymal transition, thereby promoting aortic valve calcification.

Abstract 4138306: Impact of Early Menopause and Hormonal Replacement Therapy on Aortic Stenosis Progressio

Background: Early menopause is associated with an increased risk of cardiovascular disease and mortality in women. The present study aimed to examine the impact of early menopause and hormonal replacement therapy (HRT) on the progression of aortic stenosis (AS). Methods: Thirty-three postmenopausal women (mean age 65 ± 10 years) with mild or moderate AS prospectively recruited in the PROGRESSA study (NCT01679431) were included in this sub-analysis. All patients underwent multidetector computed tomography and Doppler-echocardiography at least twice during follow-up to assess both anatomic and hemodynamic AS severity, based on aortic valve calcification (AVC), mean pressure gradient (MG), and aortic valve area indexed to body surface area (AVA). Annualized changes in AVC, MG and AVAi were calculated between baseline and the last follow-up. Results: Over a median follow-up of 2 [1-4] years, early menopausal women had a faster progression rate of AVC, MG, and AVAi compared to other women: (100[58-130] vs. 23[2-71] AU/year, p=0.03); (2.37[0.82-3.61] vs. 0.31[0.01-1.78] mmHg/year, p=0.04); and (-0.12[-0.23-0.002] vs. -0.004[-0.07-0.08] cm 2 /m 2 /year, p=0.08) respectively. In multivariate analysis adjusted for age, AS severity at baseline, and comorbidities, early menopause remained significantly associated with faster AVC progression (p=0.003). Moreover, after comprehensive adjustment, women who received HRT (45%) had a slower progression rate of AVC (20[10-42] AU/year vs. 62[2-100], adjusted p=0.04). Conclusion: Early menopause is associated with faster progression of AS, both anatomically and hemodynamically. However, the use of HRT is associated with slower progression of AS. Integrating female-specific risk factors, particularly menopausal history and hormonal therapy status, into the clinical management of AS could enhance patient care.

Abstract 4136289: Aortic Valve Calcium as a Predictor of Chronic Kidney Disease in a Multi-Ethnic Cohort: The MESA Study

Background: Aortic valve calcium (AVC) is associated with an increased risk of cardiovascular disease, non-cardiovascular disease such as dementia, and all-cause mortality. Traditional atherosclerotic cardiovascular disease risk factors are associated with both AVC and chronic kidney disease (CKD), but whether there is an association between AVC and CKD is unknown. Objectives: To ascertain whether AVC quantified by cardiac CT scanning is independently associated with the long-term risk of incident CKD among individuals without a previous history of cardiovascular disease. Methods: We examined 6,346 Multi-Ethnic Study of Atherosclerosis (MESA) participants who underwent cardiac CT scanning at Visit 1 (2000-02) and had an eGFR of ≥ 60 mL/min/1.73 m 2 . AVC was quantified using the Agatston method and categorized as 0, 1-99, and ≥100. Incident CKD was defined as an eGFR &lt; 60 mL/min/1.73 m 2 accompanied with an at least 40% decline in eGFR from baseline, and/or a diagnosis of CKD and indicators of end stage renal disease extracted from hospital records using the International Classification of Disease (ICD) codes. We performed Kaplan-Meier survival curve analyses along with multivariable Cox proportional hazard regression models, adjusted for age, gender, race/ethnicity, highest level of education and traditional cardiovascular risk factors along with coronary artery calcium (CAC), lipoprotein (a) (Lp[a]), and the APOE-ε4 genotype to examine the association between AVC (categorical and log-transformed) and incident CKD. Results: Participants had a mean age 62.2±10.1 years, 53% were women, and AVC &gt;0 was present in 795 (12%) participants. During a median follow-up time of 16.9 years, 982 (15%) participants developed incident CKD. AVC examined as a continuous variable was associated with a significantly increased risk of developing CKD (per log-unit [AVC+1] HR 1.06 [95% CI: 1.02-1.10]; p = 0.005). There was a stepwise increased risk for CKD with higher AVC levels ( Figure ). Similarly, in the multivariable adjusted Cox models, participants with AVC ≥100 had a higher risk of incident CKD, compared with the AVC=0 group (HR 1.48 [95% CI: 1.15-1.89]; p = 0.002). The observed associations remained after further adjusting for CAC score ( p = 0.024), Lp (a) ( p = 0.004), and the APOE-ε4 genotype ( p = 0.004). Conclusions: In a multi-ethnic cohort of participants free of CKD at baseline, AVC was independently associated with a higher risk of incident CKD.

Abstract 4119560: Oxidized Phospholipids and Calcific Aortic Valvular Disease

Introduction: Oxidized phospholipids (OxPL) are carried by apolipoprotein B-100-containing lipoproteins (OxPL-apoB) including lipoprotein(a) [Lp(a)]. Both OxPL-apoB and Lp(a) have been associated with calcific aortic valve disease (CAVD). Aims: We aimed to evaluate the independent associations between OxPL-apoB, Lp(a) and the prevalence, incidence, and progression of CAVD. Methods: OxPL-apoB and Lp(a) were evaluated in the Multi-Ethnic Study of Atherosclerosis (MESA) and a participant-level meta-analysis of four randomized trials of participants with established aortic stenosis (AS). In MESA, the association of OxPL-apoB and Lp(a) with aortic valve calcium (AVC) at baseline and 9.5 years was evaluated using multivariable ordinal regression models. In the meta-analysis, the association between OxPL-apoB and Lp(a) with AS progression (annualized change in peak aortic valve jet velocity (V max )) was evaluated using multivariable linear regression models. Results: In MESA, both OxPL-apoB and Lp(a) were independently associated with prevalent AVC (OR (95% CI) per SD: 1.19 (1.07-1.32) and 1.13 (1.01-1.27), respectively) with a significant interaction between the two (p&lt;0.01). Both OxPL-apoB and Lp(a) were associated with incident AVC at 9.5 years when evaluated independently (interaction p&lt;0.01). The OxPL-apoB*Lp(a) interaction demonstrated higher odds of prevalent and incident AVC for OxPL-apoB with increasing Lp(a) levels. Mediation analyses demonstrated that Lp(a) partially mediated the association between OxPL-apoB and AVC. In a 2x2 analysis, the greatest risk for both prevalent and incident AVC was observed when Lp(a) and OxPL-apoB were both above the 80 th percentile ( Figure ). In the meta-analysis, when analyzed separately, both OxPL-apoB and Lp(a) were independently associated with faster increase in V max , but when evaluated together, only OxPL-apoB remained significant (ß 0.07, 95% CI 0.01-0.12, Figure ). Conclusions: OxPL-apoB is an independent predictor of the presence, incidence and progression of AVC and established AS, particularly in the setting of elevated Lp(a) levels and may represent a novel therapeutic target for CAVD.

Abstract 4117772: Age-Related Differences in Aortic Valve Calcium Progression and the Risk for Aortic Stenosis: Multi-Ethnic Study of Atherosclerosis

Background: Aortic valve calcium (AVC) is strongly associated with an increased risk for severe aortic stenosis (AS). The prevalence of AVC increases with age affecting 40-50% of individuals ≥80 years. The impact of age on the progression of AVC and its association with incident AS remains unknown. Methods: Our study included 6,810 participants (52.9% women) free of cardiovascular disease between ages 45 and 84 from the Multi-Ethnic Study of Atherosclerosis. AVC was measured using non-contrast cardiac CT at Visit 1. Progression was calculated as the change in AVC divided by years between CT scans with up to 10 years between scans. Long term incident AS was adjudicated using medical chart review and echocardiogram data from Visit 6 with a median follow up of 16 years. Multivariable adjusted 1) linear regression was used to examine AVC progression and 2) multivariable adjusted Cox proportional hazards ratios (HR) were used to examine the association of AVC with incident AS. Results: The prevalence of AVC &gt;0 was 4.9% among participants &lt;65 and 23.2% for those ≥65 years old. Among participants with AVC &gt;0, the median AVC was 34.1 (IQR 13-1,113) for participants &lt;65 versus 69.0 (IQR 23-2,453) for participants ≥65. Participants &lt;65 years and ≥65 years had no significant difference in median annualized AVC progression within the baseline AVC categories of 1-99 (10 versus 12 AU/year, p=0.303) and AVC &gt;100 (50 versus 47 AU/year, p=0.846) ( Figure 1 ). Overall, linear regression models showed older age was associated with greater AVC progression (p=0.001), but after additional adjustment for baseline AVC, the association became non-significant (p=0.134). AVC &gt;0 was associated with significantly increased risk of incident AS for both younger (HR 13.37; 95% CI 5.67-31.52) and older participants (HR 10.59, 95% CI 6.77-16.56). Conclusion: We observed a similar progression of AVC for younger versus older persons after adjusting for baseline AVC burden. Additionally, AVC &gt;0 independently conferred at least a ten-fold higher risk for severe AS among both younger and older participants. These findings demonstrate that the AVC progression is primarily associated with baseline AVC burden and that AVC is a strong marker of risk for severe AS for both younger and older persons.

Abstract 4135861: Lipoprotein(a) and Its Impact on Left Ventricular Remodeling Over a Decade: The Multi-Ethnic Study of Atherosclerosis

Background: Lipoprotein (a) (Lp[a]) is associated with an increased risk of cardiovascular disease and mortality, as well as heart failure and myocardial fibrosis. However, the link between Lp(a) and cardiac remodeling as a pathway to adverse cardiac outcomes remains unknown. Objectives: This study investigated the relationship between Lp(a) levels and longitudinal changes in the left ventricular (LV) remodeling over a decade among individuals without a previous history of cardiovascular disease. Methods: 2,366 Multi-Ethnic Study of Atherosclerosis (MESA) participants who underwent cardiac MRI at Visit 1 (2000-02) and Visit 5 (2010-12) and had available Lp(a) at baseline were examined. Lp(a) was analyzed as a continuous and a categorical variable based on quartiles (Q1[&lt;7.6 mg/dL], Q2[7.6-16.7 mg/dL], Q3[16.8-38.8 mg/dL], Q4[&gt;38.8 mg/dL]). Multivariable linear regression analysis was used to examine the association of Lp(a) with changes in cardiac MRI measures of LV remodeling ( Table ). Results: Participants had a mean age 60±9 years and 53% were women. Over 10-year follow-up, LV indexed volumes decreased, while LV indexed mass and mass to volume ratio increased across all the Lp(a) quartiles. However, LV ejection fraction only decreased in the third and fourth Lp(a) quartiles. Lp(a) examined as a continuous variable was associated with an increase in LV end-systolic indexed volume (per log-unit Lp[a]; β 0.32 mL/m 2 ; P = 0.01), LV indexed mass (per log-unit Lp[a]; β 0.38 g/m 2 ; P = 0.02), and a decrease in LV ejection fraction (per log-unit Lp[a]; β -0.29 %; P = 0.02) over 10 years after adjusting for sociodemographic and traditional cardiovascular risk factors ( Table ). Similarly, the fourth Lp(a) quartile was associated with an increase in LV end-systolic indexed volume (β 1.07 mL/m 2 ; P = 0.01), LV indexed mass (β 1.17 g/m 2 ; P = 0.02) and a decrease in LV ejection fraction (β -1.01 %; P = 0.01) compared to the first Lp(a) quartile after controlling for risk factors. The observed associations remained significant after further adjusting for aortic valve calcium score at Visit 1 ( Table - Model 3), and baseline coronary artery calcium score and interim myocardial infarction ( Table - Model 4). Conclusions: In a multi-ethnic cohort of participants free of cardiovascular disease at baseline, higher Lp(a) levels were independently associated with an increase in LV end-systolic volume and LV mass as well as a decrease in LV ejection fraction over the span of a decade.

Association of Self-Expanding Valves with Increased Capture of Larger Debris by Cerebral Protection System in Transcatheter Aortic Valve Replacement for Severe Aortic Stenosis.

Mixed evidence exists regarding stroke rates when comparing self-expanding valves (SEVs) to balloon-expandable valves (BEVs) in transcatheter aortic valve replacement (TAVR). This study investigates the debris captured by the SENTINEL cerebral protection system (CPS) during TAVR. Seventy-five consecutive patients who underwent TAVR with CPS from March to December 2023 were recruited. Collected debris underwent histopathologic analysis, categorized by size (< 2 mm, 2-5 mm, > 5 mm) and quantity. Logistic regression analysis was used to identify predictors for the presence of particles > 5 mm in size. Of the 75 patients, 39 received SEVs and 36 received BEVs. Baseline characteristics were similar between the groups. The BEV group had significantly more frequent concomitant percutaneous coronary interventions (p = 0.013), while the SEV group had longer TAVR procedure (p = 0.019) and fluoroscopy times (p = 0.006). All patients had visible debris, predominantly valve tissue (SEV vs. BEV = 79.8% vs. 47.2%; p = 0.308), calcification (SEV vs. BEV = 23.1% vs. 36.1%; p = 0.215), and thrombus (SEV vs. BEV = 15.4% vs. 5.6%; p = 0.855). No significant differences were observed in particle count and particle size < 5 mm between the SEV and BEV groups. However, logistic regression analysis revealed that the patients who received SEVs had a 16.78-fold increased likelihood of having captured debris > 5 mm compared to those who received BEVs. Our study demonstrated that significantly more particles sized > 5 mm were captured by the CPS during TAVR in the SEV group, underscoring the importance of using the CPS during TAVR, especially in younger patients receiving SEVs.

Volumen de calcificación de la válvula aórtica y su pronóstico en pacientes sometidos a implante percutáneo de válvula aórtica

Introduction and objectivesIt is unknown whether aortic valve calcium volume, as measured by contrast-enhanced computed tomography angiography (angio-CT), is associated with mortality in patients undergoing transcatheter aortic valve implantation (TAVI). We aimed to confirm that contrast-enhanced aortic valve calcium correlates with noncontrast-enhanced calcium score and provides useful prognostic information in patients undergoing TAVI. MethodsThis retrospective observational study included patients from 2 high-volume TAVI centers in Germany, all of whom underwent high-quality angio-CT prior to TAVI. Calcium volume in contrast-enhanced angio-CT was calculated using 3Mensio software (Pie Medical, The Netherlands), while the calcium score from noncontrast-enhanced angio-CT was obtained using the Syngo.via (Siemens Healthineers, Germany) workstation to validate contrast-enhanced angio-CT values. Calcium volume was dichotomized using the median based on to sex-specific values from contrast-enhanced angio-CT, and the risk associated with increased calcium volume was determined using Cox proportional hazard regression analysis. ResultsWe included 3318 TAVI patients. A good correlation was observed between noncontrast-enhanced and contrast-enhanced angio-CT (r2=0.680; P<.001). The median values for sex-specific contrast-enhanced angio-CT calcium volume were 514 mm3 for women and 1025 mm3 for men. Patients with higher calcium volumes showed lower mortality at 1 year (8.8% vs 12.1%; adjusted HR, 0.86; 95%CI, 0.75-0.98; P=.02) compared with those with lower calcium volumes. ConclusionsCalcium volume in contrast-enhanced angio-CT correlated well with noncontrast-enhanced angio-CT calcium score. Patients with higher calcium volume showed lower mortality at 1 year after TAVI.

Impact of sex-specific thresholds for low flow in assessment of prognosis in concordantly and discordantly graded aortic valve stenosis.

Sex-specific low flow was recently defined as stroke volume index (SVi) ≤40 ml/m² in men and ≤32 ml/m² in women. We tested the prognostic association of these cut-offs in patients with aortic stenosis (AS) with concordantly and discordantly graded AS (CGASEL and DGASEL) based on pressure recovery adjusted aortic valve area (energy loss, EL). Data from 1351 patients with asymptomatic AS, peak jet velocity <4m/s and preserved left ventricular ejection fraction enrolled in the Simvastatin and Ezetimibe in AS study was used. DGASEL was defined as EL <1.0 cm² with mean aortic gradient <40 mmHg, and CGASEL as EL ≥1.0 cm² with mean aortic gradient <40mmHg. Patients were further grouped into normal and low flow. Outcome was combined all-cause death and hospitalization for heart failure. CGASEL with normal/low flow was present in 915/253 patients, and DGASEL with normal/low flow in 57/126 patients. During median 4.3 years follow-up, event-free survival was lower in patients with DGASEL irrespective of flow compared to CGASEL with normal flow (p<0.05). In Cox regression analysis, DGASEL with normal or low flow were both associated with increased risk of all-cause death and hospitalization for heart failure after adjustment for age, sex, heart rate, randomized study treatment, hypertension, aortic valve replacement and aortic valve calcification (p<0.05). No survival difference was found between patients with normal vs. low flow within groups of DGASEL or CGASEL. Identification of low flow by the proposed sex-specific thresholds of SVi needs more prognostic validation before application in clinical practice.