Baseline Aortic Stenosis Severity Research Articles

Improving risk stratification of moderate aortic stenosis

Abstract Background The clinical course of patients with moderate aortic stenosis (AS) remains ill-defined. While a watchful waiting approach is advocated by international guidelines, several studies suggest that the long-term prognosis of these patients is worse than previously considered and may even be similar to patients with severe AS. Whether these findings reflect a subgroup of moderate AS with a high comorbid burden or rapid progression to severe AS is not known. Purpose This study sought to 1) analyze the clinical course of AS throughout all stages of the disease, 2) unveil different trajectories of progression through clustering analysis, 3) explore their impact in all-cause death. Methods Patients with mild to severe AS in seriated echocardiograms (TTE) were retrospectively identified after excluding for abnormal flow conditions. Aortic peak velocity (APV) was used to monitor disease progression. A sigmoid function was used to model APV throughout time. Individual acceleration rates coefficients were calculated using random-effects models and patients were then clustered into rapid (RP) and slow progressors (SP). Results This study included 914 patients (age 76 ± 8 years, 52% female, median follow-up time 6.8 years). 483 patients were clustered as RP (53%) and 431 as SP (47%) based on their individual acceleration rate coefficients (core parameter of sigmoid model). Since the core parameter is constant throughout time and evaluations, only two consecutive TTEs per patient are needed to calculate the acceleration rate coefficient. The time interval required between these seriated TTEs varies between 9 and 14 months. No clinical variables were consistently associated with each cluster. When comparing mortality hazard rates for SP with RP across the range of APV, we found that rapid progression was persistently associated with excess mortality (HR 1.35, CI [1.07-1.69]; p=0.01; after adjusting for demographics, comorbidities, baseline AS severity, and time-dependent aortic valve replacement [AVR]). Using the upper limit of the mortality rate of a SP with an APV of 4 m/s as a reference, we found that a RP significantly exceeded this threshold with an APV velocity of only 3.2 m/s. We built a predictive model which incorporated the AS progression on top of guideline-derived AVR triggers to assign patients with a predicted probability of death ≥ 50% at 5 years to AVR. Using this model, we estimated that an extra death can be prevented for every 100 patients treated without exposing more patients to unnecessary AVR. Conclusion We identified two clusters of AS progressors, based on APV from two consecutive TTEs. RP displayed higher mortality rates across all the range of APV which can explain why same patients with moderate AS have a dismal prognosis. Since RP patients have excess adverse outcomes in early stages of AS (moderate AS), a lower APV threshold may be required to better reflect the prognosis of AS and trigger treatment.

Aortic stenosis progression among patients with bicuspid aortic valve

Abstract Background Bicuspid aortic valve (BAV) is associated with an increased risk of aortic stenosis (AS). The role of AS progression rate, its determinants, and prognostic implications need to be better understood in patients with BAV-AS. Aim This study aims to compare AS progression rate between patients with BAV and tricuspid aortic valve (TAV), its determinants, and its impact on clinical outcomes. Methods We retrospectively included patients who had undergone > 1 transthoracic echocardiogram (TTE) documenting AS and preserved left ventricular ejection fraction (LVEF). Moderate to severe aortic valve regurgitation and aortic prosthetic valves were excluded. Patients with suspected BAV in TTE and a confirmatory CT scan were identified. A greedy matching was used to match patients with BAV and patients with TAV on age and sex in a ratio 1:1. Aortic peak velocity (APV) was modeled as a function of time using a mixed-effects nonlinear model to capture possible biphasic progression. A core model parameter reflecting AS rate of progression was calculated and compared between patients with BAV-AS and TAV-AS. Multivariate linear regression was used to explore possible predictors of AS progression. All-cause death was compared between patients with BAV and TAV. Results We matched 80 patient-pairs from within our study cohort by age and sex (age 54 ± 11 years, 40 % female). Follow-up time was higher for patients with tricuspid aortic valves (TAV) (5.9±2.6 years vs. 4.6±2.8 years, p<0.01). Patients with TAV-AS had a higher prevalence of cardiovascular risk factors (arterial hypertension [81 % vs. 41 %, p<0.001], diabetes mellitus [39% vs. 8%, p<0.001], and dyslipidemia [71 % vs. 26 %, p<0.001]). Baseline APV was similar between patients with TAV-AS and BAV-AS (2.9±0.9 m/s vs. 2.7±1.0 m/s, p=0.05), but AS progression rate was higher among patients with TAV-AS (logistic growth rate: 0.11±0.04/year vs. 0.02±0.04/year, p<0.001). No interaction was seen between aortic valve morphology and comorbidities with respect to AS progression rate. TAV-AS was associated with increased rate of all-cause death (p=0.02) but failed to remain a significant predictor of mortality after multivariate adjustment for baseline comorbidities and AS rate of progression. Conclusion In our matched cohort, the BAV-AS progression rate was lower than TAV-AS. BAV-AS was associated with lower mortality despite similar baseline AS severity, possibly reflecting a slower AS progression and a decreased burden of cardiovascular risk factors in this population.

Impact of glycemic control on the progression of aortic stenosis: a single-center cohort study using a common data model

BackgroundDiabetes mellitus (DM) is a well-established risk factor for the progression of degenerative aortic stenosis (AS). However, no study has investigated the impact of glycemic control on the rate of AS progression. We aimed to assess the association between the degree of glycemic control and the AS progression, using an electronic health record-based common data model (CDM).MethodsWe identified patients with mild AS (aortic valve [AV] maximal velocity [Vpeak] 2.0–3.0 m/sec) or moderate AS (Vpeak 3.0–4.0 m/sec) at baseline, and follow-up echocardiography performed at an interval of ≥ 6 months, using the CDM of a tertiary hospital database. Patients were divided into 3 groups: no DM (n = 1,027), well-controlled DM (mean glycated hemoglobin [HbA1c] < 7.0% during the study period; n = 193), and poorly controlled DM (mean HbA1c ≥ 7.0% during the study period; n = 144). The primary outcome was the AS progression rate, calculated as the annualized change in the Vpeak (△Vpeak/year).ResultsAmong the total study population (n = 1,364), the median age was 74 (IQR 65–80) years, 47% were male, the median HbA1c was 6.1% (IQR 5.6–6.9), and the median Vpeak was 2.5 m/sec (IQR 2.2–2.9). During follow-up (median 18.4 months), 16.1% of the 1,031 patients with mild AS at baseline progressed to moderate AS, and 1.8% progressed to severe AS. Among the 333 patients with moderate AS, 36.3% progressed to severe AS. The mean HbA1c level during follow-up showed a positive relationship with the AS progression rate (β = 2.620; 95% confidence interval [CI] 0.732–4.507; p = 0.007); a 1%-unit increase in HbA1c was associated with a 27% higher risk of accelerated AS progression defined as △Vpeak/year values > 0.2 m/sec/year (adjusted OR = 1.267 per 1%-unit increase in HbA1c; 95% CI 1.106–1.453; p < 0.001), and HbA1c ≥ 7.0% was significantly associated with an accelerated AS progression (adjusted odds ratio = 1.524; 95% CI 1.010–2.285; p = 0.043). This association between the degree of glycemic control and AS progression rate was observed regardless of the baseline AS severity.ConclusionIn patients with mild to moderate AS, the presence of DM, as well as the degree of glycemic control, is significantly associated with accelerated AS progression.

Abstract 11290: Sex Differences in the Progression and Long-Term Outcomes of Native Mild to Moderate Aortic Stenosis

Background: Despite evidence of sex-based divergences in the natural history of aortic stenosis (AS), there is limited data on the sex differences in the hemodynamic progression and long-term outcomes of early-stage AS. Methods: This is a retrospective longitudinal study of patients aged ≥ 60 years with mild to moderate native AS who were identified from a tertiary care referral center between 2008-2016 and followed until 2018. All patients had at minimum 2 echocardiograms. The primary outcomes of all-cause mortality and aortic valve replacement (AVR) were both assessed by time-to-event analyses with multivariable-adjusted Cox regression. The secondary outcome of AS progression was assessed by annualized changes in echocardiographic parameters in a 1:1 propensity-matched group of males and females. Results: Of 2,660 included patients followed over a median duration of 5.6 years, the mean age was 74 years and 1,128 (42%) were female. There was no difference in all-cause mortality between sexes, irrespective of age, baseline AS severity, and receipt of AVR. Relative to males, females had a lower risk of AVR (aHR=0.77, 95% CI [0.65-0.92]; p=0.004) irrespective of age, type of aortic valve and baseline severity of AS (Figure). This finding persisted on sensitivity analyses excluding patients with a history of coronary artery disease, prior coronary bypass surgery (CABG), and who underwent concomitant CABG and AVR. On 1:1 propensity-matched analysis, females had significantly slower annualized decrease in indexed aortic valve area (-0.039 vs. -0.021 cm 2 /m 2 /year, p=0.04) and slower increase in mean gradient (1.60 vs. 1.01 mmHg/year, p&lt;0.001),and maximum transvalvular velocity (0.08 vs. 0.11 m/s/year; p=0.04). Conclusion: In patients with mild to moderate AS, females had slower hemodynamic progression of AS and lower incidence of AVR despite similar mortality between sexes. Our findings suggest the need for sex-specific evaluation and management of native AS.

Aortic Stenosis Progression, Cardiac Damage, and Survival: Comparison Between Bicuspid and Tricuspid Aortic Valves

ObjectivesThis study sought to compare aortic stenosis (AS) progression rates, AS-related cardiac damage (AS-CD) indicator incidence and determinants, and survival between patients with tricuspid aortic valve (TAV)-AS and those with bicuspid aortic valve (BAV)-AS. BackgroundDifferences in AS progression and AS-CD between patients with BAV and patients with TAV are unknown. MethodsWe retrospectively studied consecutive patients with baseline peak aortic valve velocity (peakV) ≥2.5 m/s and left ventricular ejection fraction ≥50%. Follow-up echocardiograms (n = 4,818) provided multiparametric AS progression rates and AS-CD. ResultsThe study included 330 BAV (age 54 ± 14 years) and 581 patients with TAV (age 72 ± 11 years). At last echocardiogram (median: 5.9 years; interquartile range: 3.9 to 8.5 years), BAV-AS exhibited similar peakV and mean pressure gradient (MPG) as TAV-AS, but larger calculated aortic valve area due to larger aortic annulus (p < 0.0001). Multiparametric progression rates were similar between BAV-AS and TAV-AS (all p ≥ 0.08) and did not predict age-/sex-adjusted survival (p ≥ 0.45). Independent determinants of rapid progression were male sex and baseline AS severity for TAV (all p ≤ 0.024), and age, baseline AS severity, and cardiac risk factors (age interaction: p = 0.02) for BAV (all p ≤ 0.005). At 12 years, patients with TAV-AS had a higher incidence of AS-CD than BAV-AS patients (p < 0.0001), resulting in significantly worse survival compared to BAV-AS (p < 0.0001). AS-CD were independently determined by multiple factors (MPG, age, sex, comorbidities, cardiac function; all p ≤ 0.039), and BAV was independently protective of most AS-CD (all p ≤ 0.05). ConclusionsIn this cohort, TAV-AS and BAV-AS progression rates were similar. Rapid progression did not affect survival and was determined by cardiac risk factors for BAV-AS (particularly in patients with BAV <60 years of age) and unmodifiable factors for TAV-AS. AS-CD and mortality were significantly higher in TAV-AS. Independent determinants of AS-CD were multifactorial, and BAV morphology was AS-CD protective. Therefore, the totality of AS burden (cardiac damage) is clinically crucial for TAV-AS, whereas attention to modifiable risk factors may be preventive for BAV-AS.

Pace of progression of aortic stenosis severity in patients with tricuspid and bicuspid valve

Abstract Background Knowledge about determinants and pace of aortic stenosis (AS) progression may improve classification to aortic valve replacement. We quantified and compared pace of AS progression in patients with tricuspid and bicuspid aortic valve (TAV and BAV) examined by transthoracic echocardiography (TTE) in years 2004–2019. Methods We analysed retrospectively 322 TTE performed in two time points (median time between examinations 31±31 months) in 161 AS patients (mean age 69±11 years, 101 male, 40 BAV), evaluating the changes of parameters reflecting AS severity: peak pressure gradient (PG), aortic valve area by planimetry (AVApl) and continuity equation (AVAce). Then we compared pace of AS progression (defined as change of parameters per year) between patients with BAV and TAV and searched for correlates of AS progression. Results Although patients with BAV were younger, cardiovascular risk factors profile and baseline AS advancement were similar in both groups, see Table. Severe AS was present in 20% in BAV and 21% in TAV, p=ns. Patients with BAV showed circa 3 times more rapid AS progression expressed as the increase of PG per year (18.5±41.3 mmHg vs 4.1±34.4 mmHg in TAV, p=0.03) and yearly AVAce decrease (−0.23±0.27 vs −0.03±0.32, p=0.028). Smaller AVA value at baseline predicted faster pace of AS progression (with correlation coefficient r=−0.34, p=0.002 for AVApl). Conclusion Progression rate of AS depends on valve morphology being more rapid in BAV with similar to TAV baseline AS severity. In the whole group pace of progression correlated negatively with baseline AVA. Funding Acknowledgement Type of funding source: None

Relationship Between Proximal Aorta Morphology and Progression Rate of Aortic Stenosis

The aim of this study was to examine the association between abnormal morphology of the proximal aorta and aortic stenosis (AS) progression rate. The main hypothesis was that morphologic changes of the proximal aorta, such as effacement of the sinotubular junction (STJ), result in increased biomechanical stresses and contribute to calcification and progression of AS. Between 2010 and 2012, 426 patients with mild to moderate AS were included in this study. Proximal aortic dimensions were measured at three different levels (i.e., sinus of Valsalva, STJ, and ascending aorta), and sinuses of Valsalva/STJ and ascending aorta/STJ ratios were used to determine degree of aortic deformity. AS progression rate was assessed by annualized increase in mean gradient (median follow-up time, 3.1years; interquartile range, 2.6-3.9years). The degree of aortic flow turbulence was examined in 18 matched patients with and without STJ effacement using cardiac magnetic resonance phase-contrast imaging. Patients' mean age was 71±13years, and 64% were men. Patients with low ratios had greater AS progression (P<.05). After comprehensive adjustment, sinuses of Valsalva/STJ (P=.025) and ascending aorta/STJ (P=.027) ratios were independently associated with greater AS progression rate. Compared with patients without STJ effacement, those with effacement of the STJ had higher degrees of aortic flow turbulence (24.4% vs 17.2%, P=.038). Effacement of the STJ is independently associated with greater AS progression, regardless of arterial hemodynamics, aortic valve phenotype, or baseline AS severity. Patients with abnormal proximal aortic geometry had disturbed aortic flow patterns. These findings suggest an interrelation between proximal aorta morphology and stenosis progression.

Prognostic Value of Exercise-Stress Echocardiography in Asymptomatic Patients With Aortic Valve Stenosis

ObjectivesThis study sought to evaluate the prognostic value of mean pressure gradient (MPG) increase and peak systolic pulmonary artery pressure (SPAP) measured during exercise stress echocardiography in asymptomatic patients with aortic stenosis (AS). BackgroundExercise testing is recommended in asymptomatic AS patients, but the additional value of exercise-stress echocardiography, especially the prognostic value of MPG increase and peak SPAP, is still debated. MethodsWe enrolled all consecutive patients with pure, isolated, asymptomatic AS and preserved ejection fraction ≥50% and normal SPAP (<50 mm Hg) who underwent symptom-limited exercise echocardiography at our institution. Occurrence of AS-related events (symptoms or congestive heart failure) or occurrence of aortic valve replacement was recorded. ResultsWe enrolled 148 patients (66 ± 15 years of age; 74% males; MPG: 47 ± 13 mm Hg; SPAP: 34 ± 6 mm Hg). No complications were observed. Thirty-six patients (24%) had an abnormal exercise test result (occurrence of symptoms, fall in blood pressure, and/or ST-segment depression) and were referred for surgery. Among the 112 patients with a normal exercise test result, 38 patients (34%) had abnormal exercise echocardiography scores (MPG increase >20 mm Hg and/or SPAP at peak exercise >60 mm Hg). These 112 patients were managed conservatively. During a mean follow-up of 14 ± 8 months, an AS-related event occurred in 30 patients, and 25 patients underwent surgery. Neither MPG increase >20 mm Hg nor peak SPAP >60 mm Hg was predictive of occurrence of AS-related events or aortic valve replacement (all p > 0.20). In contrast, baseline AS severity was an important prognostic factor (all p < 0.01). ConclusionsIn this observational study including 148 patients with asymptomatic AS, we confirmed and extended the importance of exercise testing for unveiling functional limitation. More importantly, neither the increase in MPG nor in SPAP at peak exercise was predictive of outcome. Our results do not support the use of these parameters in risk-stratification and clinical management of asymptomatic AS patients.

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.

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)

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.

Predictors and Progression of Aortic Stenosis in Patients With Preserved Left Ventricular Ejection Fraction

We aimed to characterize the hemodynamic progression of aortic stenosis (AS) in a contemporary unselected cohort of patients with preserved left ventricular ejection fraction. Current guidelines recommend echocardiographic surveillance of hemodynamic progression. However, limited data exist on the expected rate of progression and whether clinical variables are associated with accelerated progression in contemporarily managed patients with AS. We conducted a retrospective analysis of patients presenting with AS and explored the trajectory of AS mean gradient over time using generalized estimating equations and fit a longitudinal linear regression model with adjustment for baseline clinical variables. A total of 1,558 patients (median age 72; interquartile range 65 to 79) having mild (n= 982), moderate (n= 363), or severe AS (n= 213) were included. In patients with mild AS at baseline (n= 983), 303 (31%) had progressed to moderate/severe AS/AVR within 5years of the index echo. In patients with moderate AS, 159 of 363 (44%) had progressed to severe AS/AVR within 2years of the index echo. The annual change in mean gradient was dependent on baseline AS severity. Average annual increases in mean gradient were 6.8% (95% confidence interval 6.0 to 7.6) and 7.1% (95% confidence interval 4.8 to 9.3) in patients with mild and moderate AS, respectively. In the subset of patients with mild AS at baseline, age (p= 0.0310) and gender (p= 0.0270) had significant interaction with change in mean gradient over time. In patients with moderate AS, age (p <0.0001), gender (p= 0.0346), renal dysfunction (p= 0.0036), and hyperlipidemia (p= 0.0010) demonstrated significant interaction with change in mean gradient over time. In conclusion, although average disease progression was slower than previously reported, a significant proportion of patients with mild and moderate AS progressed to higher grades within the currently recommended time windows for echocardiographic follow-up.

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.

Progression of aortic stenosis in elderly patients over long-term follow up

BackgroundThe natural history of aortic stenosis (AS) in elderly patients remains poorly defined. In an elderly cohort over long-term follow-up, we assessed: 1) rates and predictors of hemodynamic progression and 2) composite aortic valve replacement (AVR) or death endpoint. MethodsConsecutive Department of Veterans' Affairs patients with AS (>60years) were prospectively enrolled between 1988 and 1994 (n=239) and followed until 2008. Patients with ≥2 trans-thoracic echocardiograms >6months apart were included in the progression analysis (n=147). Baseline demographics, comorbidities and echocardiography parameters were recorded. Follow-up was censored at AVR/death. ResultsThe age of patients was 73±6 years; 82% were male. Baseline AS severity was mild (67%), moderate (23%) and severe (10%). Follow-up was 6.5±4 years (range: 1–17years). Annualized mean aortic valve gradient progression rates were: mild AS 4±4mmHg/year; moderate AS 6±5mmHg/year and severe AS 10±8mmHg/year (p<0.001). Five-year event-free survival was 66±5%, 23±7% and 20±10% for mild, moderate and severe AS respectively. Progression to severe AS occurred in 35% and 74% of patients with mild and moderate AS respectively. Independent predictors of rapid progression were: baseline AS severity (per grade) (OR 2.6, p=0.001), aortic valve calcification (per grade) (OR 2.1, p=0.01), severe renal impairment (OR 4.0, p=0.04) and anemia (OR 2.3, p=0.05). ConclusionsIn elderly patients, hemodynamic progression of AS is predicted by AS severity, renal function, aortic valve calcification and history of anemia. These factors identify patients at high risk of rapid hemodynamic progression, for whom more frequent clinical and echocardiographic surveillance is advisable.

461 Angiotensine-receptors blockers but not angiotensin-converting enzime inhibitors delay the progression of aortic stenosis

Background was signicantly (p=0.01) lower in patients with ARBs (0.12 ±0.20 m.s -1 .y -1 ) compared to those with no RAS medication (0.21 ±0.22 m.s -1 .y -1 ). After adjustment for propensity score, ARBs was signicantly (p=0.001) associated with slower� AS progression, compared to other groups. On multivariable regression model including age, male gender, diabetes, baseline peak aortic jet velocity, valvulo-arterial impedance and propensity score, treatment with ARBs (p=0.005) but notwith ACEIs (p=0.72), was an independent predictor of lower AS progression. Conclusion: This study suggests that ARBs but not ACEIs delayAS progression. These results could be explained by the fact that ARBs provide more complete blockade ofinammatory andbro-calcic processes contributing toAS progression. Thesendings open new avenues for the pharmacological treatment of AS and provide impetus for the elaboration of randomized studies focusing on ARBs in this population.

Impact of Baseline Severity of Aortic Valve Stenosis on Effect of Intensive Lipid Lowering Therapy (from the SEAS Study)

Retrospective studies have suggested a beneficial effect of lipid-lowering treatment on the progression of aortic stenosis (AS) in milder stages of the disease. In the randomized, placebo-controlled Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study, 4.3 years of combined treatment with simvastatin 40 mg and ezetimibe 10 mg did not reduce aortic valve events (AVEs), while ischemic cardiovascular events (ICEs) were significantly reduced in the overall study population. However, the impact of baseline AS severity on treatment effect has not been reported. Baseline and outcomes data in 1,763 SEAS patients (mean age 67 years, 39% women) were used. The study population was divided into tertiles of baseline peak aortic jet velocity (tertile 1: ≤ 2.8 m/s; tertile 2: > 2.8 to 3.3 m/s; tertile 3: > 3.3 m/s). Treatment effect and interaction were tested in Cox regression analyses. The rates of AVEs and ICEs increased with increasing baseline severity of AS. In Cox regression analyses, higher baseline peak aortic jet velocity predicted higher rates of AVEs and ICEs in all tertiles (all p values < 0.05) and in the total study population (p < 0.001). Simvastatin-ezetimibe treatment was not associated with a statistically significant reduction in AVEs in any individual tertile. A significant quantitative interaction between the severity of AS and simvastatin-ezetimibe treatment effect was demonstrated for ICEs (p < 0.05) but not for AVEs (p = 0.10). In conclusion, the SEAS study results demonstrate a strong relation between baseline the severity of AS and the rate of cardiovascular events but no significant effect of lipid-lowering treatment on AVEs, even in the group with the mildest AS.