Aortic Stenosis Progression Rate Research Articles

Prediction of the Individual Aortic Stenosis Progression Rate and its Association With Clinical Outcomes

BackgroundThe progression rate of aortic stenosis differs between patients, complicating clinical follow-up and management. ObjectivesThis study aimed to identify predictors associated with the progression rate of aortic stenosis. MethodsIn this retrospective longitudinal single-center cohort study, all patients with moderate aortic stenosis who presented between December 2011 and December 2022 and had echocardiograms available were included. The individual aortic stenosis progression rate was calculated based on aortic valve area (AVA) from at least 2 echocardiograms performed at least 6 months apart. Baseline factors associated with the progression rate of AVA were determined using linear mixed-effects models, and the association of progression rate with clinical outcomes was evaluated using Cox regression. ResultsThe study included 540 patients (median age 69 years and 38% female) with 2,937 echocardiograms (median 5 per patient). Patients had a linear progression with a median AVA decrease of 0.09 cm2/y and a median peak jet velocity increase of 0.17 m/s/y. Rapid progression was independently associated with all-cause mortality (HR: 1.77, 95% CI: 1.26-2.48) and aortic valve replacement (HR: 3.44, 95% CI: 2.55-4.64). Older age, greater left ventricular mass index, atrial fibrillation, and chronic kidney disease were associated with a faster decline of AVA. ConclusionsAVA decreases linearly in individual patients, and faster progression is independently associated with higher mortality. Routine clinical and echocardiographic variables accurately predict the individual progression rate and may aid clinicians in determining the optimal follow-up interval for patients with aortic stenosis.

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.

The impact of resting heart rate on adverse outcomes and haemodynamic progression of aortic stenosis

Abstract Introduction A high resting heart rate (RHR) is an established risk factor for cardiovascular disease, adverse cardiac events, accelerated calcification in coronary artery disease and carotid stenosis, and increased aortic valve calcification in patients with and without a confirmed diagnosis of aortic stenosis (AS). Aortic valve calcification is the most common precursor to AS and is associated with significantly faster disease progression. There are few studies exploring the effects of RHR on the progression of AS, the development of severe stenosis, and the risk of complications and death. Purpose We hypothesised that an elevated RHR would be associated with poorer outcomes and more rapid haemodynamic disease progression in patients with AS and tested this in a large cohort of patients without severe disease. Methods Using the National Echocardiography Database of Australia (NEDA) we undertook a retrospective observational study on patients without severe AS, a bicuspid aortic valve or prior aortic valve replacement. The association between baseline RHR and time to the composite primary endpoint of severe AS, aortic valve replacement or cardiovascular death was tested using Cox proportional hazards regression. In addition, the relationship between baseline RHR and the components of this composite was investigated. Subsequently, the relationship between annualised AS progression rate, defined as change in standard indices of AS severity (maximal jet velocity [Vmax], mean pressure gradient [MPG], and aortic valve area [AVA]), and RHR were analysed using general linear models. Results The initial study cohort comprised 55 585 individuals: 54% male, mean age 63 years and median baseline RHR 70 bpm. The composite primary endpoint, reached by 7 434 patients, was independently associated with RHR (hazard ratio [per 10bpm increase], 1.04; 95% CI, 1.02-1.05; p < 0.001). RHR was also independently associated with time to developing severe AS (hazard ratio [per 10bpm increase], 1.06; 95% CI, 1.01-1.12; p = 0.017) and cardiovascular death (hazard ratio [per 10bpm increase], 1.04; 95% CI, 1.02-1.06; p < 0.001). The event rate was significantly higher in patients with a RHR of at least 70 bpm (the median RHR) compared to those with an RHR less than 70 bpm. In addition, RHR was independently associated with rate of change of each individual measurement index of AS severity including Vmax (β = 0.65 cm/s/year [per 10 bpm increase]; p < 0.001), MPG (β = 0.05 mmHg/ year [per 10 bpm increase]; p<0.001), and AVA (β = -0.01 cm2/year [per 10 bpm increase]; p < 0.001). Conclusions RHR is independently associated with adverse clinical outcomes and haemodynamic progression of AS in patients without severe disease. Future randomised controlled trials should investigate the effect of lowering RHR on clinical endpoints and progression of AS.

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 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&lt;0.0001) and the decline in DASI score (coeff.: -9; 95% CI: -11 to -6; p&lt;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.

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.

Abstract 14073: Deterioration of Functional Status and Timing of Intervention in Patients With Aortic Stenosis: Results From the PROGRESSA Study

Introduction: The assessment of changes in functional status during follow-up is critical to determine the timing of intervention in patients with aortic stenosis (AS). Fast progression of AS (annualized progression of peak jet velocity [V peak ] ≥30 cm/s) is among the risk markers recommended in the guidelines to trigger early intervention in asymptomatic severe AS. We investigated the association between the progression of AS hemodynamic severity and the change in functional status during follow-up of patients with asymptomatic mild to moderate AS. Methods: 285 patients with AS prospectively recruited in the PROGRESSA study (NCT01679431) were included in this analysis. Functional status was evaluated using the New York Heart Association (NYHA) classification. Results: Baseline NYHA class was similar (class I, II, III: 57%, 41%, 2% versus 58%, 41%, 1%; p=0.75) between patients with moderate (V peak progression ≥12 cm/s/year; median of cohort) versus those with slow AS progression rate. During a mean follow-up of 3.9±2.4 years, patients with moderate AS progression rate had larger increase in NYHA class compared to those with slow progression (+0.13±0.48 versus +0.01±0.21 class/year; p=0.008). From baseline to 2 years, a significant worsening of NYHA class occurred but only in the moderate AS progression group ( Figure ). In multivariable analysis, AS progression rate remained significantly associated with the change in NYHA class (p=0.04).A total of 156 clinical events (110 AVR and 46 deaths) occurred during a mean follow-up of 1.1±1.5 years after the last echocardiographic visit. Patients with ≥1 class increase in NYHA (n=70) had significantly higher risk of events (adjusted hazard ratio: 1.75 [95% CI: 1.12-2.75]; p=0.01). Conclusions: In this prospective cohort of patients with mild to moderate AS at baseline, the decline in functional status occurs early in the course of the disease and is in large part determined by the progression rate of AS hemodynamic severity.

The progression rate of aortic stenosis: key to tailoring the management and potential target for treatment.

Aortic stenosis is the most frequent valvular disease to require intervention in the western world and has always been featured as a progressive disease. The rate of progression can be assessed by carefully performed Doppler echocardiography and can vary greatly between individuals with a profound impact on prognosis. Unfortunately, the determinants of disease progression had been insufficiently studied and remain challenging to define, particularly in the outpatient setting. Multiple factors have been proposed and tested, but at present, there are no proven therapies to slow the course of the stenotic process. Heart valve clinics may be particularly important to define the progression rate and tailor follow-up and management at an individual level. This review enlightens knowledge and gaps regarding the progression-rate of aortic valve stenosis, from the historical perspective to the molecular one.

BONE MINERAL DENSITY AND PROGRESSION RATE OF CALCIFIC AORTIC VALVE STENOSIS - RESULTS FROM THE PROGRESSA STUDY

Recent data suggest that there may be an association between low bone mineral density (BMD) and/or altered bone metabolism and calcific aortic stenosis (AS). We examined the association between BMD and faster hemodynamic and anatomic progression rate of AS.

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.

Progression rate of severity of aortic stenosis in patients with rheumatoid arthritis.

Valvular heart disease is common in patients with rheumatoid arthritis (RA). However, there is uncertainty about how often to perform echocardiographic surveillance in this population. The objective of this study was to assess the progression rate of mild and moderate aortic stenosis (AS) in patients with RA. A population-based cohort of patients with RA and either mild (2.0-2.9m/second) or moderate (3.0-3.9m/second) AS was identified. Demographic, clinical, and echocardiographic data were collected. Annual progression rate of AS was then calculated for the study cohort and the impact of pertinent RA variables on progression rate determined. Sixty-eight patients with RA and mild or moderate AS met the inclusion requirements. Peak aortic valve (AV) velocity and mean AV gradient increased during the study period, whereas AV area decreased, consistent with progression of AS (P<.001). Mean (SD) annual increase in peak AV jet velocity was 0.05m/second (0.01) and in mean AV gradient was 1.0mm Hg (0.18). Mean annual decrease in AV area was 0.04 (0.01) cm2 . The progression rate of AS was higher in patients with increased erythrocyte sedimentation rates (ESR) (P=.001). The rate of AS progression in the RA population was higher in patients with increased ESR but less than that of the reported rate of AS progression in the general population. Although the cause for this finding is uncertain, these results suggest that patients with RA who have mild or moderate AS should undergo echocardiographic surveillance for disease progression similar to that of the general population.

Predictors of Rapid Progression and Clinical Outcome of Asymptomatic Severe Aortic Stenosis.

The optimal timing of aortic valve replacement (AVR) is controversial in patients with asymptomatic severe aortic stenosis (AS) except when very severe. Prediction of progression of severe AS is helpful in deciding on the timing of AVR. The purpose of this study was to clarify the predictors of progression rate and clinical outcomes of severe AS. We retrospectively investigated 140 consecutive patients with asymptomatic severe AS (aortic valve area [AVA], 0.75-1.0 cm(2)). First-year progression rate and annual progression rate of AVA and of aortic jet velocity (AV-Vel) were calculated. Cardiac events were examined and the predictors of rapid progression and cardiac events were analyzed. The median follow-up period was 36 months. The median annual progression rate was -0.05 cm(2)/year for AVA and 0.22 m/s/year for AV-Vel. Dyslipidemia, moderate-severe calcification, and first-year AV-Vel progression ≥0.22 m/s/year were independent predictors of cardiac events. Cardiac event-free rate was lower in patients with AV-Vel first-year progression rate ≥0.22 m/s/year than in those with a lower rate. Diabetes and moderate-severe calcification were related to first-year rapid progression. The annual progression rate of severe AS was -0.05 cm(2)/year for AVA and 0.22 m/s/year for AV-Vel. Patients with first-year rapid progression or severely calcified aortic valve should be carefully observed while considering an early operation. (Circ J 2016; 80: 1863-1869).

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.

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.

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.

Inflammation Is Associated with the Remodeling of Calcific Aortic Valve Disease

Calcific aortic valve disease (CAVD) is the most frequent heart valve disorder. Studies indicate that mineralization of the aortic valve may be related to the inflammatory process. However, no clear evidence has been given regarding clinical evolution of aortic stenosis and the inflammatory process within the aortic valve. Aortic valves excised from 285 patients with CAVD undergoing aortic valve replacement were analyzed for the presence of chronic inflammatory infiltrates, and those findings were related to the hemodynamic severity of aortic stenosis. In a subset of 57 patients, in whom additional valvular tissue and the clinical progression rate of aortic stenosis were available, the density of leukocytes was determined as well as the number of TNF-α transcripts. Histological analyses revealed that in 81 (28.4%) patients, the presence of chronic inflammatory infiltrates was documented within CAVD tissue, which was characterized by the existence of a cluster of cells as well as the presence of neovascularisation and osseous metaplasia. The presence of an inflammatory process within the CAVD tissue was independently related to the remodeling process and the peak transaortic gradient. In addition, the density of leukocytes within CAVD tended to correlate (r = 0.25, p = 0.05) with the progression rate of aortic stenosis. Dense inflammatory infiltrate within CAVD is associated with an active remodeling process, the severity of aortic stenosis, and the hemodynamic progression rate.