Progression Of Aortic Stenosis Research Articles

Ion Channels in the Development and Remodeling of the Aortic Valve.

The role of ion channels is extensively described in the context of the electrical activity of excitable cells and in excitation-contraction coupling. They are, through this phenomenon, a key element for cardiac activity and its dysfunction. They also participate in cardiac morphological remodeling, in particular in situations of hypertrophy. Alongside this, a new field of exploration concerns the role of ion channels in valve development and remodeling. Cardiac valves are important components in the coordinated functioning of the heart by ensuring unidirectional circulation essential to the good efficiency of the cardiac pump. In this review, we will focus on the ion channels involved in both the development and/or the pathological remodeling of the aortic valve. Regarding valve development, mutations in genes encoding for several ion channels have been observed in patients suffering from malformation, including the bicuspid aortic valve. Ion channels were also reported to be involved in the morphological remodeling of the valve, characterized by the development of fibrosis and calcification of the leaflets leading to aortic stenosis. The final stage of aortic stenosis requires, until now, the replacement of the valve. Thus, understanding the role of ion channels in the progression of aortic stenosis is an essential step in designing new therapeutic approaches in order to avoid valve replacement.

Impact of C-reactive protein levels on lipoprotein(a)-associated aortic stenosis incidence and progression.

Elevated lipoprotein(a) [Lp(a)] levels are associated with the risk of coronary artery disease (CAD) and calcific aortic valve stenosis (CAVS). Observational studies revealed that Lp(a) and C-reactive protein (CRP) levels, a biomarker of systemic inflammation, may jointly predict CAD risk. Whether Lp(a) and CRP levels also jointly predict CAVS incidence and progression is unknown. We investigated the association of Lp(a) with CAVS according to CRP levels in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk study (n = 18 226, 406 incident cases) and the UK Biobank (n = 438 260, 4582 incident cases), as well as in the ASTRONOMER study (n = 220), which assessed the haemodynamic progression rate of pre-existing mild-to-moderate aortic stenosis. In EPIC-Norfolk, in comparison to individuals with low Lp(a) levels (<50 mg/dL) and low CRP levels (<2.0 mg/L), those with elevated Lp(a) (>50 mg/dL) and low CRP levels (<2.0 mg/L) and those with elevated Lp(a) (>50 mg/dL) and elevated CRP levels (>2.0 mg/L) had a higher CAVS risk [hazard ratio (HR) = 1.86 (95% confidence intervals, 1.30-2.67) and 2.08 (1.44-2.99), respectively]. A comparable predictive value of Lp(a) in patients with vs. without elevated CRP levels was also noted in the UK Biobank. In ASTRONOMER, CAVS progression was comparable in patients with elevated Lp(a) levels with or without elevated CRP levels. Lp(a) predicts the incidence and possibly progression of CAVS regardless of plasma CRP levels. Lowering Lp(a) levels may warrant further investigation in the prevention and treatment of CAVS, regardless of systemic inflammation.

Aortic stenosis progression: Still a long way to go

Aortic stenosis progression: Still a long way to go

Serum lipoprotein(a) and bioprosthetic aortic valve degeneration.

Bioprosthetic aortic valve degeneration demonstrates pathological similarities to aortic stenosis. Lipoprotein(a) [Lp(a)] is a well-recognized risk factor for incident aortic stenosis and disease progression. The aim of this study is to investigate whether serum Lp(a) concentrations are associated with bioprosthetic aortic valve degeneration. In a post hoc analysis of a prospective multimodality imaging study (NCT02304276), serum Lp(a) concentrations, echocardiography, contrast-enhanced computed tomography (CT) angiography, and 18F-sodium fluoride (18F-NaF) positron emission tomography (PET) were assessed in patients with bioprosthetic aortic valves. Patients were also followed up for 2 years with serial echocardiography. Serum Lp(a) concentrations [median 19.9 (8.4-76.4) mg/dL] were available in 97 participants (mean age 75 ± 7 years, 54% men). There were no baseline differences across the tertiles of serum Lp(a) concentrations for disease severity assessed by echocardiography [median peak aortic valve velocity: highest tertile 2.5 (2.3-2.9) m/s vs. lower tertiles 2.7 (2.4-3.0) m/s, P = 0.204], or valve degeneration on CT angiography (highest tertile n = 8 vs. lower tertiles n = 12, P = 0.552) and 18F-NaF PET (median tissue-to-background ratio: highest tertile 1.13 (1.05-1.41) vs. lower tertiles 1.17 (1.06-1.53), P = 0.889]. After 2 years of follow-up, there were no differences in annualized change in bioprosthetic hemodynamic progression [change in peak aortic valve velocity: highest tertile [0.0 (-0.1-0.2) m/s/year vs. lower tertiles 0.1 (0.0-0.2) m/s/year, P = 0.528] or the development of structural valve degeneration. Serum lipoprotein(a) concentrations do not appear to be a major determinant or mediator of bioprosthetic aortic valve degeneration.

Left ventricular hypertrophy, diastolic dysfunction and right ventricular load predict outcome in moderate aortic stenosis.

Predictors of progression of moderate aortic valve stenosis (AS) are incompletely understood. The objective of this study was to evaluate the prognostic value of left ventricular hypertrophy (LVH), diastolic dysfunction, and right ventricular (RV) load in moderate AS. Moderate AS was defined by aortic valve area (AVA), peak transvalvular velocity (Vmax) or mean pressure gradient (PGmean). A total of 131 Patients were divided into two groups according to the number of pathophysiological changes (LVH, diastolic dysfunction with increased LV filling pressures and/or RV load): <2 (group 1); ≥2 (group 2). The primary outcome was survival without aortic valve replacement (AVR). After follow-up of 30 months, the reduction of AVA (-0.06 ± 0.16 vs. -0.24 ± 0.19 cm2, P < 0.001), the increase of PGmean (2.89 ± 6.35 vs 6.29 ± 7.13 mmHg, P < 0.001) and the decrease of the global longitudinal strain (0.8 ± 2.56 vs. 1.57 ± 3.42%, P < 0.001) from baseline to follow-up were significantly more pronounced in group 2. Survival without AVR was 82% (group 1) and 56% (group 2) [HR 3.94 (1.74-8.94), P < 0.001]. Survival without AVR or progression of AS was 77% (group 1) and 46% (group 2) [HR 3.80 (1.84-7.86), P < 0.001]. The presence of ≥2 pathophysiological changes predicted outcome whereas age, comorbidities, LDL-cholesterol did not. The presence of ≥2 pathophysiological changes is a strong predictor of outcome in moderate AS and may be useful for risk stratification, particularly for scheduling follow-up time intervals and deciding the timing of AVR.

Aortic valve replacement reduces mortality in moderate aortic stenosis: a systematic review and meta-analysis.

With the introduction of transcatheter aortic valve replacement and an evolving understanding of the natural progression and history of aortic stenosis, the potential for earlier intervention in appropriate patients is promising; however, the benefit of aortic valve replacement in moderate aortic stenosis remains unclear. Pubmed, Embase, and the Cochrane Library databases were searched up until 30th of December 2021 using keywords including moderate aortic stenosis and aortic valve replacement. Studies reporting all-cause mortality and outcomes in early aortic valve replacement (AVR) compared to conservative management in patients with moderate aortic stenosis were included. Hazard ratios were generated using random-effects meta-analysis to determine effect estimates. 3470 publications were screened with title and abstract review, which left 169 articles for full-text review. Of these studies, 7 met inclusion criteria and were included, totalling 4,827 patients. All studies treated AVR as a time-dependent co-variable in cox-regression multivariate analysis of all-cause mortality. Intervention with surgical or transcatheter AVR was associated with a 45% decreased risk of all-cause mortality (HR = 0.55 [0.42-0.68], I 2 = 51.5%, P < 0.001). All studies were representative of the overall cohort with appropriate sample sizes, with no evidence of publication, detection, or information biases in any of the studies. In this systematic review and meta-analysis, we report a 45% reduction in all-cause mortality in patients with moderate aortic stenosis who were treated with early aortic valve replacement compared to a strategy of conservative management. Randomised control trials are awaited to determine the utility of AVR in moderate aortic stenosis.

Aortic valve stenosis progression rate according to baseline severity: A systematic review and meta-analysis

Aortic valve stenosis progression rate according to baseline severity: A systematic review and meta-analysis

149 QUANTIFICATION OF FIBROCALCIFIC VOLUME IN AORTIC VALVE STENOSIS BY A NOVEL CONTRAST COMPUTED TOMOGRAPHY METHOD BASED ON A GAUSSIAN MIXTURE MODEL

Abstract Background Discordant echocardiographic measurements are observed in up to one third of patients with aortic stenosis (AS), in whom computed tomography (CT) derived aortic valve calcium scoring is now recommended. Nonetheless, CT calcium scoring only evaluates calcific valve thickening and is unable to assess non-calcific fibrotic thickening, which could be a relevant contributor of AS. Aim of the present study was to generate a quick and robust contrast-CT method based on a gaussian mixture model (GMM) for the assessment of fibro-calcific aortic valve thickening in AS patients, and to investigate its reproducibility and associations with echocardiographic parameters of AS severity and disease progression. Methods A post-hoc analysis of 136 patients with calcific AS (24 with severe, 81 moderate and 31 mild AS) enrolled in the SALTIRE2 trial (Study Investigating the Effects of Drugs used to Treat Osteoporosis on the Progression of Aortic Stenosis) (NCT-02132026) was performed. Aortic valve fibrocalcific volume was calculated using a GMM applied on contrast-CT at baseline and at 1-year follow up. The software estimated the Hounsfield Units (HU) distribution of 3 compartments (blood pool, non-calcific and calcific tissue) within the aortic valve volume of interest, automatically generating thresholds for non-calcific and calcific volumes, respectively computed as the lower 99.7 and the upper 99.7 percentile of the blood pool HU distribution (Figure). Thus, Fibrocalcific volume was measured as the sum of non-calcific and calcific volumes, indexed for CT annulus area and compared to echo parameters of AS severity. Scan-rescan reproducibility and analysis of AS progression were also assessed. Results Image analysis took 5.8 ± 1.0 minutes per scan and showed excellent scan-rescan reproducibility (mean difference -1%, limits of agreement -9% to 7%). Indexed-fibrocalcific volume correlated well with echocardiographic aortic peak velocity (rho=0.70, p&amp;lt;0.0001), better than non-calcific and calcific volumes alone (rho=0.30 and rho=0.61 respectively, both p&amp;lt;0.0001) and Agatston calcium score (rho=0.63, p&amp;lt;0.0001). Baseline indexed-fibrocalcific volume was also the strongest predictor of subsequent AS progression in terms of change in aortic valve peak velocity (rho=0.29, p=0.006) and mean gradient (rho=0.39, p&amp;lt;0.0001). Progression-to-noise ratio for fibrocalcific volume was favourable (Cohen's statistic d=0.62), indicating that groups sizes of 21, 46 and 170 participants would be required to demonstrate 30%, 20% and 10% reductions in fibro-calcific volume progression with a novel drug respectively (alpha=0.05, power=80%). Conclusions This contrast CT-based approach based on a GMM is able to provide robust and relatively rapid assessment of fibrocalcific thickening in patients with AS. Fibrocalcific volume measured using this method, correlates well with other markers of AS severity, predicts disease progression and holds promise in tracking disease progression and response to novel therapies.

Aortic Stenosis Progression: A Systematic Review and Meta-Analysis

BackgroundAortic valve stenosis is a progressive disorder with variable progression rates. The factors affecting aortic stenosis (AS) progression remain largely unknown. ObjectivesThis systematic review and meta-analysis sought to determine AS progression rates and to assess the impact of baseline AS severity and sex on disease progression. MethodsThe authors searched Medline, Embase, and the Cochrane Central Register of Controlled Trials from inception to July 1, 2020, for prospective studies evaluating the progression of AS with the use of echocardiography (mean gradient [MG], peak velocity [PV], peak gradient [PG], or aortic valve area [AVA]) or computed tomography (calcium score [AVC]). Random-effects meta-analysis was performed to evaluate the rate of AS progression for each parameter stratified by baseline severity, and meta-regression was performed to determine the impact of baseline severity and of sex on AS progression rate. ResultsA total of 24 studies including 5,450 patients (40% female) met inclusion criteria. The pooled annualized progression of MG was +4.10 mm Hg (95% CI: 2.80-5.41 mm Hg), AVA −0.08 cm2 (95% CI: 0.06-0.10 cm2), PV +0.19 m/s (95% CI: 0.13-0.24 m/s), PG +7.86 mm Hg (95% CI: 4.98-10.75 mm Hg), and AVC +158.5 AU (95% CI: 55.0-261.9 AU). Increasing baseline severity of AS was predictive of higher rates of progression for MG (P < 0.001), PV (P = 0.001), and AVC (P < 0.001), but not AVA (P = 0.34) or PG (P = 0.21). Only 4 studies reported AS progression stratified by sex, with only PV and AVC having 3 studies to perform a meta-analysis. No difference between sex was observed for PV (P = 0.397) or AVC (P = 0.572), but the level of confidence was low. ConclusionsThis study provides progression rates for both hemodynamic and anatomic parameters of AS and shows that increasing hemodynamic and anatomic baseline severity is associated with faster AS progression. More studies are needed to determine if sex differences affect AS progression. (Aortic Valve Stenosis Progression Rate: A Systematic Review and Meta-Analysis; CRD42021207726)

Abstract 12263: Lack of Diversity in Aortic Stenosis Progression Cohorts: A Systematic Review

Introduction: Aortic stenosis (AS) is characterized by highly variable progression rates. Differential rates of AS progression have been proposed to explain apparent disparities in the treatment of severe AS. However, the evidence supporting this claim is uncertain. Methods: We conducted a systematic review of MEDLINE and EMBASE from 1989 to 2022 to identify prospective cohort studies of AS hemodynamic progression. We evaluated the pooled patient demographics, AS severity, baseline and mean annual changes in echocardiographic markers, and prognostic factors. Results: We identified 32 prospective cohort studies. Overall, 11,432 patients were followed for 27 +/- 15 months on average. The average age was 67 +/- 8 years. The average percent female was 36 +/- 14%. Race was reported in only 4 (13%) cohorts; the average proportion of white patients was 93.9 +/- 6.1%. The average baseline hemodynamic severity was consistent with aortic sclerosis, mild AS, moderate AS, and severe AS in 3 (9.4%), 8 (25.0%), 19 (59.3%), and 2 (6.3%) studies, respectively. Overall, average baseline and annual changes in echocardiographic values were: peak aortic jet velocity (Vmax) 3.21 +/- 0.61 m/s (0.20 +/- 0.09 m/s/yr); aortic valve area (AVA) 1.23 +/- 0.31 cm2 (-0.09 +/- 0.05 cm2/yr); and mean aortic valve gradient (MG) 26.2 +/- 7.6 mmHg (3.9 +/- 1.6 mmHg/yr). Age, sex, coronary artery disease, hypertension, diabetes, hyperlipidemia, and smoking were not associated with AS progression in &gt;75% cohorts. Baseline Vmax and MG were associated with greater AS progression in 6 cohorts (75%). Baseline aortic valve calcification (AVC) and AVA were consistently associated with greater AS progression in 9 cohorts (100%). One cohort found that women have a greater ΔMG for a given level of AVC. A univariate analysis of race in one cohort showed that African American ethnicity was associated with lower risk of progression from normal aortic valves to incident AS. Conclusion: There is limited representation of women and ethnic minorities in prospective AS progression cohorts. Active recruitment of diverse populations in these cohorts is needed. The available clinical evidence provides limited support for claims of differential progression as the cause of racial disparities in AS treatment.

Abstract 12076: Longitudinal Echocardiographic Analysis of Aortic Valve Stenosis Progression

Introduction: Despite its high prevalence, the rate of progression of aortic valve stenosis (AS) remains incompletely characterized and assumed to be constant across the spectrum of AS severity. Previous studies involve limited number of patients, short follow-up, and focused on more severe stages of AS. Hypothesis: The annual rate of AS progression as defined by aortic valve mean gradient (AVMG) increases in magnitude as AS class severity increases. Methods: The study cohort included adult patients with native AS from the MGH echocardiography database from 1990 to 2020. Patients were included if AVMG was reported in at least two echocardiograms in mild, moderate, or severe AS stages. Generalized linear mixed models were employed to simultaneously model fixed effects and random effects stratified by AS severity grade. Multivariable models included age, sex, race, dyslipidemia, DM2, kidney disease, LVEF, moderate/severe AI, and AV morphology. A linear model identified risk factors for rapid progression in severe AS. Results: In 8,848 patients with 29,513 echocardiograms, baseline mean gradient for mild, moderate, and severe AS was 7.0, 20.9, and 43.0 mmHg, respectively. The annual rate of progression in mild, moderate, and severe AS was found to be 0.3, 1.0, and 4.0 mmHg/year. Female gender and white race increased the rate of AVMG by 0.57mmHg/year and 1.05mmHg/year. Conclusions: The progression of AS accelerates with worsening severity of AS. The rate of AVMG progression in severe AS is similar to historically accepted values, but rates are slower for mild and moderate AS. Female gender and white race may be associated with faster progression in severe AS.

Abstract 9260: Rate of Progression of Aortic Stenosis in Patients With Cirrhosis

Introduction: There is currently no published data studying the effect that cirrhosis may have on the rate of progression of aortic stenosis (AS). We hypothesize that AS may have accelerated progression in patients with cirrhosis compared with the general population due to high stroke volumes, hyperdynamic left ventricular function, and a pro-inflammatory state. The aim of this study is to determine the rate of progression of AS in patients with cirrhosis, elucidate risk factors, and assess progression based on the severity of cirrhosis as determined by Model for End Stage Liver Disease (MELD-Na) scores. Methods: This single center retrospective study included 48 patients with the diagnosis of cirrhosis and at least mild AS confirmed by two or more transthoracic echocardiograms (TTEs) taken ≥ 6 months apart. Historical data describing rates of AS progression in non-cirrhotic patients were used for comparison. Results: There was not a significant difference in the rate of AS progression between patients with cirrhosis and those without (table). Using univariate regression analysis, the yearly rate of aortic valve area (AVA) decline was positively correlated with the diagnosis of hyperlipidemia (HLD) (r=.228, P=0.047, B=0.116), initial AVA (r=0.504, P&lt;0.001, B=0.224), initial left ventricular outflow track to aortic valve velocity time integral ratio (LVOT:AV VTI) (r=0.519, P&lt;0.001, B=0.75) and initial left-ventricular stroke volume index (LV-SVI) (r=0.385, P=0.0070, B=0.0070). The yearly decrease of the LVOT:AV peak velocity ratio was inversely correlated with beta-blocker use (r=0.313, P=0.030, B=-0.047). There was not a significant relationship between MELD-Na scores and the rate of AS progression. Conclusion: Patients with cirrhosis can expect a similar rate of AS progression compared with those without cirrhosis. A higher initial LV-SVI and a history of HLD were both associated with faster AS progression in our study cohort.

An endogenous inhibitor of angiogenesis downregulated by hypoxia in human aortic valve stenosis promotes disease pathogenesis

Aortic valve stenosis is the most common valve disease in the western world. Central to the pathogenesis of this disease is the growth of new blood vessels (angiogenesis) within the aortic valve allowing infiltration of immune cells and development of intra-valve inflammation. Identifying the cellular mediators involved in this angiogenesis is important as this may reveal new therapeutic targets which could ultimately prevent the progression of aortic valve stenosis. Aortic valves from patients undergoing surgery for aortic valve replacement or dilation of the aortic arch were examined both ex vivo and in vitro. We now demonstrate that the anti-angiogenic protein, soluble fms-like tyrosine kinase 1 (sFlt1), a non-signalling soluble receptor for vascular endothelial growth factor, is constitutively expressed in non-diseased valves. sFlt-1 expression was, however, significantly reduced in aortic valve tissue from patients with aortic valve stenosis while protein markers of hypoxia were simultaneously increased. Exposure of primary-cultured valve interstitial cells to hypoxia resulted in a decrease in the expression of sFlt-1. We further reveal using a bioassay that siRNA knock-down of sFlt1 in valve interstitial cells directly results in a pro-angiogenic environment. Finally, incubation of aortic valves with sphingosine 1-phosphate, a bioactive lipid-mediator, increased sFlt-1 expression and inhibited angiogenesis within valve tissue. In conclusion, this study demonstrates that sFlt1 expression is directly correlated with angiogenesis in aortic valves and the observed decrease in sFlt-1 expression in aortic valve stenosis could increase valve inflammation, promoting disease progression. This could be a viable therapeutic target in treating this disease.

Predicting progression of aortic stenosis by measuring serum calcification propensity.

The aim of this prospective, double-blinded study in patients with aortic sclerosis was to determine whether a new calcification propensity measure in the serum could predict disease progression. We included 129 consecutive patients with aortic sclerosis as assessed during a routine clinical echocardiographic exam. Clinical, echocardiographic, and serum laboratory parameters were collected, including a new blood test providing an overall measure of calcification propensity by monitoring the maturation time of calciprotein particles (T50 test). The echocardiographic exam was repeated after 1 year. Multiple regression analysis was performed to identify independent predictors of the annual increase of peak transvalvular Doppler velocity (∆vmax). Furthermore, the accuracy of the T50 test to detect patients with the most marked stenosis progression was assessed by receiver operating characteristic (ROC)-analysis. Mean age was 75 ± 9 years, 79% were men. The T50 was 271 ± 58 min. Overall, there was no significant stenosis progression between baseline and follow-up (∆vmax 3.8 ± 29.8 cm/s, p = ns). The T50 test was not found to be an independent linear predictor in multivariate testing. By ROC-analysis, however, a T50-value ≤ 242 min was able to significantly detect a ∆vmax above the 90th percentile (∆vmax ≥ 43 cm/s, AUC = 0.67, p = .04, Sensitivity = 69%, Specificity = 70%). The T50 test showed a modest but significant ability to identify a pronounced aortic stenosis progression in patients with aortic sclerosis. The test could not be established as an independent linear predictor of disease progression, possibly due to the low valvular disease burden and short follow-up interval.

Which is the best time to perform balloon valvuloplasty in critically fetal aortic stenosis: Prenatally or after birth?

Fetal aortic valvuloplasty may prevent the progression of severe fetal aortic stenosis to hypoplastic left heart syndrome at birth. Since it is an high risk procedure a careful selection of fetuses that can benefit from the prenatal treatment instead of waiting for postnatal intervention.

Factors Affecting Rate of Progression of Aortic Stenosis and Its Impact on Outcomes

The rate of aortic stenosis (AS) progression in patients with moderate AS is unclear. This study examined the risk factors of progression from moderate to severe AS and its impact on clinical outcomes. A total of 954 patients with moderate AS (valve area >1.0 and ≤1.5cm²) and follow-up echocardiograms were included. AS progressed to severe (valve area <1.0cm1) in 589 patients (61.7%) over a median follow-up of 2.46 (interquartile range [IQR] 1.29 to 3.91) years. Of those who progressed to severe AS, patients were subdivided into Slow (n=294, over 3.91 [IQR 3.11 to 5.10] years) versus Fast (n=295, over 1.29 [IQR 0.85 to 1.85] years) Progressors, according to the median time between the 2 echocardiograms. The correlates of fast AS progression and its impact on cumulative survival and freedom from valve intervention were evaluated. On multivariate analysis, age, thickened left ventricle posterior wall, severe renal impairment, and aortic valve area were significantly associated with fast AS progression. Over a median follow-up of 6.34 (IQR 4.05 to 9.55) years, 228 patients (38.7%) died. Despite similar aortic valve intervention rates, Fast Progressors had worse 5-year survival (61.2% vs 81.9%, log-rank p<0.001) and event-free (valve intervention and all-cause mortality) survival rates (16.2% vs 55.9%, log-rank p<0.001). On multivariable Cox analysis, shorter progression to severe AS (in years) was independently associated with increased risk of all-cause mortality (hazard ratio1.26, 95% confidence interval 1.16 to 1.37, p<0.001), or combined aortic valve intervention and death (hazard ratio1.46, 95% confidence interval 1.38 to 1.55, p<0.001). In conclusion, fast progression from moderate to severe AS is associated with worse outcomes.

Association of anti-citrullinated peptide antibodies with the progression of aortic stenosis

Abstract Background/Purpose Aortic stenosis (AS) is common in an aging population, but disease activity biomarkers are lacking. The pathophysiology of calcific AS shares many similarities with atherosclerosis, including lipid deposition, inflammation, and calcification. Citrullination is a part of many chronic inflammatory processes and citrullinated proteins have been found within atherosclerotic plaque. Thus, we investigated whether the presence of anti-citrullinated peptide antibody, especially anti-CCP antibody, might be associated with AS. Methods A retrospective observational study was conducted for 678 patients who underwent echocardiography and anti-CCP antibody test between April 2004 and July 2020. Anti-CCP antibody status was regarded as positive when concentrations exceeded the upper limit of normal (ULN), and any lower value was considered negative. The anti-CCP antibody-positive group was subdivided into two groups: low-positive for ≥ ULN but &amp;lt; the median, and high-positive ≥ the median value (Figure 1A). Also, aortic valve (AV) tissues were obtained from the patients with AS or not at the time of surgical aortic valve replacement or heart transplantation, who did not have rheumatoid arthritis. We analyzed the presence of citrullinated proteins in the AV by immunohistochemistry and Western blotting. Results 241 (35.5%) subjects showed AV degeneration in baseline echocardiography. They had a higher anti-CCP antibody positivity rate (42.7% vs. 34.6%, p=0.035) than the subjects without AV degeneration. Of total patients, 331 (48.8%) subjects underwent follow-up echocardiography (median follow-up duration 4.6 years [interquartile range 2.0–8.0 years]). AS progression, which was defined as an increase of at least one grade in AS severity classification on follow-up echocardiography, was observed in 34 (10.3%) patients. The progression of AS occurred more in the high-positive group than in the low-positive or negative group (19.0% vs. 11.3% vs. 8.4%, respectively; p=0.041) (Figure 1B). In multivariate analysis, the high-positivity of anti-CCP antibody was an independent predictor of AS progression (Odds ratio: 2.312; 95% confidence interval: 1.006–5.310; p=0.048) (Figure 1C). Increased citrullination was visualized in areas with diseased AV compared with normal AV tissue by immunohistochemistry (Figure 2A, 2B) and Western blotting (Figure 2C, 2D). These results suggested the possible association with the citrullinated peptide-related inflammation process and the pathophysiology of AS. Conclusion A positive result of anti-CCP antibody, especially with a high titer, was associated with AV degenerative change at baseline echocardiography. Also, anti-CCP antibody positivity was an independent factor for predicting the progression of AS. These findings suggest that citrullination can be a part of the pathophysiology of AS. Furthermore, the anti-CCP antibody can be a biomarker predicting AS progression. Further research will be needed. Funding Acknowledgement Type of funding sources: None.

Live longer and better without aortic valve stenosis

Live longer and better without aortic valve stenosis

Enduring Reactive Oxygen Species Emission Causes Aberrant Protein S-Glutathionylation Transitioning Human Aortic Valve Cells from a Sclerotic to a Stenotic Phenotype.

Aims: During calcific aortic valve stenosis (CAVS) progression, oxidative stress and endothelial dysfunction mark the initial pathogenic steps with a parallel dysregulation of the antioxidant systems. Here, we tested whether oxidation-induced protein S-glutathionylation (P-SSG) accounts for a phenotypic switch in human aortic valvular tissue, eventually leading to calcium deposition. Next, we tested whether countering this reactive oxygen species (ROS) surge would prevent these perturbations. Results: We employed state-of-the-art technologies, such as electron paramagnetic resonance (EPR), liquid chromatography-tandem mass spectrometry, imaging flow-cytometry, and live-cell imaging on human excised aortic valves and primary valve endothelial cells (VECs). We observed that a net rise in EPR-detected ROS emission marked the transition from fibrotic to calcific in human CAVS specimens, coupled to a progressive increment in P-SSG deposition. In human VECs (hVECs), treatment with 2-acetylamino-3-[4-(2-acetylamino-2-carboxyethylsulfanylthiocarbonylamino)phenylthiocarbamoylsulfanyl]propionic acid triggered highly oxidizing conditions prompting P-SSG accumulation, damaging mitochondria, and inducing endothelial nitric oxide synthase uncoupling. All the events conjured up in morphing these cells from their native endothelial phenotype into a damaged calcification-inducing one. As proof of principle, the use of the antioxidant N-acetyl-L-cysteine prevented these alterations. Innovation: Borne as a compensatory system to face excessive oxidative burden, with time, P-SSG contributes to the morphing of hVECs from their innate phenotype into a damaged one, paving the way to calcium deposition. Conclusion: Our data suggest that, in the human aortic valve, unremitted ROS emission along with a P-SSG build-up occurs and accounts, at least in part, for the morphological/functional changes leading to CAVS. Antioxid. Redox Signal. 37, 1051-1071.

Determinants of Aortic Stenosis Progression in Bicuspid and Tricuspid Aortic Valves.

Bicuspid aortic valve (BAV) is associated with a faster progression of aortic stenosis (AS). Whether the determinants of AS progression are the same or different in patients with BAV vs tricuspid aortic valve (TAV) is unknown. The aim of this study was to identify the factors associated with the progression of AS in patients with BAV vs patients with TAV. Patients with AS were prospectively recruited in the Metabolic Determinants of the Progression of Aortic Stenosis (PROGRESSA) study (ClinicalTrials.gov Identifier: NCT01679431). The haemodynamic progression rate of AS was assessed by the annualized progression rate of peak aortic jet velocity (Vpeak). Univariable and multivariable linear regression analyses were used to identify the factors associated with a faster progression of AS in patients with BAV vs patients with TAV. There were 79 patients with BAV and 208 patients with TAV. The baseline severity of AS was similar between the 2 groups of patients as well as the annualized progression rate of AS. In patients with BAV, obesity (β= 0.25, P= 0.04), diabetes (β= 0.26, P= 0.02), and BAV with right-noncoronary cusp fusion (β= 0.29, P= 0.01) were found to be independently associated with a faster progression of AS, whereas in patients with TAV, AS baseline severity (baseline Vpeak, β= 0.14, P= 0.04) and chronic kidney disease (β= 0.16, P= 0.02) were significantly associated with AS progression. Factors associated with progression rate of AS are different in BAV and TAV. The main factors associated with a faster progression of AS appear to be obesity, diabetes, right-noncoronary cusp fusion in patients with BAV vs chronic kidney disease in patients with TAV.