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Importance: There are currently no pharmacological treatments available to slow hemodynamic progression of aortic stenosis. Plasma lipoprotein(a) concentrations predict incident aortic stenosis but its association with hemodynamic progression is controversial., Objective: To determine the association between plasma lipoprotein(a) concentrations and hemodynamic progression in patients with aortic stenosis., Design, Settings and Participants: The study included patients with aortic stenosis from 5 longitudinal clinical studies conducted from March 2001 to March 2023 in Canada and the UK. Of 757 total patients, data on plasma lipoprotein(a) concentrations and rates of hemodynamic progression assessed by echocardiography were available for 710, who were included in this analysis. Data were analyzed from March 2023 to April 2024., Exposure: Cohort-specific plasma lipoprotein(a) concentration tertiles., Main Outcomes and Measures: Hemodynamic aortic stenosis progression on echocardiography as assessed by annualized change in peak aortic jet velocity, mean transvalvular gradient, and aortic valve area., Results: Among the included patients, 497 (70%) were male and 213 (30%) were female. The mean (SD) age was 65.2 (13.1) years. Patients in the top lipoprotein(a) tertile demonstrated 41% (estimate, 1.41; 95% CI, 1.13-1.75) faster progression of peak aortic jet velocity and 57% (estimate, 1.57; 95% CI, 1.18-2.10) faster progression of mean transvalvular gradient than patients in the bottom tertile. There was no evidence of heterogeneity across the individual cohorts. Progression of aortic valve area was comparable between groups (estimate, 1.23; 95% CI, 0.71-2.12). Similar results were observed when plasma lipoprotein(a) concentrations were treated as a continuous variable., Conclusions and Relevance: In this study, higher plasma lipoprotein(a) concentrations were associated with faster rates of hemodynamic progression in patients with aortic stenosis. Lowering plasma lipoprotein(a) concentrations warrants further investigation in the prevention and treatment of aortic stenosis.

Background: Aortic valve calcification (AVC), Lp(a) [lipoprotein(a)], and low-density lipoprotein cholesterol (LDL-C) are associated with severe aortic stenosis (AS). We aimed to determine which of these risk factors were most strongly associated with the risk of incident severe AS., Methods: A total of 6792 participants from the MESA study (Multi-Ethnic Study of Atherosclerosis) had computed tomography-quantified AVC, Lp(a), and LDL-C values at MESA visit 1 (2000-2002). We calculated the absolute event rate of incident adjudicated severe AS per 1000 person-years and performed multivariable adjusted Cox proportional hazards regression., Results: The mean age was 62 years old, and 47% were women. Over a median 16.7-year follow-up, the rate of incident severe AS increased exponentially with higher AVC, regardless of Lp(a) or LDL-C values. Participants with AVC=0 had a very low rate of severe AS even with elevated Lp(a) ≥50 mg/dL (<0.1/1000 person-years) or LDL-C ≥130 mg/dL (0.1/1000 person-years). AVC >0 was strongly associated with severe AS when Lp(a) <50 mg/dL hazard ratio (HR) of 33.8 (95% CI, 16.4-70.0) or ≥50 mg/dL HR of 61.5 (95% CI, 7.7-494.2) and when LDL-C <130 mg/dL HR of 31.1 (95% CI, 14.4-67.1) or ≥130 mg/dL HR of 50.2 (95% CI, 13.2-191.9)., Conclusions: AVC better identifies people at high risk for severe AS compared with Lp(a) or LDL-C, and people with AVC=0 have a very low long-term rate of severe AS regardless of Lp(a) or LDL-C level. These results suggest AVC should be the preferred prognostic risk marker to identify patients at high risk for severe AS, which may help inform participant selection for future trials testing novel strategies to prevent severe AS., Competing Interests: Disclosures None.

Objective: We aimed to investigate the effect of ambulatory blood pressure (BP) on aortic valve calcification (AVC) and coronary artery calcification (CAC), which are subclinical atherosclerotic diseases., Methods: In this population-based, cross-sectional study, we assessed office BP, mean ambulatory BP (24-h, awake, and asleep), and variability of ambulatory BP, as determined by the coefficient of variation (awake and asleep). AVC and CAC were quantified using an Agatston score (>0) based on computed tomography scanning. We calculated relative risks (RRs) and 95% confidence intervals (CIs) with a 1-standard deviation increment in each BP index for the presence of AVC and CAC using a multivariate-adjusted Poisson regression with robust error variance., Results: Of 483 participants (mean age: 66.8 years), 154 (31.9%) and 310 (64.2%) had AVC and CAC, respectively. The presence of AVC was associated with office systolic BP (SBP; RR, 1.15; 95% CI, 1.03-1.28), awake diastolic BP (DBP) variability (RR, 1.12; 95% CI, 1.01-1.25), and asleep SBP variability (RR, 1.14; 95% CI, 1.03-1.27). The presence of CAC was associated with office SBP (RR, 1.08; 95% CI, 1.01-1.15), mean 24-h SBP (RR, 1.10; 95% CI, 1.04-1.16), mean awake SBP (RR, 1.11; 95% CI, 1.04-1.17), mean asleep SBP (RR, 1.07; 95% CI, 1.01-1.13), and asleep SBP variability (RR, 1.07; 95% CI, 1.01-1.13)., Conclusion: These findings highlight the association of ambulatory BP indices with both AVC and CAC, but with different effects on their presences., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: High plasma lipoprotein(a) and high body mass index are both causal risk factors for calcific aortic valve disease., Objectives: This study sought to test the hypothesis that risk of calcific aortic valve disease is the highest when both plasma lipoprotein(a) and body mass index are extremely high., Methods: From the Copenhagen General Population Study, we used information on 69,988 randomly selected individuals recruited from 2003 to 2015 (median follow-up 7.4 years) to evaluate the association between high lipoprotein(a) and high body mass index with risk of calcific aortic valve disease., Results: Compared with individuals in the 1st to 49th percentiles for both lipoprotein(a) and body mass index, the multivariable adjusted HRs for calcific aortic valve disease were 1.6 (95% CI: 1.3-1.9) for the 50th to 89th percentiles of both (16% of all individuals) and 3.5 (95% CI: 2.5-5.1) for the 90th to 100th percentiles of both (1.1%) (P for interaction = 0.92). The 10-year absolute risk of calcific aortic valve disease increased with higher lipoprotein(a), body mass index, and age, and was higher in men than in women. For women and men 70-79 years of age with body mass index ≥30.0 kg/m 2 , 10-year absolute risks were 5% and 8% for lipoprotein(a) ≤42 mg/dL (88 nmol/L), 7% and 11% for 42-79 mg/dL (89-169 nmol/L), and 9% and 14% for lipoprotein(a) ≥80 mg/dL (170 nmol/L), respectively., Conclusions: Extremely high lipoprotein(a) levels and extremely high body mass index together conferred a 3.5-fold risk of calcific aortic valve disease. Ten-year absolute risk of calcific aortic valve disease by categories of lipoprotein(a) levels, body mass index, age, and sex ranged from 0.4% to 14%., Competing Interests: Funding Support and Author Disclosures This work was supported by Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark; the Novo Nordisk Foundation (grant NNF18OC0052893), Denmark; and Chief Physician Johan Boserup and Lise Boserup‘s Fund, Denmark. The Copenhagen General Population Study is supported by the Copenhagen County Foundation and Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark. Dr Kamstrup has served as a consultant for Silence Therapeutics. Dr Nordestgaard has served as a consultant and lecturer for AstraZeneca, Sanofi, Regeneron, Akcea, Amgen, Kowa, Denka, Amarin, Novartis, Novo Nordisk, Silence Therapeutics, and Esperion. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Human aortic valve interstitial cells (hAVICs) are a key factor in the pathogenesis of calcific aortic valve disease (CAVD). This research examines the role and mechanism of microRNA miR-138-5p in osteogenic differentiation of hAVICs., Methods: RT-qPCR analysis was applied for detecting miR-138-5p and RUNX2 expression in valve tissues of CAVD patients and controls. On completion of induction of osteogenic differentiation of hAVICs, and after overexpression or interference of miR-138-5p expression, the condition of osteogenic differentiation and calcification of hAVICs was confirmed using alkaline phosphatase staining and alizarin red staining. Subsequently, western blot was utilized to detect the expression of osteogenesis-related proteins OPN and ALP, and Wnt/β-catenin signaling pathway-related proteins. Finally, the relationship between miR-138-5p and RUNX2 was validated by dual-luciferase reporter assay and Pearson's correlation test., Results: Down-regulation of miR-138-5p was found in CAVD patients and during osteogenic differentiation of hAVICs. Overexpression of miR-138-5p contribute to the inhibition of osteoblast differentiation and calcium deposition in hAVICs, and of ALP and OPN protein expression. RUNX2 was a target gene of miR-138-5p, and it was negatively correlated with miR-138-5p in CAVD. Additionally, overexpression of RUNX2 could reverse the inhibitory effect of miR-138-5p on osteogenic differentiation of hAVICs., Conclusion: miR-138-5p can act as a positive regulator of osteogenic differentiation in CAVD patients to involve in inhibiting valve calcification, which is achieved through RUNX2 and Wnt/β-catenin signaling pathway., (© 2022. The Author(s).)

Background: Guidelines recommend measurement of the aortic valve calcification (AVC) score to help differentiate between severe and nonsevere aortic stenosis, but a paucity exists in data about AVC in the general population. The aim of this study was to describe the natural history of AVC progression in the general population and to identify potential sex differences in factors associated with this progression rate., Methods: Noncontrast cardiac computed tomography was performed in 1298 randomly selected women and men aged 65 to 74 years who participated in the DANCAVAS trial (Danish Cardiovascular Screening). Participants were invited to attend a reexamination after 4 years. The AVC score was measured at the computed tomography, and AVC progression (ΔAVC) was defined as the difference between AVC scores at baseline and follow-up. Multivariable regression analyses were performed to identify factors associated with ΔAVC., Results: Among the 1298 invited citizens, 823 accepted to participate in the follow-up examination. The mean age at follow-up was 73 years. Men had significantly higher AVC scores at baseline (median AVC score 13 Agatston Units [AU; interquartile range, 0-94 AU] versus 1 AU [interquartile range, 0-22 AU], P <0.001) and a higher ΔAVC (median 26 AU [interquartile range, 0-101 AU] versus 4 AU [interquartile range, 0-37 AU], P <0.001) than women. In the fully adjusted model, the most important factor associated with ΔAVC was the baseline AVC score. However, hypertension was associated with ΔAVC in women (incidence rate ratios, 1.58 [95% CI, 1.06-2.34], P =0.024) but not in men, whereas dyslipidemia was associated with ΔAVC in men (incidence rate ratio: 1.66 [95% CI, 1.18-2.34], P =0.004) but not in women., Conclusions: The magnitude of the AVC score was the most important marker of AVC progression. However, sex differences were significant; hence, dyslipidemia was associated with AVC progression only among men; hypertension with AVC progression only among women. Registration: URL: https://www.isrctn.com; Unique identifier: ISRCTN12157806.

Background: A small aortic annulus is associated with increased risk of prosthesis-patient mismatch (PPM) after transcatheter aortic valve implantation (TAVI). Whether specific transcatheter heart valve (THV) designs yield superior hemodynamic performance in these small anatomies remains unclear., Methods: Data from 8411 consecutive patients treated with TAVI from May 2012 to April 2019 at four German centers were retrospectively evaluated. A small aortic annulus was defined as multidetector computed tomography-derived annulus area < 400 mm 2 . TAVI was performed with a balloon-expanding intra-annular (Sapien-3, n = 288), self-expanding intra-annular (Portico, n = 110), self-expanding supra-annular (Evolut, n = 179 and Acurate-Neo, n = 428) and mechanically expanding infra-annular (Lotus, n = 64) THV according to local practice. PPM was defined as indexed effective orifice area ≤ 0.85cm 2 /m 2 ., Results: A small annulus was found in 1069 (12.7%) patients. PPM was detected in 38.3% overall with a higher prevalence after implantation of a balloon-expanding intra-annular or mechanically expanding infra-annular THV compared to self-expanding intra- and supra-annular THV. Multivariable analysis linked self-expanding THV (Evolut: Odds ratio [OR] 0.341, Acurate-Neo: OR 0.436, Portico: OR 0.291), postdilatation (OR 0.648) and age (OR 0.968) to lower rates of PPM, while aortic valve calcification was associated with an increased risk (OR 1.001). Paravalvular regurgitation > mild was more frequent after TAVI with self-expanding THV (p = 0.04)., Conclusion: In this large contemporary multicenter patient population, a substantial number of patients with a small aortic anatomy were left with PPM after TAVI. Self-expanding supra- and intra-annular THV demonstrated superior hemodynamics in these patients at risk, however at the cost of higher rates of residual paravalvular regurgitation., (© 2021. The Author(s).)

Objectives: Optimizing valve implantation depth (ID) plays a crucial role in minimizing conduction disturbances and achieving optimal functional integrity. Until now, the impact of intraprocedural fast (FP) or rapid ventricular pacing (RP) on the implantation depth has not been investigated. Therefore, we aimed to (1) evaluate the impact of different pacing maneuvers on ID, and (2) identify the independent predictors of deep ID., Methods: 473 TAVR patients with newer-generation self-expanding devices were retrospectively enrolled and one-to-one propensity-score-matching was performed, resulting in a matching of 189 FP and RP patients in each cohort. The final ID was analyzed, and the underlying functional, anatomical, and procedural conditions were evaluated by univariate and multivariate analysis., Results: The highest ID was reached under RP in severe aortic valve calcification and valve size 26 mm. Multivariate analysis identified left ventricular outflow (LVOT) calcification [OR 0.50 (0.31-0.81) p = 0.005*], a "flare" aortic root [OR 0.42 (0.25-0.71), p = 0.001*], and RP (OR 0.49 [0.30-0.79], p = 0.004*) as independent highly preventable predictors of a deep ID. In a model of protective factors, ID was significantly reduced with the number of protective criteria (0-2 criteria: - 5.7 mm ± 2.6 vs. 3-4 criteria - 4.3 mm ± 2.0; p < 0.0001*)., Conclusion: Data from this retrospective analysis indicate that RP is an independent predictor to reach a higher implantation depth using self-expanding devices. Randomized studies should prove for validation compared to fast and non-pacing maneuvers during valve delivery and their impact on implantation depth., Trail Registration: Clinical Trial registration: NCT01805739., Study Design: Evaluation of the impact of different pacing maneuvers (fast ventricular pacing-FP vs. rapid ventricular pacing-RP) on implantation depth (ID). After one-to-one-propensity-score-matching, independent protective and risk factors for a very deep ID beneath 6 mm toward the LVOT (< - 6 mm) were identified. Stent frame pictures as a courtesy by Medtronic ® . AVC aortic valve calcification., (© 2021. The Author(s).)

Objectives: Non-contrast CT aortic valve calcium scoring ignores the contribution of valvular fibrosis in aortic stenosis. We assessed aortic valve calcific and non-calcific disease using contrast-enhanced CT., Methods: This was a post hoc analysis of 164 patients (median age 71 (IQR 66-77) years, 78% male) with aortic stenosis (41 mild, 89 moderate, 34 severe; 7% bicuspid) who underwent echocardiography and contrast-enhanced CT as part of imaging studies. Calcific and non-calcific (fibrosis) valve tissue volumes were quantified and indexed to annulus area, using Hounsfield unit thresholds calibrated against blood pool radiodensity. The fibrocalcific ratio assessed the relative contributions of valve fibrosis and calcification. The fibrocalcific volume (sum of indexed non-calcific and calcific volumes) was compared with aortic valve peak velocity and, in a subgroup, histology and valve weight., Results: Contrast-enhanced CT calcium volumes correlated with CT calcium score (r=0.80, p<0.001) and peak aortic jet velocity (r=0.55, p<0.001). The fibrocalcific ratio decreased with increasing aortic stenosis severity (mild: 1.29 (0.98-2.38), moderate: 0.87 (1.48-1.72), severe: 0.47 (0.33-0.78), p<0.001) while the fibrocalcific volume increased (mild: 109 (75-150), moderate: 191 (117-253), severe: 274 (213-344) mm 3 /cm 2 ). Fibrocalcific volume correlated with ex vivo valve weight (r=0.72, p<0.001). Compared with the Agatston score, fibrocalcific volume demonstrated a better correlation with peak aortic jet velocity (r=0.59 and r=0.67, respectively), particularly in females (r=0.38 and r=0.72, respectively)., Conclusions: Contrast-enhanced CT assessment of aortic valve calcific and non-calcific volumes correlates with aortic stenosis severity and may be preferable to non-contrast CT when fibrosis is a significant contributor to valve obstruction., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

The early stages of aortic valve calcification (AVC) and coronary artery calcification (CAC) include shared ASCVD risk factors, yet there is considerable heterogeneity between the burden of AVC, and CAC. We sought to identify the markers associated with limited CAC among persons with significant AVC. There were 325 participants from the Multi-Ethnic Study of Atherosclerosis without clinical ASCVD and with AVC ≥100 Agatston units (AU) at Visit 1. Multivariable-adjusted prevalence ratios for limited CAC (0 to 99 AU) were calculated using modified Poisson regression. Participants had a mean age of 72.1 years, median AVC score of 209, and 34% were women. A total of 133 (41%) participants had CAC <100, of whom 46/133 had CAC = 0. Younger age (PR = 1.40, 95% CI: 1.22 to 1.62, per 10-years), female gender (PR = 1.68, 95% CI: 1.28 to 2.20), and low 10-year ASCVD risk (PR = 2.30, 95% CI: 1.85 to 2.85) were most strongly associated with limited CAC. Neither a normal lipoprotein(a) nor normal measures of inflammation were significantly associated with limited CAC. Lower serum phosphate (PR = 1.15, 95% CI: 1.01 to 1.31; per 0.5 mg/dl lower) and calcium-phosphate product (PR = 1.16, 95% CI: 1.02 to 1.34; per SD lower) were associated with an approximately 15% higher prevalence of limited CAC. In conclusion, more than 40% of persons with significant AVC had CAC. Beyond traditional risk factors, lower serum phosphate, and lower calcium-phosphate product were associated with a higher prevalence of limited CAC., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aortic valve calcium (AVC) is a strong predictor of aortic stenosis (AS) severity and is typically calculated by multidetector computed tomography (MDCT). We propose a novel method using pixel density quantification software to objectively quantify AVC by two-dimensional (2D) transthoracic echocardiography (TTE) and distinguish severe from non-severe AS. A total of 90 patients (mean age 76 ± 10 years, 75% male, mean AV gradient 32 ± 11 mmHg, peak AV velocity 3.6 ± 0.6 m/s, AV area (AVA) 1.0 ± 0.3 cm 2 , dimensionless index (DI) 0.27 ± 0.08) with suspected severe aortic stenosis undergoing 2D echocardiography were retrospectively evaluated. Parasternal short axis aortic valve views were used to calculate a gain-independent ratio between the average pixel density of the entire aortic valve in short axis at end diastole and the average pixel density of the aortic annulus in short axis (2D-AVC ratio). The 2D-AVC ratio was compared to echocardiographic hemodynamic parameters associated with AS, MDCT AVC quantification, and expert reader interpretation of AS severity based on echocardiographic AVC interpretation. The 2D-AVC ratio exhibited strong correlations with mean AV gradient (r = 0.72, p < 0.001), peak AV velocity (r = 0.74, p < 0.001), AVC quantified by MDCT (r = 0.71, p <0.001) and excellent accuracy in distinguishing severe from non-severe AS (area under the curve = 0.93). Conversely, expert reader interpretation of AS severity based on echocardiographic AVC was not significantly related to AV mean gradient (t = 0.23, p = 0.64), AVA (t = 2.94, p = 0.11), peak velocity (t = 0.59, p = 0.46), or DI (t = 0.02, p = 0.89). In conclusion, these data suggest that the 2D-AVC ratio may be a complementary method for AS severity adjudication that is readily quantifiable at time of TTE., (Published by Elsevier Inc.)

Objective: Aortic valve calcification (AVC) and coronary artery calcification (CAC) are predictors of cardiovascular disease (CVD), presumably sharing risk factors. Our objectives were to determine the prevalence and extent of AVC in a large population of men aged 60-74 years and to assess the association between AVC and cardiovascular risk factors including CAC and biomarkers., Methods: Participants from the DANish CArdioVAscular Screening and intervention trial (DANCAVAS) with AVC and CAC scores and without previous valve replacement were included in the study. Calcification scores were calculated on non-contrast CT scans. Cardiovascular risk factors were self-reported, measured or both, and further explored using descriptive and regression analysis for AVC association., Results: 14 073 men aged 60-74 years were included. The AVC scores ranged from 0 to 9067 AU, with a median AVC of 6 AU (IQR 0-82). In 8156 individuals (58.0%), the AVC score was >0 and 215 (1.5%) had an AVC score ≥1200. In the regression analysis, all cardiovascular risk factors were associated with AVC; however, after inclusion of CAC ≥400, only age (ratio of expected counts (REC) 1.07 (95% CI 1.06 to 1.09)), hypertension (REC 1.24 (95% CI 1.09 to 1.41)), obesity (REC 1.34 (95% CI 1.20 to 1.50)), known CVD (REC 1.16 (95% CI 1.03 to 1.31)) and serum phosphate (REC 2.25 (95% CI 1.66 to 3.10) remained significantly associated, while smoking, diabetes, hyperlipidaemia, estimated glomerular filtration rate and serum calcium were not., Conclusions: AVC was prevalent in the general population of men aged 60-74 years and was significantly associated with all modifiable cardiovascular risk factors, but only selectively after adjustment for CAC ≥400 AU., Trial Registration Number: NCT03946410 and ISRCTN12157806., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Elevated levels of lipoprotein(a) [Lp(a)] have been identified as an independent and causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and, more recently, calcific aortic valve disease (CAVD). CAVD is a slow, progressive disorder presenting as severe trileaflet calcification known as aortic valve stenosis (AS) that impairs valve motion and restricts ventricular outflow. AS afflicts 2% of the aging population (≥ 65 years) and tends to be quite advanced by the time it presents clinical symptoms of exertional angina, syncope, or heart failure. Currently, the only effective clinical therapy for AS patients is surgical or transcatheter aortic valve replacement. Evidence is accumulating that Lp(a) can exacerbate pathophysiological processes in CAVD, specifically, endothelial dysfunction, formation of foam cells, and promotion of a pro-inflammatory state. In the valve milieu, the pro-inflammatory effects of Lp(a) are manifested in valve thickening and mineralization through pro-osteogenic signaling and changes in gene expression in valve interstitial cells that is primarily facilitated by the oxidized phospholipid content of Lp(a). In AS pathogenesis, an incomplete understanding of the role of Lp(a) at the molecular level and the absence of appropriate animal models are barriers for the development of specific and effective clinical interventions designed to mitigate the role of Lp(a) in AS. However, the advent of effective therapies that dramatically lower Lp(a) provides the possibility of the first medical treatment to halt AS progression., (Copyright © 2020. Published by Elsevier Inc.)

Calcific aortic valve disease is dramatically increasing in global burden, yet no therapy exists outside of prosthetic replacement. The increasing proportion of younger and more active patients mandates alternative therapies. Studies suggest a window of opportunity for biologically based diagnostics and therapeutics to alleviate or delay calcific aortic valve disease progression. Advancement, however, has been hampered by limited understanding of the complex mechanisms driving calcific aortic valve disease initiation and progression towards clinically relevant interventions.

Sex- and flow-related aortic valve calcification (AVC) studies are still limited in number, and data on the exact calcium quantity and distribution are scarce. Therefore, we aimed to (1) re-define the best threshold of AVC load to distinguish severe from moderate aortic stenosis (AS) in common AS entities and to (2) evaluate differences in the aortic annulus and left ventricular outflow tract (LVOT) calcium load. Nine hundred and thirty-eight patients with contrast-enhanced cardiac MSCT and moderate-to-severe aortic stenosis (AS) were retrospectively enrolled. Patients with severe AS ≤ 1.0 cm 2 (n = 841) were further separated into three AS entities: high gradient (HGAS, n = 370, 44.0%), paradoxical low gradient (pLGAS, n = 333, 39.6%), and classical low gradient (LGAS, n = 138, 16.4%). AVC, leaflet, and LVOT calcification were quantified. Aortic valve calcification scores were highest in severe HGAS, and lower in severe pLGAS and classical LGAS. In all severity and AS entities, the non-coronary cusp (NCC) was the most calcified one. LVOT calcification was consistently comparable between gender and AS entities. Accuracy of logistic regression was the highest in HGAS (male vs. female: AVC > 2156 Agatston units (AU), c-index 0.76; vs. AVC > 1292 AU, c-index 0.85; or AVC density > 406 AU/cm 2 , c-index 0.82; vs. > 259 AU/cm 2 , c-index 0.86; each p < 0.0001*) to diagnose severe AS. AVC could only be used in men to differentiate between severe LGAS and moderate AS. Data from this retrospective analysis indicate that the NCC is subject to pre-dominant degeneration throughout gender, AS severity, and several AS entities. AVC was consistently comparable in severe pLGAS and classical LGAS, but only AVC in severe LGAS could sufficiently distinguish from moderate AS in men. LVOT calcification failed to be a reliable indicator of accelerating AS.

Background: The CoreValve Evolut R and PRO (Medtronic, Minneapolis, MN, USA) are among the newest-generation of self-expandable transcatheter aortic valve replacement (TAVR) devices and show excellent results. Treating patients with severely calcified (SC) native aortic valve anatomy may be challenging because of the increased risk of periprocedural complications. This study investigated the performance of Evolut R and PRO in this special patient subset., Methods: Patients who underwent TAVR with the CoreValve Evolut R or PRO (n=381) from September 2015 to March 2018 were divided by aortic valve calcification extent. Patients with SC aortic valve anatomy (n=98; men, >2,062 and women, >1,377 Agatston units) were compared with those with non-severely calcified (NCS) aortic valve anatomy after 1:2 propensity score matching. Outcomes were evaluated according to the updated valve academic research consortium criteria., Results: Patients with SC anatomy were older (83 years vs 80 years, p<0.001) and had a smaller aortic valve area (0.63 cm 2 vs 0.70 cm 2 , p=0.028). Pre-dilatation was more often performed (30.6% vs 15.8%, p=0.003) and a permanent pacemaker implantation was more often necessary (32.9% vs 8.8%, p<0.001) in the SC group. None/mild aortic regurgitation (AR) was evenly distributed (SC, 96.9% vs NCS, 99.5%, p=0.109); moderate AR was present in 3.1% of SC patients and in 0.5% of NSC patients. Severe AR was not observed., Conclusion: The CoreValve Evolut R and PRO showed good clinical safety profiles and excellent haemodynamic results in patients with SC anatomy and who more often required permanent pacemaker implantation., (Copyright © 2020 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Background: The prognostic value of aortic valve calcification (AVC) measured by using multidetector computed tomography imaging has been well validated in native aortic stenosis, and sex-specific thresholds have been proposed. However, few data are available regarding the impact of leaflet calcification on outcomes after biological aortic valve replacement (AVR)., Objectives: The goal of this study was to analyze the association of quantitative bioprosthetic leaflet AVC with hemodynamic and clinical outcomes, as well as its possible interaction with sex., Methods: From 2008 to 2010, a total of 204 patients were prospectively enrolled with a median of 7.0 years (interquartile range: 5.1 to 9.2 years) after biological surgical AVR. AVC measured by using the Agatston method was indexed to the cross-sectional area of aortic annulus measured by echocardiography to calculate the AVC density (AVCd). Presence of hemodynamic valve deterioration (HVD; increase in mean gradient [MG] ≥10 mm Hg and/or increase in transprosthetic regurgitation ≥1) was assessed by echocardiography in 137 patients at the 3-year follow-up. The primary clinical endpoint was mortality or aortic valve re-intervention., Results: There was no significant sex-related difference in the relationship between bioprosthetic AVCd and the progression of MG. Baseline AVCd showed an independent association with HVD at 3 years. During follow-up, there were 134 (65.7%) deaths (n = 100) or valve re-interventions (n = 47). AVCd ≥58 AU/cm 2 was independently associated with an increased risk of mortality or aortic valve re-intervention (adjusted hazard ratio: 2.23; 95% confidence interval: 1.44 to 3.35; p < 0.001). The AVCd threshold combined with an MG progression threshold of 10 mm Hg amplified the stratification of patients at risk (log-rank, p < 0.001). The addition of AVCd threshold into the prediction model including traditional risk factors improved outcome prediction (net classification improvement: 0.25, p = 0.04; likelihood ratio test, p < 0.001)., Conclusions: Aortic bioprosthetic leaflet calcification is strongly and independently associated with HVD and the risk of death or aortic valve re-intervention. As opposed to native aortic stenosis, there is no sex-related differences in the relationship between AVCd and hemodynamic or clinical outcomes., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Lipoprotein-associated phospholipase A2 (Lp-PLA2) activity has been shown to predict calcific aortic valve stenosis (CAVS) outcomes. Our objective was to test the association between plasma Lp-PLA2 activity and genetically elevated Lp-PLA2 mass/activity with CAVS in humans., Methods and Results: Lp-PLA2 activity was measured in 890 patients undergoing cardiac surgery, including 476 patients undergoing aortic valve replacement for CAVS and 414 control patients undergoing coronary artery bypass grafting. After multivariable adjustment, Lp-PLA2 activity was positively associated with the presence of CAVS (OR=1.21 (95% CI 1.04 to 1.41) per SD increment). We selected four single nucleotide polymorphisms (SNPs) at the PLA2G7 locus associated with either Lp-PLA2 mass or activity (rs7756935, rs1421368, rs1805017 and rs4498351). Genetic association studies were performed in eight cohorts: Quebec-CAVS (1009 cases/1017 controls), UK Biobank (1350 cases/349 043 controls), European Prospective Investigation into Cancer and Nutrition-Norfolk (504 cases/20 307 controls), Genetic Epidemiology Research on Aging (3469 cases/51 723 controls), Malmö Diet and Cancer Study (682 cases/5963 controls) and three French cohorts (3123 cases/6532 controls), totalling 10 137 CAVS cases and 434 585 controls. A fixed-effect meta-analysis using the inverse-variance weighted method revealed that none of the four SNPs was associated with CAVS (OR=0.99 (95% CI 0.96 to 1.02, p=0.55) for rs7756935, 0.97 (95% CI 0.93 to 1.01, p=0.11) for rs1421368, 1.00 (95% CI 1.00 to 1.01, p=0.29) for rs1805017, and 1.00 (95% CI 0.97 to 1.04, p=0.87) for rs4498351)., Conclusions: Higher Lp-PLA2 activity is significantly associated with the presence of CAVS and might represent a biomarker of CAVS in patients with heart disease. Results of our genetic association study suggest that Lp-PLA2 is however unlikely to represent a causal risk factor or therapeutic target for CAVS., Competing Interests: Competing interests: BA has received research funding from Pfizer, Merck and Ionis Pharmaceuticals and is a consultant for Novartis. PM is a consultant for Casebia Therapeutics., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Traditionally, quantification of aortic valve calcium (AVC) has been performed with noncontrast computed tomography (NCCT) using the Agatston method. This study sought to derive and validate a systematic method enabling AVC quantification using computed tomographic angiography (CTA) in patients with aortic stenosis (AS)., Methods: The study included 134 consecutive patients with AS who underwent both NCCT and CTA and were subdivided into derivation (n = 71) and validation cohorts (n = 63). AVC on NCCT (AVC NCCT ) was quantified using the Agatston method using the software developed for semiautomatic assessment of coronary calcium. On CTA, the mean contrast attenuation of the aorta in Hounsfield units (Aorta HU ) and SD was measured in the region of interest at the level of the sinotubular junction., Results: Using an adjusted calcium detection threshold of Aorta HU  + 2 SD, we calculated AVC on CTA (AVC CTA ) using the same software without modifying other variables. Correlation between AVC NCCT and AVC CTA in the derivation cohort was excellent (r = 0.9679; P < .001). We used a linear regression model to derive a formula for predicting AVC CTA that enabled conversion of AVC CTA to AVC Derived (AVC Derived  = 1.821 × AVC CTA ). Applying this formula in validation cohort, we calculated AVC Derived , which showed excellent agreement with AVC NCCT (intraclass correlation coefficient, 0.9648; 95% confidence interval, 0.9427-0.9782). Excellent correlation was also found between categorized AVC NCCT and AVC Derived scores (κ = 0.9044; 95% confidence interval, 0.7989-1.0000), with 95.24% (60 of 63) of scores falling within the same severity category., Conclusions: AVC quantification on CTA is feasible with high accuracy and reliability and shows excellent agreement with the standard AVC NCCT score. With the systematic approach using "dynamic thresholds" being largely independent of the scan acquisition protocol, AVC Derived can potentially replace AVC NCCT , eliminating the need for separate NCCT acquisition solely for AVC quantification., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background Aortic stenosis (AS) is highly prevalent in patients with atherosclerotic cardiovascular disease. Advanced glycation end products (AGEs) and the receptor for AGEs (RAGE) play a pivotal role for vascular calcification in atherosclerosis. We hypothesize that the AGEs-RAGE axis could also be involved in the pathophysiological mechanism of calcified AS. Methods and Results A total of 54 patients with calcified AS who underwent aortic valve replacement were prospectively enrolled from 2014 to 2016 (mean age 75.3±7.7 years). Aortic valve specimens were obtained from 47 patients and 16 deceased control subjects without aortic valve disease (mean age 63.2±14.5 years). The valvular expression of RAGE was evaluated by immunohistochemistry. Serum levels of AGEs and soluble RAGE were measured in 50 patients with calcified AS and 70 age-matched and sex-matched control subjects without heart disease. The valvular RAGE expression in patients with calcified AS was higher than controls ( P =0.004) and was significantly associated with a decreased ankle-brachial pressure index ( P =0.007) and an increased intima-media thickness ( P =0.026). RAGE and α-smooth muscle actin were coexpressed and were partially costained with osteocalcin and alkaline phosphatase. The serum levels of AGEs and soluble RAGE were significantly higher in the patients with calcified AS than in the controls ( P =0.013 and P <0.001, respectively). Soluble RAGE (inversely) and use of aspirin were independently correlated with changes in left ventricular systolic function after aortic valve replacement ( P =0.012 and P =0.002, respectively). Conclusions Our present study suggests that RAGE may play a role in the pathogenesis of calcified AS, which is a prognostic marker in patients with AS after aortic valve replacement.

Homozygous familial hypercholesterolemia (HoFH; Fredrickson IIa) is a rare autosomal dominant hereditary disease associated with increased low-density lipoprotein cholesterol. We hereby report anesthetic challenges in a rare case of HoFH having severe progressive aortic stenosis, mitral regurgitation, diffuse aortic and carotid vessel involvement, and severe left ventricular dysfunction. The patient underwent a Konno aortoventriculoplasty with mechanical prosthesis along with mitral valve repair.

Familial homozygous hypercholesterolemia is a rare disease with diverse clinical presentations ranging from premature ischemic heart disease to aortic root stenosis but rarely presents with anginal symptoms due to supravalvular and valvular aortic stenosis. We report a 19-year-old male patient with familial homozygous hypercholesterolemia with progressive supravalvular and valvular aortic stenosis that ultimately required aortic root enlargement and aortic valve replacement using a mechanical prosthesis, despite aggressive medical therapy. Surgical importance of this rare condition is highlighted.

Calcific aortic valve disease (CAVD) is the most common form of valve disease where the only available treatment strategy is surgical valve replacement. Technologies for the early detection of CAVD would benefit the development of prevention, mitigation and alternate therapeutic strategies. Two-photon excited fluorescence (TPEF) microscopy is a label-free, non-destructive imaging technique that has been shown to correlate with multiple markers for cellular differentiation and phenotypic changes in cancer and wound healing. Here we show how specific TPEF markers, namely, the optical redox ratio and mitochondrial fractal dimension, correlate with structural, functional and phenotypic changes occurring in the aortic valve interstitial cells (VICs) during osteogenic differentiation. The optical redox ratio, and fractal dimension of mitochondria were assessed and correlated with gene expression and nuclear morphology of VICs. The optical redox ratio decreased for VICs during early osteogenic differentiation and correlated with biological markers for CAVD progression. Fractal dimension correlated with structural and osteogenic markers as well as measures of nuclear morphology. Our study suggests that TPEF imaging markers, specifically the optical redox ratio and mitochondrial fractal dimension, can be potentially used as a tool for assessing early CAVD progression in vitro.

Objective: This study assessed whether apolipoprotein CIII-lipoprotein(a) complexes (ApoCIII-Lp(a)) associate with progression of calcific aortic valve stenosis (AS)., Methods: Immunostaining for ApoC-III was performed in explanted aortic valve leaflets in 68 patients with leaflet pathological grades of 1-4. Assays measuring circulating levels of ApoCIII-Lp(a) complexes were measured in 218 patients with mild-moderate AS from the AS Progression Observation: Measuring Effects of Rosuvastatin (ASTRONOMER) trial. The progression rate of AS, measured as annualised changes in peak aortic jet velocity (V peak ), and combined rates of aortic valve replacement (AVR) and cardiac death were determined. For further confirmation of the assay data, a proteomic analysis of purified Lp(a) was performed to confirm the presence of apoC-III on Lp(a)., Results: Immunohistochemically detected ApoC-III was prominent in all grades of leaflet lesion severity. Significant interactions were present between ApoCIII-Lp(a) and Lp(a), oxidised phospholipids on apolipoprotein B-100 (OxPL-apoB) or on apolipoprotein (a) (OxPL-apo(a)) with annualised V peak (all p<0.05). After multivariable adjustment, patients in the top tertile of both apoCIII-Lp(a) and Lp(a) had significantly higher annualised V peak (p<0.001) and risk of AVR/cardiac death (p=0.03). Similar results were noted with OxPL-apoB and OxPL-apo(a). There was no association between autotaxin (ATX) on ApoB and ATX on Lp(a) with faster progression of AS. Proteomic analysis of purified Lp(a) showed that apoC-III was prominently present on Lp(a)., Conclusion: ApoC-III is present on Lp(a) and in aortic valve leaflets. Elevated levels of ApoCIII-Lp(a) complexes in conjunction with Lp(a), OxPL-apoB or OxPL-apo(a) identify patients with pre-existing mild-moderate AS who display rapid progression of AS and higher rates of AVR/cardiac death., Trial Registration: NCT00800800., Competing Interests: Competing interests: J-PD has served as a speaker for Abbott Laboratories, AstraZeneca, Solvay Pharma, GlaxoSmithKline, and Pfizer Canada, Inc.; has received research funding from Eli Lilly Canada; and has served on the advisory boards of Novartis, Theratechnologies, Torrent Pharmaceuticals Ltd., and Sanofi-Aventis. PM has a patent application on the use of Lp-PLA2 inhibitors in the treatment of AS. BA has received research funding from Ionis Pharmaceuticals, Merck and Pfizer. ST and JLW are co-inventors and receive royalties from patents owned by UCSD on oxidation-specific antibodies and of biomarkers related to oxidised lipoproteins and are co-founders of Oxitope, Inc. ST is a consultant to Boston Heart Diagnostics, a co-founder of Oxitope, Inc. and has a dual appointment at UCSD and Ionis Pharmaceuticals. JLW is a consultant to Ionis Pharmaceuticals and a co-founder of Oxitope, Inc., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

The aortic pulse contour displays characteristic changes associated with the progression of aortic stenosis (AS). A diminished and delayed aortic pulse contour is indicative of significant AS, but the aortic contour may also be affected by factors including aging, hypertension and increased peripheral arterial elastance. This review describes the components of the aortic pulse contour in AS and how it can be affected by different conditions and interventions., (© 2019 Wiley Periodicals, Inc.)

On occasion in patients with stenotic congenitally bicuspid aortic valves (BAVs), the quantity of calcium in one of the cusps is considerably greater than in the other cusp. We examined operatively excised stenotic congenitally BAVs in 630 patients having isolated aortic valve replacement (No other cardiac valve was replaced, and none had had infective endocarditis.) Of the 630 valves, 3 contained a perforation in the mildly calcified cusp due to a large calcific "spur" extending across the orifice from a heavily calcified cusp. In conclusion, heavy calcific deposits in 1 of 2 BAVs may extend across the orifice causing a perforation in the noncalcified portion of the opposing cusp., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Cardiovascular diseases (CVD), including ischemic heart diseases and cerebrovascular diseases, are the leading causes of morbidity and mortality worldwide. Atherosclerosis is the major underlying factor for most CVD. It is well-established that oxidative stress and inflammation are two major mechanisms leading to atherosclerosis. Under oxidative stress, polyunsaturated fatty acids (PUFA)-containing phospholipids and cholesterol esters in cellular membrane and lipoproteins can be readily oxidized through a free radical-induced lipid peroxidation (LPO) process to form a complex mixture of oxidation products. Overwhelming evidence demonstrates that these oxidized lipids are actively involved in the inflammatory responses in atherosclerosis by interacting with immune cells (such as macrophages) and endothelial cells. In addition to lipid lowering in the prevention and treatment of atherosclerotic CVD, targeting chronic inflammation has been entering the medical realm. Clinical trials are under way to lower the lipoprotein (a) (Lp(a)) and its associated oxidized phospholipids, which will provide clinical evidence that targeting inflammation caused by oxidized lipids is a viable approach for CVD. In this review, we aim to give an update on our understanding of the free radical oxidation of LPO, analytical technique to analyze the oxidation products, especially the oxidized phospholipids and cholesterol esters in low density lipoproteins (LDL), and focusing on the experimental and clinical evidence on the role of lipid oxidation in the inflammatory responses associated with CVD, including myocardial infarction and calcific aortic valve stenosis. The challenges and future directions in understanding the role of LPO in CVD will also be discussed., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Chronic kidney disease (CKD) is a major risk factor for valvular heart disease (VHD). Mitral annular and aortic valve calcifications are highly prevalent in CKD patients and commonly lead to valvular stenosis and regurgitation, as well as complications including conduction system abnormalities and endocarditis. VHD, especially mitral regurgitation and aortic stenosis, is associated with significantly reduced survival among CKD patients. Knowledge related to VHD in the general population is not always applicable to CKD patients because the pathophysiology may be different, and CKD patients have a high prevalence of comorbid conditions and elevated risk for periprocedural complications and mortality. This Kidney Disease: Improving Global Outcomes (KDIGO) review of CKD and VHD seeks to improve understanding of the epidemiology, pathophysiology, diagnosis, and treatment of VHD in CKD by summarizing knowledge gaps, areas of controversy, and priorities for research., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

TAVI complications may occur in the peri- and postprocedural periods. A 79-year-old woman with known severe degenerative calcified aortic stenosis underwent transfemoral TAVI; prior to groin closure, she became hypotensive. Prosthetic valve thrombosis was confirmed with transesophageal echocardiography and computed tomography aortogram, which showed thrombus on the immobile non-coronary cusp leaflet.

Crossing the aortic annulus with a prosthetic valve was impossible due to severe calcification. A snare catheter technique was used to centralize the entire system with the aortic orifice.

Objectives: Although many challenges related to the acute implantation of transcatheter aortic valves have been resolved, durability and early degeneration are currently the main concerns. Recent reports indicate the potential for early valve degeneration and calcification. However, only little is known about the underlying mechanisms behind the early degeneration of these valves. The goal of this study was to test whether stent crimping increases the risk for early calcification., Methods: Stented valves that were crimped at 18-Fr and 14-Fr catheter and uncrimped controls were exposed to a standard calcifying solution for 50 million cycles in an accelerated wear test system. Subsequently, the leaflets of the valves were imaged by microcomputed tomography (micro-CT) followed by histochemical staining and microscopic analyses to quantify calcification and other changes in the leaflets' characteristics., Results: Heavily calcified regions were found over the stent-crimped leaflets compared to uncrimped controls, particularly around the stent's struts. Micro-CT studies measured the total volume of calcification in the uncrimped valves as 77.31 ± 1.63 mm3 vs 95.32 ± 5.20 mm3 in 18-Fr and 110.01 ± 8.33 mm3 in 14-Fr stent-crimped valves, respectively. These results were congruent with the increase in leaflet thickness measured by CT scans (0.44 ± 0.07 mm in uncrimped valves vs 0.69 ± 0.15 mm and 0.75 ± 0.09 mm in 18-Fr and 14-Fr stent-crimped valves, respectively). Histological studies confirmed the micro-CT results, denoting that the percentage of calcification in uncrimped leaflets at the valve's posts was 5.34 ± 3.97 compared to 19.97 ± 6.18 and 27.64 ± 13.17 in the 18-Fr and 14-Fr stent-crimped leaflets, respectively., Conclusions: This study concludes that stent-crimping damage is associated with a higher level of passive leaflet calcification, which may contribute to early valve degeneration., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Degenerative aortic valve disease in combination with diabetes is an increasing burden worldwide. There is growing evidence that particularly small leucine-rich proteoglycans are involved in the development of degenerative aortic valve disease. Nevertheless, the role of these molecules in this disease in the course of diabetes has not been elucidated in detail and previous studies remain controversial. Therefore, the aim of this study is to broaden the knowledge about small leucine-rich proteoglycans in degenerative aortic valve disease and the influence of diabetes and hyperglycaemia on aortic valves and valvular interstitial cells is examined. Analyses were performed using reverse-transcription polymerase chain reaction, Western blot, enzyme-linked immunosorbent assay, (immuno)histology and colorimetric assays. We could show that biglycan, but not decorin and lumican, is upregulated in degenerated human aortic valve cusps. Subgroup analysis reveals that upregulation of biglycan is stage-dependent. In vivo, loss of biglycan leads to stage-dependent calcification and also to migratory effects on interstitial cells within the extracellular matrix. In late stages of degenerative aortic valve disease, diabetes increases the expression of biglycan in aortic valves. In vitro, the combinations of hyperglycaemic with pro-degenerative conditions lead to an upregulation of biglycan. In conclusion, biglycan represents a potential link between degenerative aortic valve disease and diabetes.

Aims: To assess the contribution of aortic valve calcification to the occurrence of transient or permanent atrioventricular block (AVB) and the need for permanent pacemaker implantation (PPI) after transcatheter aortic valve implantation (TAVI) in a large single-centre cohort., Methods and Results: We retrospectively analysed pre-operative contrast-enhanced multidetector computed tomography scans of patients who underwent TAVI in our centre between 2012 and 2016. Calcium volume was calculated for each aortic cusp above (aortic valve), and below [left ventricular outflow tract (LVOT)] the basal plane. Clinical and procedural data as well as pre-operative electrocardiograms were evaluated. Multivariate analysis was performed to evaluate risk factors for transient and permanent AVB. A total of 342 patients receiving a balloon-expandable prosthesis were included in the study. Overall incidence of transient and permanent AVB was 4% (n = 14) and 7.6% (n = 26), respectively. On logistic regression analysis, baseline right bundle branch block [odds ratio (OR) 7.36, 95% confidence interval (CI) 2.6-20.6; P < 0.01], degree of oversizing (OR 1.04, 95% CI 1.01-1.07 P = 0.02), prior percutaneous coronary intervention (OR 2.8, 95% CI 1.1-7.3), and LVOT calcification beneath the non-coronary cusp (OR for an increase of 10 mm3 = 1.06, 95% CI 1-1.1; P = 0.03) were found to be independently associated with permanent AVB and PPI, whereas calcification of LVOT beneath the right coronary cusp (OR for an increase of 10 mm3 = 1.16, 95% CI 1.02-1.3; P = 0.02) and balloon post-dilation (OR 3.8, 95% CI 1.2-11.8; P = 0.02) were associated with reversible AVB., Conclusion: Left ventricular outflow tract calcifications are associated with transient and non-reversible AVB after TAVI, and its evaluation could help in predicting onset and reversibility of AVB., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

The neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP) are emerging indirect blood markers to roughly reflect the inflammation level in our body while some pathological changes occurring in aortic valve tissue. Few recent studies demonstrated that NLR is related to calcific aortic valve disease (CAVD). However, the extent of the relationship between them and the impact of CRP on CAVD are not clear. This study aimed to investigate the diagnostic influence and surgical predictive effect of NLR and CRP on CAVD.A total of 278 consecutive patients with CAVD (123 patients with bicuspid aortic valve and others with tricuspid aortic valve) and 108 healthy individuals who were included in the control group were enrolled in the study. The NLR was calculated from the complete blood count, and the CRP was measured from peripheral blood samples. Echocardiography was used to evaluate the severity of aortic stenosis. Intraoperation/postoperation indicators were collected in 166 patients from the total consecutive patients who underwent aortic valve replacement (AVR) alone.Significantly higher NLR was measured in both the BAV group (1.96 ± 0.78 versus 0.97 ± 0.15, P < 0.001) and the TAV group (2.51 ± 2.03 versus 0.97 ± 0.15, P < 0.001) compared with the control group. Moreover, the NLR level was significantly higher (P < 0.001) and the CRP level was significantly lower (P = 0.007) of the TAV group than that of the BAV group; a significant positive correlation between the NLR and the maximum gradient of aortic valve was detected. Furthermore, there was a moderate correlation between the NLR and the postoperative mechanical ventilation time.Our results indicated that the NLR and CRP were novel and useful predictive factors in patients with CAVD, and these two potential factors have guiding significance for the prediction of different pathological typing (BAV or TAV). Higher NLR level will not extend the cardiopulmonary bypass time (CPB); however, it will prolong the operation time and the postoperative mechanical ventilation time.

Background: Bioprosthetic aortic valve degeneration is increasingly common, often unheralded, and can have catastrophic consequences., Objectives: The authors sought to assess whether 18 F-fluoride positron emission tomography (PET)-computed tomography (CT) can detect bioprosthetic aortic valve degeneration and predict valve dysfunction., Methods: Explanted degenerate bioprosthetic valves were examined ex vivo. Patients with bioprosthetic aortic valves were recruited into 2 cohorts with and without prosthetic valve dysfunction and underwent in vivo contrast-enhanced CT angiography, 18 F-fluoride PET, and serial echocardiography during 2 years of follow-up., Results: All ex vivo, degenerate bioprosthetic valves displayed 18 F-fluoride PET uptake that colocalized with tissue degeneration on histology. In 71 patients without known bioprosthesis dysfunction, 14 had abnormal leaflet pathology on CT, and 24 demonstrated 18 F-fluoride PET uptake (target-to-background ratio 1.55 [interquartile range (IQR): 1.44 to 1.88]). Patients with increased 18 F-fluoride uptake exhibited more rapid deterioration in valve function compared with those without (annualized change in peak transvalvular velocity 0.30 [IQR: 0.13 to 0.61] vs. 0.01 [IQR: -0.05 to 0.16] ms -1 /year; p < 0.001). Indeed 18 F-fluoride uptake correlated with deterioration in all the conventional echocardiographic measures of valve function assessed (e.g., change in peak velocity, r = 0.72; p < 0.001). Each of the 10 patients who developed new overt bioprosthesis dysfunction during follow-up had evidence of 18 F-fluoride uptake at baseline (target-to-background ratio 1.89 [IQR: 1.46 to 2.59]). On multivariable analysis, 18 F-fluoride uptake was the only independent predictor of future bioprosthetic dysfunction., Conclusions: 18 F-fluoride PET-CT identifies subclinical bioprosthetic valve degeneration, providing powerful prediction of subsequent valvular dysfunction and highlighting patients at risk of valve failure. This technique holds major promise in the diagnosis of valvular degeneration and the surveillance of patients with bioprosthetic valves. (18F-Fluoride Assessment of Aortic Bioprosthesis Durability and Outcome [18F-FAABULOUS]; NCT02304276)., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Intraleaflet hematomas are associated with advanced stages of aortic valve calcification and suspected to be involved in disease progression. However, the mechanism by which the entry of blood cells into the valves affects the biology of aortic valvular interstitial cells (VICs) remains to be elucidated., Objectives: This study sought to evaluate the putative link between intraleaflet hematoma and aortic valve calcification and to assess its pathophysiological implications., Methods: The spatial relationship between calcium deposits and intraleaflet hematomas was analyzed by whole-mount staining of calcified and noncalcified human aortic valves, obtained in the context of heart transplantation and from patients who underwent surgical valve replacement. Endothelial microfissuring was evaluated by en face immunofluorescence and scanning electron microscopic analyses of the fibrosa surface. Red blood cell (RBC) preparations were used in vitro to assess, by immunofluorescence microscopy and Alizarin red staining, the potential impact of intraleaflet hematomas on phenotypic changes in VICs., Results: Intraleaflet hematomas, revealed by iron deposits and RBCs into the fibrosa, secondary to endothelial microfissuring, were consistently found in noncalcified valves. The contact of primary VICs derived from these valves with RBCs resulted in a global inflammatory and osteoblastic phenotype, reflected by the up-regulation of interleukin-6, interleukin-1β, bone sialoprotein, osteoprotegerin, receptor activator of nuclear factor kappa B, bone morphogenic protein 2, and muscle segment homeobox 2, the production of osteocalcin, and the formation of calcium deposits., Conclusions: The acquisition of an osteoblastic phenotype in VICs that come into contact with the senescent RBCs of intraleaflet hematomas may play a critical role in the initiation of calcium deposition into the fibrosa of human aortic valves., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background The aortic valve of the heart experiences constant mechanical stress under physiological conditions. Maladaptive valve injury responses contribute to the development of valvular heart disease. Here, we test the hypothesis that MG 53 (mitsugumin 53), an essential cell membrane repair protein, can protect valvular cells from injury and fibrocalcific remodeling processes associated with valvular heart disease. Methods and Results We found that MG 53 is expressed in pig and human patient aortic valves and observed aortic valve disease in aged Mg53-/- mice. Aortic valves of Mg53-/- mice showed compromised cell membrane integrity. In vitro studies demonstrated that recombinant human MG 53 protein protects primary valve interstitial cells from mechanical injury and that, in addition to mediating membrane repair, recombinant human MG 53 can enter valve interstitial cells and suppress transforming growth factor-β-dependent activation of fibrocalcific signaling. Conclusions Together, our data characterize valve interstitial cell membrane repair as a novel mechanism of protection against valvular remodeling and assess potential in vivo roles of MG 53 in preventing valvular heart disease.

Background: Balloon aortic valvuloplasty (BAV) is routinely performed preceding transcatheter aortic valve implantation (TAVI). Among risks inherent in BAV is low cardiac output due to rapid ventricular pacing (RVP), especially in patients with severely impaired left ventricular function. We herein report early experience utilizing a non-occlusive balloon for BAV (TrueFlow™, BARD, Peripheral Vascular, Tempe, AZ, US), which does not require RVP., Methods: Between 11/2016 and 10/2017, 27 consecutive patients received TAVI using a non-occlusive balloon valvuloplasty catheter for predilatation and a self-expandable transcatheter heart valve (77.8% female, 81.7 ± 6.6 years, logEuroSCORE I 15.8 ± 10.3%, STS Prom Score 2.5 ± 0.5%). Hemodynamic measurements and acute outcome data were analyzed according to updated Valve Academic Research Consortium definitions., Results: Procedure time, fluoroscopy time and amount of contrast agent were 74.5 ± 17.4 min, 16.7 ± 6.9 min and 156.9 ± 92.7 ml. Device success and early combined safety were 100% and 92.6% (25/27). Effective BAV without RVP after the first inflation was achieved in 92.6% of the patients (25/27). Continuous recording of hemodynamics documented no relevant systemic pressure drop during BAV. Postdilatation with a regular balloon was required in 10/27 patients. No death was observed during 30-day follow-up. Resultant mean transvalvular gradient was 6.0 ± 3.5 mm Hg. In one patient a moderate paravalvular leakage was seen., Conclusions: In this series of TAVI utilizing a novel non-occlusive balloon, safety and efficacy were demonstrated. Adequate predilatation was achieved in all cases without need for RVP and with stable hemodynamics. These results will have to be confirmed in larger patient cohorts., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: Cardiac valve calcification (VC) is very common in patients on hemodialysis. However, the definite effect of VC on left ventricular (LV) geometry and function in this population is unknown, especially when LV ejection fraction (LVEF) is normal. The aim of this study was to determine the effect of VC on LV geometry and function in long-term hemodialysis patients by conventional echocardiography and two-dimensional speckle tracking echocardiography (2D-STE)., Methods: A total of 47 hemodialysis patients (2-3 times weekly for 5 years or more) were enrolled in this study. Cardiac VC was defined as bright echoes of more than 1 mm on one or more cusps of the aortic valve or mitral valve or mitral annulus using echocardiography as the screening method. LV longitudinal global strain (GLS) was assessed on the apical four-chamber view and calculated as the mean strain of 6 segments. LV global circumferential strain was acquired on the LV short axis view at the level of papillary muscles., Results: Twenty-five patients with VC had higher mean values of interventricular septum thickness, LV posterior wall thickness, LV mass index, relative wall thickness, and LV mass/end-diastolic volume than 22 patients without VC (p < 0.05, respectively), indicating more obvious LV hypertrophy (LVH). VC patients had higher mitral annular E/E' values, especially at the septal side representing increased LV filling pressure compatible with diastolic dysfunction, while only the E/E' ratio of the septal side was significantly different between the 2 groups (16.7 ± 4.1 vs. 12.3 ± 4.4, p < 0.01). When assessed by GLS, LV longitudinal systolic function was also lower in in patients with VC compared with those without VC (-0.18 ± 0.03 vs. -0.25 ± 0.04; p < 0.01)., Conclusions: Cardiac VC diagnosed by echocardiography when it occurs in long-term hemodialysis patients may indicate more severe LVH, myocardial damage, and worse heart function in comparison to those without VC. Tissue Doppler imaging and 2D-STE can detect the subtle change of heart function in this population in the early stage of LV dysfunction when LVEF is normal., (© 2018 S. Karger AG, Basel.)

Background: Successful transcatheter aortic valve replacement (TAVR) requires an understanding of how a prosthetic valve will interact with a patient's anatomy in advance of surgical deployment. To improve this understanding, we developed a benchtop workflow that allows for testing of physical interactions between prosthetic valves and patient-specific aortic root anatomy, including calcified leaflets, prior to actual prosthetic valve placement., Methods: This was a retrospective study of 30 patients who underwent TAVR at a single high volume center. By design, the dataset contained 15 patients with a successful annular seal (defined by an absence of paravalvular leaks) and 15 patients with a sub-optimal seal (presence of paravalvular leaks) on post-procedure transthoracic echocardiogram (TTE). Patients received either a balloon-expandable (Edwards Sapien or Sapien XT, n = 15), or a self-expanding (Medtronic CoreValve or Core Evolut, n = 14, St. Jude Portico, n = 1) valve. Pre-procedural computed tomography (CT) angiograms, parametric geometry modeling, and multi-material 3D printing were utilized to create flexible aortic root physical models, including displaceable calcified valve leaflets. A 3D printed adjustable sizing device was then positioned in the aortic root models and sequentially opened to larger valve sizes, progressively flattening the calcified leaflets against the aortic wall. Optimal valve size and fit were determined by visual inspection and quantitative pressure mapping of interactions between the sizer and models., Results: Benchtop-predicted "best fit" valve size showed a statistically significant correlation with gold standard CT measurements of the average annulus diameter (n = 30, p < 0.0001 Wilcoxon matched-pairs signed rank test). Adequateness of seal (presence or absence of paravalvular leak) was correctly predicted in 11/15 (73.3%) patients who received a balloon-expandable valve, and in 9/15 (60%) patients who received a self-expanding valve. Pressure testing provided a physical map of areas with an inadequate seal; these corresponded to areas of paravalvular leak documented by post-procedural transthoracic echocardiography., Conclusion: We present and demonstrate the potential of a workflow for determining optimal prosthetic valve size that accounts for aortic annular dimensions as well as the active displacement of calcified valve leaflets during prosthetic valve deployment. The workflow's open source framework offers a platform for providing predictive insights into the design and testing of future prosthetic valves., (Published by Elsevier Inc.)

Background: Transcatheter aortic valve replacement (TAVR) in cases with left ventricular outflow tract calcification (LVOT-CA) remains a challenging procedure. The aim of this study was to compare the early outcomes of patients undergoing TAVR in LVOT-CA with new-generation devices vs early-generation devices., Methods: Between January 2014 and December 2016, a total of 433 patients with severe aortic stenosis who had a preprocedural multidetector computed tomography underwent TAVR in a LVOT-CA. After propensity matching, data from 119 patients in each group were analyzed. TAVR endpoints and adverse events were defined according to the Valve Academic Research Consortium-2., Results: Compared with early-generation devices (Edwards Sapien/Sapien XT/CoreValve), new-generation devices (Sapien 3/Evolut R) had significantly lower incidence of mild-moderate paravalvular leak (PVL) (1.7% new vs 7.6% early; P=.03), tended to have lower incidence of moderate or severe PVL (5.0% new vs 11.8% early; P=.06), had no significant difference in device success (89.1% new vs 83.2% early; P=.19), and had a significantly higher early safety rate at 30 days (93.3% new vs 84.9% early; P=.04). For cardiac conduction disturbances, new-generation and early-generation devices had similarly high rates of new permanent pacemaker implantation (16.8% new vs 15.1% early; P=.72), whereas the number of patients who developed new-onset left bundle-branch block (LBBB) were significantly higher in those with new-generation devices (16.0% new vs 6.7% early; P=.03)., Conclusion: In the setting of LVOT-CA, patients with new-generation devices compared to those with early-generation devices had acceptable clinical outcomes except for cardiac conduction disturbances, especially in new-onset LBBB.

Objectives: Radiation exposure is a concern for both patients and operators during transcatheter aortic valve implantation (TAVI). Efforts to reduce radiation dose are warranted. We aimed at investigating if per-operative advanced image processing can reduce patient and operator irradiation use during TAVI., Methods: We performed a prospective single-centre observational study comparing patient and operator radiation exposure using standard fluoroscopy (control group) or a novel technology of live advanced fluoroscopic image processing (test group) among consecutive patients undergoing TAVI between August 2015 and April 2016. Patient irradiation (dose-area product, effective dose and air kerma), contrast media volume and clinical outcomes were assessed., Results: Among 152 elderly [median age (interquartile range): 83 (78-87)] patients (n = 76 per group) undergoing TAVI, baseline clinical characteristics were similar between the control and test groups, except for a higher median EuroSCORE II (2.8% vs 2.3%, P = 0.02) and higher rate of TAVI for failing surgical bioprosthesis (11.8% vs 2.6%, P = 0.03) in the control group. The dose-area product was reduced in the test group: mean reduction of -27.5 Gy × cm2 [95% confidence intervals (CIs): 15.9-39.1, P < 0.001]. Furthermore, effective dose [mean reduction -6.5 (95% CI: 5.9-7.2) mSv, P < 0.001] and air kerma [mean reduction -167.5 (95% CI 163.4-177.3) mGy, P < 0.001] were lower in the test group. Fluoroscopy time, contrast volume and clinical outcomes were similar., Conclusions: Patient radiation exposure was significantly reduced using a novel live advanced fluoroscopy image processing with calcification enhancement and fusion of the virtual aortic annulus without compromising patient safety.

Background Prospectively collected frailty markers are associated with an incremental 1-year mortality risk after transcatheter aortic valve replacement (TAVR) compared with comorbidities alone. Whether information on frailty markers captured retrospectively in administrative billing data is similarly predictive of long-term mortality after TAVR is unknown. We sought to characterize the prognostic importance of frailty factors as identified in healthcare billing records in comparison to validated measures of frailty for the prediction of long-term mortality after TAVR. Methods and Results Adult patients undergoing TAVR between August 25, 2011, and September 29, 2015, were identified among Medicare fee-for-service beneficiaries. The Johns Hopkins Claims-based Frailty Indicator was used to identify frail patients. We used nested Cox regression models to identify claims-based predictors of mortality up to 4 years post-procedure. Four groups of variables, including cardiac risk factors, noncardiac risk factors, patient procedural risk factors, and nontraditional markers of frailty, were introduced sequentially, and their integrated discrimination improvement was assessed. A total of 52 338 TAVR patients from 558 clinical sites were identified, with a mean follow-up time period of 16 months. In total, 14 174 (27.1%) patients died within the study period. The mortality rate was 53.9% at 4 years post-TAVR. A total of 34 863 (66.6%) patients were defined as frail. The discrimination of each of the 4 models was 0.60 (95% CI, 0.59-60), 0.65 (95% CI, 0.64-0.65), 0.68 (95% CI, 0.67-0.68), and 0.70 (95% CI, 0.69-0.70), respectively. The addition of nontraditional frailty markers as identified in claims improved mortality prediction above and beyond traditional risk factors (integrated discrimination improvement: 0.019; P<0.001). Conclusions Risk prediction models that include frailty as identified in claims data can be used to predict long-term mortality risk after TAVR. Linkage to claims data may allow enhanced mortality risk prediction for studies that do not collect information on frailty.