Faster Aortic Stenosis Progression Research Articles

Abstract 14799: Sex Differences in Health Status Decline of Patients With Aortic Valve Stenosis: Results From the Progressa Study

Introduction: The assessment of symptoms status is pivotal to optimize the timing of aortic valve intervention in aortic stenosis (AS). However, little is known about the effect of sex on health status decline (i.e. functional status and quality of life) in AS patients. We evaluated the change in health status according to sex in patients with mild to moderate AS. Methods: Two hundred eighty-five patients with AS (peak aortic jet velocity [V peak ]≥2.0 m/s) prospectively recruited in the PROGRESSA study (NCT01679431) were included in this analysis. Health status was evaluated using the New York Heart Association (NYHA) classification and the Duke Activity Score Index (DASI). Results: At baseline, men were older (67±12 vs 61±17 yr; p=0.001), had more comorbidities including hypertension, coronary artery disease, and atrial fibrillation (all, p≤0.01), and more severe AS compared to women (2.8±0.5 vs 2.6±0.4 m/s; p=0.01). However, women had more symptoms (class I, II, III: 44%, 53%, 3% versus 63%, 36%, 1%; p=0.02) and significantly lower DASI (38±14 vs 43±13; p=0.006). During a mean follow-up of 3.9±2.4 years, despite faster AS progression rate in men (V peak increase: 0.16±0.2 vs 0.12±0.2 m/s/year; p=0.02), the worsening of symptoms (NYHA ≥I class; n=70) and decline in DASI score were comparable according to sex (Figure). However, for the same hemodynamic AS progression rate, women had significantly faster decline in DASI score (Figure). In linear mixed analysis adjusted for several clinical and echocardiographic risk factors, female sex remained significantly associated with the worsening of NYHA class (odds ratio: 3.9; 95% CI: 2.1 to 7.2; p<0.0001) and the decline in DASI score (coeff.: -9; 95% CI: -11 to -6; p<0.0001). Conclusion: Despite a better clinical profile and less severe AS, women generally had worse symptomatic status compared to men, and this difference was accentuated throughout follow-up. These findings raise the question of symptoms minimisation in women.

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<0.001, B=0.224), initial left ventricular outflow track to aortic valve velocity time integral ratio (LVOT:AV VTI) (r=0.519, P<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.

Higher rate of aortic stenosis progression in patients with bicuspid versus tricuspid aortic valve – A single center experience

PurposeWe sought to investigate aortic stenosis (AS) progression rate (pr) with the comparison between bicuspid aortic valve (BAV) and tricuspid aortic valve (TAV) morphology. Materials and methodsWe compared ASpr in patients with BAV and TAV examined by transthoracic echocardiography (TTE) in the years 2004–2019. ResultsData from 363 TTEs in 161 AS patients (median age 70 [61–77] years; 63% men; 25% with BAV; 20% with severe AS) performed at different time points (median time interval 10 months) was analyzed. We assessed changes of AS severity with peak velocity through aortic valve (Vmax), mean/peak pressure gradients (MG/PG), aortic valve area by planimetry and continuity equation (AVAce). We compared pr (defined as parameter change per year) between the BAV and the TAV groups. BAV patients showed faster ASpr with odds ratio 3.467 and 95% confidence intervals 1.36 to 8.86, moreover, expressed as a quicker AVAce decrease 0 (−0.4-0.0) in the BAV vs. 0 (−0.15 – 0.0) cm2/year in the TAV group, p ​= ​0.02. Furthermore, in BAV, female sex was associated with lower ASpr (p ​= ​0.01), and in the whole group a larger aortic diameter was a predictor of faster progression (p ​< ​0.001). ConclusionThe ASpr, expressed as a decrease in the AVAce, was faster in BAV. Moreover, ASpr depends on both: valve morphology being faster in BAV and Vmax increase. Furthermore, the female sex was related to slower pace of AVA reduction in BAV subgroup whereas the larger baseline aortic diameter associated to faster AS progression in the whole studied group.

Abstract 18719: Relationship Between Proximal Aorta Morphology and Progression Rate of Aortic Stenosis

Background: Morphological changes of the proximal aorta, such as effacement of the sinotubular junction (STJ), may result in increased mechanical stress on the aortic valve leaflets and contribute to calcification and progression of aortic stenosis (AS). The aim of this study was to examine the association between abnormal morphology of proximal aorta and AS progression rate. Methods: Between 2010 and 2012, 426 patients with mild to moderate AS (peak aortic jet velocity &gt;2.5 and &lt;4 m/s) and LVEF≥50% with at least two years of follow up were included in this study. Aortic dimensions were measured at 3 different levels: sinus of Valsalva (SVal), STJ and ascending aorta (Aa). The ratios of SVal by STJ (SVal/STJ) and Aa by STJ (Aa/STJ) were used to determine degree of aortic deformity with smaller ratios consistent with greater perturbation of normal geometry. SVal/STJ&lt;1.13 and Aa/STJ&lt;1.09 were defined as significant low ratios per normal range reported in Guidelines. AS progression rate was assessed by annualized increase in mean gradient (MG; follow-up time = 3.2±0.8 yrs). Results: Mean age was 71±13 yrs and 64% were male. 16% had bicuspid aortic valve and MG was 21±8 mmHg. SVal, STJ and Aa dimensions were respectively 33±4 mm, 27±4 mm and 36±5 mm. Mean SVal/STJ ratio was 1.21±0.15 and Aa/STJ ratio was 1.29±0.19. Patients with significant low ratios had faster AS progression (p≤0.05; figure). After adjustment for age, gender, hypertension, diabetes, renal disease, bicuspid aortic valve, baseline MG, LVEF, aortic regurgitation and indexed STJ, SVal/STJ (p=0.025) or Aa/STJ (p=0.027) were independently associated with faster AS progression. Conclusion: Abnormal aortic root geometry such as effacement of the sinotubular junction is a strong and independent predictor of faster AS progression, regardless of arterial hemodynamics, aortic valve phenotype and baseline AS severity. This finding suggests an interrelation between proximal aorta morphology and stenosis progression.

Abstract 18449: Apolipoprotein B/Apolipoprotein A-I Ratio and Progression of Aortic Valve Stenosis - Results From the PROGRESSA Study

Introduction: Calcific aortic stenosis (AS) is an active and complex disorder, which involves atherosclerotic-like processes. However, previous studies reported that the association between atherosclerotic risk factors and AS progression appears to be stronger in younger middle-aged patients compared to elderly ones. Hypothesis: Apolipoprotein B/apolipoprotein A-I (apoB/apoA-I) ratio reflects the balance between proatherogenic versus antiatherogenic lipid profile. The objective of this study was to examine the association between apoB/apoA-I ratio and progression of AS according to patient’s age. Methods: One hundred sixty five patients with AS were prospectively recruited in the PROGRESSA study. AS progression was assessed by increase in peak aortic jet velocity (Vpeak) measured by Doppler echocardiography between baseline and 2-year follow-up. Blood samples were collected to measure plasma levels of apoB and apoA-I. Results: The mean age was 66±13 years and 72% were male. During the 2-year follow-up, AS progression was similar in younger patients (age &lt;69 y.o. [median age for the whole cohort]; n=82) and older patients (Vpeak: +0.24±0.04 vs +0.25±0.03 m/s; p=0.82). There was a significant interaction (p&lt;0.01) between patient’s age and baseline apoB/apoA-I ratio for AS progression. Younger patients with high baseline apoB/apoA-I ratio (i.e. apoB/apoA-I ≥0.53; n=41) had faster AS progression compared to those with lower apoB/apoA-I ratio (Vpeak: +0.32±0.06 vs +0.16±0.04 m/s; p=0.03). In older patients, there was no significant association between apoB/apoA-I ratio and AS progression (Vpeak: +0.23±0.05 vs +0.27±0.04 m/s; p=0.55). After adjustment for sex, hypertension, dyslipidemia, diabetes, metabolic syndrome, creatinine level, degree of aortic valve calcification and baseline Vpeak, higher apoB/apoA-I ratio remained independently associated with faster progression of AS in younger patients (p=0.003). Conclusions: This prospective study shows for the first time that higher apoB/apoA-I ratio is a powerful and independent predictor of faster AS progression in younger patients. These findings suggest that the pathological processes involved in the progression of AS are different in younger versus older patients.

Oxidized Phospholipids, Lipoprotein(a), and Progression of Calcific Aortic Valve Stenosis

BackgroundElevated lipoprotein(a) (Lp[a]) is associated with aortic stenosis (AS). Oxidized phospholipids (OxPL) are key mediators of calcification in valvular cells and are carried by Lp(a). ObjectivesThis study sought to determine whether Lp(a) and OxPL are associated with hemodynamic progression of AS and AS-related events. MethodsOxPL on apolipoprotein B-100 (OxPL-apoB), which reflects the biological activity of Lp(a), and Lp(a) levels were measured in 220 patients with mild-to-moderate AS. The primary endpoint was the progression rate of AS, measured by the annualized increase in peak aortic jet velocity in m/s/year by Doppler echocardiography; the secondary endpoint was need for aortic valve replacement and cardiac death during 3.5 ± 1.2 years of follow-up. ResultsAS progression was faster in patients in the top tertiles of Lp(a) (peak aortic jet velocity: +0.26 ± 0.26 vs. +0.17 ± 0.21 m/s/year; p = 0.005) and OxPL-apoB (+0.26 ± 0.26 m/s/year vs. +0.17 ± 0.21 m/s/year; p = 0.01). After multivariable adjustment, elevated Lp(a) or OxPL-apoB levels remained independent predictors of faster AS progression. After adjustment for age, sex, and baseline AS severity, patients in the top tertile of Lp(a) or OxPL-apoB had increased risk of aortic valve replacement and cardiac death. ConclusionsElevated Lp(a) and OxPL-apoB levels are associated with faster AS progression and need for aortic valve replacement. These findings support the hypothesis that Lp(a) mediates AS progression through its associated OxPL and provide a rationale for randomized trials of Lp(a)-lowering and OxPL-apoB-lowering therapies in AS. (Aortic Stenosis Progression Observation: Measuring Effects of Rosuvastatin [ASTRONOMER]; NCT00800800)

Implementation of diagnosis in asymptomatic patients with aortic stenosis: the Implementation of Diagnosis in asymptomatic patiEnts with Aortic Stenosis registry.

Frequently in clinical practice, some physicians refer patients with aortic stenosis for an invasive approach in the asymptomatic phase of the disease. This empirical behaviour, which is in contrast with the recommendations of the current international clinical guidelines, is due to the perception that the prognosis of these patients is truly worse than retained. Actually, the management of asymptomatic patients with aortic stenosis remains controversial, and there is no clear agreement on how to reduce excess clinical events associated with the presence of aortic stenosis mortality and morbidity demonstrated in these patients by recent randomized clinical trials. The prevailing attention of the attending physicians is often limited to the assessment of the aortic stenosis severity and appearance of symptoms, but it has been clearly shown, instead, that the prognosis of these patients is associated with excessive left-ventricular mass growth and increased atherosclerosis leading to coronary artery disease, heart failure, stroke and death. Thus, apart from the markers of faster aortic stenosis progression, many other clinical and echocardiographic variables should be considered, collected and used together with the clinical/echocardiographic prognostic scores recently validated by several authors in clinical practice, where the vast majority of these variables are guiltily not taken into any consideration. The registry on the Implementation of Diagnosis in asymptomatic patiEnts with Aortic Stenosis is a prospective study designed with the aim to improve the diagnostic evaluation and improve the prognostic stratification of patients with asymptomatic aortic stenosis.

Abstract 16680: Lipoprotein(a) and Progression Rate of Aortic Valve Stenosis - A Pooled-Analysis of Two Prospective Studies

BACKGROUND: Recent studies have reported a single nucleotide polymorphism (i.e. rs10455872) at the LPA gene locus, encoding the lipoprotein(a) [Lp(a)], is associated with the presence of aortic valve calcification and clinical aortic stenosis (AS). The objectives of this study were to examine the association of Lp(a) plasma levels and rs 10455872 with the progression rate of AS. METHODS: Lp(a) plasma levels were measured in 203 patients with AS included in the ASTRONOMER (NCT00800800) trial and 246 patients in the PROGRESSA study (NCT01679431). The polymorphism rs10455872 was genotyped in the PROGRESSA cohort. Hemodynamic progression rate of AS severity was assessed by measuring the annualized increase in peak aortic jet velocity (Vpeak) by Doppler-echocardiography. RESULTS: Twenty-seven (13%) patients of the ASTRONOMER trial and 47 (19%) of the PROGRESSA study had high Lp(a) plasma levels (i.e. &gt;50mg/dL). Baseline AS severity was similar in patients with high vs. low Lp(a) levels (p&gt;0.10). In the pooled-analysis of both cohorts (a total of 449 patients with mean follow-up: 3.0 ±1.4 yrs), AS progression rate was similar in patients with Lp(a)&gt;50 mg/dL compared to those with Lp(a)≤50 mg/dL (annualized change in Vpeak: +0.17±0.21 vs. +0.17±0.21 m/s/yr; p=0.97). Stratified analyses by cohort provided consistent results (ASTRONOMER: +0.20±0.21 vs. +0.25±0.19 m/s/yr; p=0.20; and PROGRESSA: +0.12±0.21 vs. +0.14±0.20 m/s/yr; p=0.46). In the PROGRESSA study, 38 (16%) patients carried at least one rs10455872 risk allele. Carriers of the risk allele had higher Lp(a) levels (58±24 vs. 20±38 mg/dL; p&lt;0.0001). Baseline AS severity was similar in carriers and non-carriers whereas there was a borderline significant association for lower AS progression rate in carriers compared to non-carriers (+0.07±0.17 vs. +0.15±0.21 m/s/yr; p=0.05). Similar results were obtained for baseline and annualized progression rate assessed by aortic valve area. CONCLUSION: This prospective study shows that neither LPA gene variant nor Lp(a) plasma levels are associated with faster AS progression rate. Our findings do not support the notion that Lp(a) levels are related to AS progression rate in patients with AS.

Impact of Plasma Lp-PLA2 Activity on the Progression of Aortic Stenosis: The PROGRESSA Study

ObjectivesThe purpose of this prospective study was to examine the relationship between plasma lipoprotein–associated phospholipase A2 (Lp-PLA2) activity and the progression rate of aortic stenosis (AS). BackgroundWe recently reported that Lp-PLA2 is highly expressed in stenotic aortic valves where it may contribute to the mineralization of valvular interstitial cells. MethodsPatients with AS were prospectively recruited in the PROGRESSA (Metabolic Determinants of the Progression of Aortic Stenosis) study. AS progression rate was assessed by annualized increase in peak aortic jet velocity (Vpeak), mean gradient (MG), and aortic valve area index (AVAi). Circulating Lp-PLA2 activity was measured and dichotomized based on the median value. ResultsOf 183 patients included in this subanalysis of the PROGRESSA study, 70% were men and the mean age was 66 ± 13 years. Over the 2.5 ± 1.4 years of follow up, the AS progression rate tended to be higher in patients with high versus low Lp-PLA2 activity (annualized Vpeak = 0.17 ± 0.23 m/s vs. 0.12 ± 0.18 m/s; p = 0.14). There was a significant interaction (p < 0.05) between baseline AS severity and Lp-PLA2 activity with respect to impact on AS progression rate. In patients with mild AS (i.e., Vpeak <3 m/s; n = 123), increased Lp-PLA2 activity was associated with a significantly faster AS progression rate (Vpeak 0.16 ± 0.18 m/s vs. 0.09 ± 0.14 m/s; p = 0.01) but not in patients with moderate or severe AS (p = 0.99). After adjustment for other risk factors, increased Lp-PLA2 activity remained independently associated with faster AS progression rate (p = 0.005) in the former subset. ConclusionsThere was no significant association between plasma Lp-PLA2 activity or mass and stenosis progression in the whole cohort. However, increased Lp-PLA2 activity was associated with a faster stenosis progression rate in the subset of patients with mild AS. These findings provide an impetus for the elaboration of a randomized trial targeting Lp-PLA2 activity in patients with early stages of calcific aortic valve disease.

LIPOPROTEIN(A) AND PROGRESSION RATE OF AORTIC VALVE STENOSIS - THE PROGRESSA STUDY

Recent studies have reported a single nucleotide polymorphism (i.e. rs10455872) at the LPA gene locus, encoding the lipoprotein(a) [Lp(a)], associated with the presence of aortic valve calcification and the incidence of clinical aortic stenosis (AS). The objectives of this study was to examine the association of rs10455872 and Lp(a) plasma levels with the progression rate of AS. 246 consecutive patients with AS were prospectively recruited in the PROGRESSA study and underwent a comprehensive Doppler-echocardiography annually. Blood-DNA and plasma samples were collected to genotype the rs10455872 polymorphism and to measure Lp(a) plasma levels. Hemodynamic progression rate of AS severity was assessed by measuring the annualized increase in peak aortic jet velocity (Vpeak). Among the 246 patients included in the study, 38 (16%) patients carried at least one rs10455872 risk allele and 47 (19%) had high Lp(a) plasma level (i.e. >50mg/dL). Carriers of the risk allele had higher Lp(a) levels (58±24 vs. 20±38 mg/dL; p<0.0001). Baseline AS severity was similar in carriers and non-carriers (Vpeak: 2.8±0.4 vs. 2.9±0.7 m/s; p=0.33), as well as in patients with high vs. low Lp(a) levels (2.9±0.5 vs. 2.9±0.6 m/s; p=0.97). There was a borderline significant association for lower AS progression rate in carriers compared to non-carriers (annualized change in Vpeak: +0.07±0.17 vs. +0.15±0.21 m/s/yr; p=0.05), whereas patients with high Lp(a) levels had similar stenosis progression rate (+0.12±0.21 vs. +0.14±0.20 m/s/yr; p=0.46). Similar results were obtained with the analysis of baseline and annualized change in aortic valve area. This prospective study shows that neither LPA gene variant nor Lp(a) plasma levels are associated with faster AS progression rate. These findings suggest that Lp(a) lowering therapy may not be efficient to delay or stop stenosis progression in patients with AS.

USEFULNESS OF AORTIC VALVE CALCIFICATION MEASURED BY COMPUTED TOMOGRAPHY TO PREDICT HEMODYNAMIC PROGRESSION OF AORTIC STENOSIS

Prediction of Aortic Stenosis (AS) progression is crucial for follow-up and surgical timing. Aortic valve calcification (AVC) measured by Multi Detector Computed Tomography (MDCT) is a fundamental measure of AS lesion severity but it is uncertain whether it predicts faster AS progression. 227 AS

Circulating Levels of Matrix Gla Protein and Progression of Aortic Stenosis: A Substudy of the Aortic Stenosis Progression Observation: Measuring Effects of Rosuvastatin (ASTRONOMER) Trial

BackgroundMatrix γ-carboxyglutamate protein is an inhibitor of cardiovascular calcification. The objective of this substudy of the Aortic Stenosis Progression Observation: Measuring Effects of Rosuvastatin (ASTRONOMER) trial was to examine the relationship between total (ie, carboxylated [active] form + uncarboxylated [inactive] form) circulating desphosphorylated matrix γ-carboxyglutamate protein (dpMGP) level and the progression rate of aortic stenosis (AS). MethodsAmong the patients included in the ASTRONOMER trial, 215 patients had measures of baseline circulating total dpMGP level and an echocardiographic follow-up (mean follow-up: 3.5 ± 1.3 years). Progression of AS was assessed according to the measurement of the annualized increase in peak aortic jet velocity. ResultsIn the whole cohort, baseline dpMGP level was associated with faster progression rate of peak aortic jet velocity (r = 0.16; P = 0.02) in individual analysis but not in multivariable analysis (P = 0.40). However, there was a significant interaction (P = 0.03) between dpMGP level and age, with respect to the effect on AS progression. After dichotomization according to median value of age (ie, 57 years old), total dpMGP level was associated with faster AS progression rate (r = 0.24; P = 0.008) in the younger patients, and this association remained significant in multivariable analysis (P = 0.04), but not in the older ones. The independent correlates of dpMGP level were fasting glucose (P = 0.009) and oxidized low-density lipoprotein (P = 0.01). ConclusionsThis is the first prospective study to demonstrate a relationship between increased circulating levels of total dpMGP and faster progression rate of AS in younger individuals. Future studies are needed to determine if dpMGP is simply a marker or a contributing factor to ectopic mineralization of aortic valve.

Impact of hypertension and renin–angiotensin system inhibitors in aortic stenosis

Experimental studies revealed that renin-angiotensin system (RAS) could play a crucial role in the pathophysiology of aortic stenosis (AS). The objectives of this study were to examine (i) the impact of hypertension on AS progression and clinical events and (ii) the effect of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs). In this observational study, we retrospectively analysed clinical and Doppler echocardiographic data prospectively collected in 338 patients with AS. Patients were separated into four groups: patients without hypertension and not treated by RAS medication (Ctrl group), patients with hypertension but not treated by RAS medication (HTN group), patients treated with ACEIs, and patients treated with ARBs. AS progression rate was assessed by the annualized increase in peak aortic jet velocity. Compared with Ctrl group, patients in HTN group had faster stenosis progression (P=0·01). Patients on ARBs had slower AS progression compared with Ctrl (trend P=0·10) and HTN (P=0·002) groups, whereas patients on ACEIs had similar progression rate compared with Ctrl group (P=NS) but lower compared with HTN group (P=0·02). On multivariable analysis, compared with Ctrl group, HTN group was associated with faster AS progression rate (P=0·002), whereas ARBs with slower progression (P=0·0008). During a mean follow-up of 6·2±2·4years, HTN (hazard ratio [HR]=2·45; P=0·006) and ACEI (HR=2·30; P=0·01) groups were associated with a significant increase in all-cause mortality compared with Ctrl group, whereas ARB group (HR: 0·89; P=0·80) not. In multivariable analysis, HTN and ACEI groups remained associated with increased mortality. Hypertension is associated with significantly faster stenosis progression and higher incidence of clinical events in patients with AS. ARBs but not ACEs were found to abolish the increased risk of mortality associated with hypertension.

Congenital valvular aortic stenosis in young adults: Predictors for rate of progression of stenosis and aortic dilatation

Congenital aortic stenosis (AS) is the most common obstructive left-sided cardiac lesion in young adults, however little is known about the progression in adults. Therefore, we aimed to evaluate the progression rate of AS and aortic dilatation in a large multicenter retrospective cohort of asymptomatic young adults with congenital valvular AS. Data were obtained from chart abstraction. Linear mixed-effects models were used to evaluate the progression of AS and aortic dilatation over time. A joint model combining longitudinal echocardiographic and survival data was used for survival analysis. A total of 414 patients (age 29 ± 10 years, 68% male) were included. Median follow-up duration was 4.1 (2.5-5.1) years (1587 patient-years). Peak aortic velocity was 3.4 ± 0.7 m/s at baseline and did not change over time in the total patient population (-0.01 ± 0.03 m/s/year). Increased left ventricular mass was significantly associated with faster AS progression (p<0.001). Aortic dilatation was present in 34% at baseline and 48% at follow-up (p<0.001). The aortic diameter linearly increased over time with a rate of 0.7 ± 0.2mm/year. Rate of aortic dissection was 0.06% per patient-year. Seventy patients required an aortic valve intervention (4.4% per patient-year), with AS progression rate as most powerful predictor (HR 5.11 (95% CI 3.47-7.53)). In the majority of patients with mild-to-moderate congenital AS, AS severity does not progress over time. However patients with left ventricular hypertrophy are at risk for faster progression and should be monitored carefully. Although aortic dissections rarely occur, aortic dilatation is common and steadily progresses over time, warranting serial aortic imaging.

584 Circulating Matrix GLA Protein and Faster Progression Rate of Aortic Stenosis - a Substudy of the Astronomer Trial

In a previous substudy of the ASTRONOMER trial, we reported that metabolic syndrome (MetS) is associated with faster progression of aortic stenosis (AS). Recent studies suggested that dysregulation of mineral metabolism or its modulators could play a role in the pathogenesis of AS. The carboxylated form of the Matrix Gla Protein (MGP) is an inhibitor of ectopic calcification. The objective of this study was to determine the association between circulating levels of the total (i.e. carboxylated and non carboxylated) MGP and AS progression rate. Among the 269 patients randomized in ASTRONOMER, mean follow-up time 3.4 ±1.3 years, 217 had baseline measurement of circulating level of total MGP. None of the patient had hypercholesterolemia, diabetes, or coronary artery disease at baseline. However, 29% had systemic hypertension and 28% had MetS. Hemodynamic progression rate of AS was measured with the use of the annualized increase in peak aortic jet velocity (Vpeak). In the whole cohort, baseline MGP level was significantly associated with AS progression rate in univariate analysis (r=0.15; p=0.03) but not in multivariate analysis (p=NS). There was a significant interaction (p=0.03) between MGP level and age with respect to its relationship with AS progression rate. In the subset of patients with age<57 years (median value), higher MGP level was significantly associated with faster AS progression rate (r=0.22; p=0.02) whereas no such relationship was observed in older patients. After adjustment for gender, hypertension, LDL-chol, creatinin, baseline valve calcification and Vpeak, and status of randomization (statin vs. placebo), higher MGP level (p=0.008) and MetS (p=0.001) were independent predictors of faster AS progression in younger patients. Baseline level of MGP was positively related to age (p=0.03), LDL-chol (p=0.02), oxidized-LDL (p=0.005), glycaemia (p=0.001), and HOMA-IR index (p=0.05). In multivariate analysis, oxidized-LDL (p=0.03) and glycaemia (p=0.01) were the only two factors independently associated with circulating MGP levels. This study reports an association between higher circulating levels of total MGP and faster progression of AS in the younger population. These findings suggest that valvular calcification may lead to increased MGP expression, perhaps in a feedback attempt to physiologically reduce bone-like formation of calcium deposits in the valve. Further studies with measures of both carboxylated and uncarboxylated forms of MGP in the blood as well as in the valvular tissues are needed to clarify the exact role of the MGP system in the pathogenesis of AS.

Impact of Metabolic Syndrome on Progression of Aortic Stenosis: Influence of Age and Statin Therapy

The aims of this study were to examine prospectively the relationship between metabolic syndrome (MetS) and aortic stenosis (AS) progression and to evaluate the effect of age and statin therapy on AS progression in patients with or without MetS. Despite the clear benefits of statin therapy in primary and secondary coronary heart disease prevention, several recent randomized trials have failed to demonstrate any significant effect of this class of drugs on the progression of AS. Previous retrospective studies have reported an association between MetS and faster AS progression. This predefined substudy included 243 of the 269 patients enrolled in the ASTRONOMER (AS Progression Observation: Measuring Effects of Rosuvastatin) trial. Follow-up was 3.4 ± 1.3 years. AS progression rate was measured by calculating the annualized increase in peak aortic jet velocity measured by Doppler echocardiography. Patients with MetS (27%) had faster stenosis progression (+0.25 ± 0.21 m/s/year vs. +0.19 ± 0.19 m/s/year, p = 0.03). Predictors of faster AS progression in multivariate analysis were older age (p = 0.01), higher degree of valve calcification (p = 0.01), higher peak aortic jet velocity at baseline (p = 0.007), and MetS (p = 0.005). Impact of MetS on AS progression was most significant in younger (< 57 years) patients (MetS: +0.24 ± 0.19 m/s/year vs. no MetS: +0.13 ± 0.18 m/s/year, p = 0.008) and among patients receiving statin therapy (+0.27 ± 0.23 m/s/year vs. +0.19 ± 0.18 m/s/year, p = 0.045). In multivariate analysis, the MetS-age interaction was significant (p = 0.01), but the MetS-statin use interaction was not. MetS was found to be a powerful and independent predictor of faster AS progression, with more pronounced impact in younger patients. These findings emphasize the importance of routinely identifying and treating MetS in AS patients. The apparent faster stenosis progression in the subset of normocholesterolemic patients with MetS receiving the statin will need to be confirmed by future studies.

Does Diabetes Accelerate the Progression of Aortic Stenosis through Enhanced Inflammatory Response within Aortic valves?

Diabetes predisposes to aortic stenosis (AS). We aimed to investigate if diabetes affects the expression of selected coagulation proteins and inflammatory markers in AS valves. Twenty patients with severe AS and concomitant type 2 diabetes mellitus (DM) and 40 well-matched patients without DM scheduled for valve replacement were recruited. Valvular tissue factor (TF), TF pathway inhibitor (TFPI), prothrombin, C-reactive protein (CRP) expression were evaluated by immunostaining and TF, prothrombin, and CRP transcripts were analyzed by real-time PCR. DM patients had elevated plasma CRP (9.2 [0.74–51.9] mg/l vs. 4.7 [0.59–23.14] mg/l, p = 0.009) and TF (293.06 [192.32–386.12] pg/ml vs. 140 [104.17–177.76] pg/ml, p = 0.003) compared to non-DM patients. In DM group, TF−, TFPI−, and prothrombin expression within valves was not related to demographics, body mass index, and concomitant diseases, whereas increased expression related to DM was found for CRP on both protein (2.87 [0.5–9]% vs. 0.94 [0–4]%, p = 0.01) and transcript levels (1.3 ± 0.61 vs. 0.22 ± 0.43, p = 0.009). CRP-positive areas were positively correlated with mRNA TF (r = 0.84, p = 0.036). Diabetes mellitus is associated with enhanced inflammation within AS valves, measured by CRP expression, which may contribute to faster AS progression.