AbstractBackgroundAortic Stenosis Research Articles

Aortic stenosis rapid progression is associated with premature cardiac damage independently of baseline severity

Abstract Background Aortic stenosis (AS) is one of the major valvular heart diseases in developed countries. Degenerative fibrocalcific AS is a progressive disease of the valve and, ultimately, the myocardium. AS is a potentially fatal disease characterized not only by a narrowing of the aortic orifice but also by gradual cardiac damage (CD) that may extend beyond the left ventricle (LV). However, the presence and extent of extra-aortic cardiac damage did not reflect the baseline hemodynamic severity of AS in retrospective studies. Purpose This study aims to determine the rate of AS progression and its impact on cardiac damage and survival. Methods We retrospectively identified 914 patients (age 76 ± 8 years, 52% female, median follow-up time 6.8 years) with AS who had undergone > 1 echocardiogram. Bayesian hierarchical nonlinear models were used to predict aortic peak velocity as a function of time and estimate individual AS acceleration rates. Then, patients were clustered into rapid (RP) and slow progressors (SP) using machine learning algorithms. Results APV was best modeled by a logistic function of time. 483 patients were clustered as RP (53 %) and 431 as SP (47 %), with acceleration rate coefficients estimated at 0.14 ± 0.02 years-1 and 0.09 ± 0.02 years-1, respectively (p < 0.01). No association between progression rate and clinical variables was found. Compared with SP, RP had significantly higher 5-year incidences of LV damage, combined left atrium and mitral valve damage and combined tricuspid valve damage and pulmonary hypertension (all p ≤ 0.01). No statistically significant differences were seen for right ventricle damage between RP and SP, as the number of events was low. After multivariate adjustment for age, gender, comorbidities and baseline AS severity, RP remained an independent predictor for all extra-aortic cardiac damages except for the RV dysfunction. Importantly, baseline AS severity was not predictive of AS-related CD. RP was associated with higher mortality (HR 1.28, p = 0.02), persisting after adjustment for demographics, comorbidities, AS severity, and time-dependent aortic valve replacement (AVR) (HR = 1.36, p < 0.01). Conclusions RP may impair cardiac adaption to rapidly changing loading conditions, which induces premature cardiac damage that may not be reversible in the late stages of AS, when guideline-triggered interventions are currently delivered.

Sex differences in aortic stenosis progression and myocardial response

Abstract Background Aortic stenosis (AS) produces an increased afterload and consequently left ventricular (LV) remodeling. While current guidelines recommend the same echo-doppler criteria for diagnosis and grading of AS for men and women, different sex-specific patterns of cardiac remodeling, and eventually damage, have been reported. Whether these different patterns are caused by sex-related AS progression rate or myocardial response is less well known. Aim We aim to compare longitudinal changes in aortic valve and cardiac function between women and men with AS to investigate sex-related differences in AS progression and cardiac remodeling. Methods Patients with mild-to-severe AS and LV ejection fraction (LVEF) ≥ 50 % at least in 2 transthoracic echocardiograms (TTE) were retrospectively identified. Prosthetic and bicuspid valves were excluded. Serial TTEs provided a multiparametric framework to compare AS severity, progression rate and induced cardiac changes between sexes. Results 914 patients were included (median follow-up time of 6.8 years) and 52 % (473) were female. Both sexes had similar baseline aortic peak velocities (APV) (2.9±0.9 m/s), mean pressure gradient (MPG) (27±13 mmHg) and LVEF (60±5 %). Women were older (75±9 vs 73±8 years; p<0.001), had smaller body surface area (BSA) (1.70±0.15 vs 1.88±0.16 m2, p<0.001), proportionally lower stroke volume (SV) (82±19 mL vs 91±22 mL, p<0.001), lower indexed LV mass (iLVM) (118±33 g/m2 vs 125±28 g/m2, p<0.001) and higher indexed left atrial (LA) volume (39±13 vs 49±20 mL/m2, p<0.001). The average annual progression rate of APV and MPG was similar for both groups (2 mmHg/year and 0.14 m s-1 year-1). After multivariate adjustment including time-dependent aortic valve replacement, women had a higher incidence of severe LV hypertrophy as measured by iLVM (HR=1.16, CI=1.08-1.91, p<0.01), moderate-to-severe tricuspid valve regurgitation (HR=2.03, CI=1.01-4.07, p<0.05) and pulmonary hypertension (PHT) (HR=1.49, CI=1.02-2.18, p=0.04) at 5 years. Similar incidence rates were seen for LV dilation, LVEF reduction and mitral valve regurgitation. All-cause mortality rates were similar between groups (p=0.30). Conclusion This study suggests that under similar static and dynamic loading conditions, women will develop severe LV hypertrophy and PHT earlier than men, possibly reflecting sex-specific response differences intrinsic to the myocardium. This suggests that the definition of AS severity may benefit from a shift from a valve-focused to a myocardial-integrative approach taking gender into account.

Using natural language processing to generate a large-scale database of aortic stenosis with long-term follow-up: the CASPER (cogstack aortic stenosis patient electronic registry) database

Abstract Background Aortic stenosis (AS) is one of the most common heart valve diseases in the Western World, with a prevalence of approximately 4% in patients over 70 years old. High quality observational data can provide insight into characteristics that define patient trajectories and inform the design of appropriately powered randomised trials. Objective The aim of this study is to develop a data pipeline to generate a large database containing information of an AS cohort in a hospital by analysing both structured and unstructured (free text) data in routinely collected electronic heath records (EHR). The unstructured data are processed using natural language processing (NLP, an artificial intelligence technique that allows machines to recognize clinical concepts in EHR with contextualisation and linked to SNOMED ontology). Methods The open-source CogStack retrieval system is used to collect clinical notes of AS patients. The natural language processing toolkit, MedCAT, is used to identify clinical concepts in the form of SNOMED terms in clinical notes. In addition to patient demographic data (including ethnicity and markers of social deprivation), a range of clinical characteristics, co-morbidities, medications and procedural interventions are extracted. Validation of the dataset was performed using 3 existing, independent data sources (structured echocardiogram reports, surgical aortic valve replacement (AVR) operation notes, transcatheter intervention (TAVI) reports). Results We identified 7,451 patients with AS from our EHR, of whom 5,754 had an echocardiogram at our centre. The mean duration of follow up was 5 years. Of those with an echocardiogram at our centre, we were able to extract data on AS severity in 91% and left ventricular function in 89%. Manual validation of procedural data suggests a sensitivity of 98% to detect TAVI and 97% to detect AVR procedures. Kaplan-Meier curves for automated detection of patient mortality are consistent with the known survival data for patients with AS. Conclusion We developed and validated an automated NLP-enabled data pipeline to identify and characterise a single retrospective centre cohort of AS patients from routinely collected EHR across the spectrum of severity, with long term mortality data. This resource has the potential to provide insights toward several outstanding questions relating to progression of AS, and the influence of ethnicity and social deprivation without the need for conventional dedicated databases. The EHR-based database also has the potential to guide the design of future randomised control trials.Data Pipeline

Prevalence of pulmonary hypertension in aortic stenosis and its influence on outcomes

Abstract Background Aortic stenosis (AS) is the commonest valve abnormality in developed countries with increasing prevalence and a long pre-symptomatic phase. Measurable variables are likely important in stratifying risk and potentially guiding management decisions. The significance of Pulmonary Hypertension (PHT) complicating AS is poorly characterised. Purpose We aimed to describe the prevalence and prognostic importance of PHT in a large cohort of adults with at least moderate AS. Methods In this retrospective study, we analysed the National Echocardiography Database of Australia (data from 2000-2019). Adults with an estimated right ventricular systolic pressure (eRVSP), left ventricular ejection fraction (LVEF) >50% and with moderate or greater AS were included (n= 14980). These subjects were then categorised according to their eRVSP. The relationship between PHT severity and mortality outcomes were evaluated (median follow-up of 2.6 years, interquartile range 1.0-4.6 years). Results Subjects were aged 77±13years and 57.4% were female. Overall, 2049 (13.7%), 5085 (33.9%), 4380 (29.3%), 1956 (13.1%) and 1510 (10.1%) patients had no (eRVSP<30.00mmHg), borderline (30.00-39.99mmHg), mild (40.00-49.99mmHg), moderate (50.00-59.99mmHg) and severe PHT (>60.00mmHg), respectively. A echocardiographic phenotype was evident with worsening PHT, showing rising E:e’ ratio and right and left atrial sizes (p<0.0001, for all). After adjustment for age and sex, the risk of long-term mortality increased as eRVSP increased (adjusted hazard ratio (aHR) 1.15, 95% confidence interval 1.05-1.26 in borderline PHT, to aHR3.04, 95%CI 2.74-3.36 in severe PHT) (Figure 1). These trends were maintained on a sensitivity analysis excluding patients with ≥moderate mitral and/or aortic regurgitation (n=12005), (aHR 1.12, 95% CI 1.002-1.24 in borderline PHT, to aHR3.00, 95%CI 2.66-3.39 in severe PHT). A mortality threshold was identified in the 4th decile of eRVSP categories (35.01–38.00mmHg; HR1.20, P=0.005), with risk progressively increasing through to the 10th decile (HR2.95 p <0.0001). Conclusions Both AS and PHT confer an increased risk of mortality as they progress. In this large cohort study, we find that PHT is common in ≥moderate AS and mortality increases as PHT becomes more severe. A threshold for higher mortality lies within the range of "borderline-mild" PHT.Adjusted Risk for All-Cause MortalityThreshold for Mortality

Cardiac damage extent in patient with isolated severe aortic stenosis referred to surgical aortic valve replacement: is it reversible after surgery?

Abstract Background Aortic stenosis (AS) may lead to progressive and adverse cardiac remodeling. A recently-proposed staging classification regarding extravalvular cardiac damage in AS patients undergoing aortic valve intervention was shown to have significant prognosis implications. However, cardiac damage evolution and reversibility after intervention remain unknown. Aims to assess extravalvular cardiac damage evolution after surgical aortic valve replacement (SAVR) in patients with isolated severe AS. Methodology we performed a single-center, prospective cohort study enrolling consecutive patients with severe aortic stenosis undergoing SAVR. Those with previous cardiomyopathy or concomitant severe valve dysfunction beyond AS were excluded. All patients performed transthoracic echocardiogram (TTE) and cardiac magnetic resonance (CMR) within 3 months before SAVR as well as at the 3rd to 6th post-operative month. Patients were classified according to the extent of cardiac damage into 4 groups: stage 0: no damage; stage 1: left ventricle (LV) hypertrophy (indexed LV mass >95 g/m2 [women] or >115 g/m2 [men]), LV diastolic (E/e′ > 14) or systolic (ejection fraction <50%) dysfunction; stage 2: dilated left atrium (>34mL/m2) or atrial fibrillation; stage 3: pulmonary hypertension (systolic pulmonary artery pressure ≥60mmHg); stage 4: significant right ventricle (RV) dysfunction. Global longitudinal strain (GLS) was also assessed to further characterize the extent of LV damage – a GLS > -14.7% was considered abnormal. Due to the impact of on-pump cardiac surgery on RV systolic longitudinal function, RV ejection fraction assessed by CMR (<45%) was used to define significant post-operative RV dysfunction. Results A total of 67 patients were included (mean age 71 ± 8 years; 50% male; mean valvular transaortic gradient 60 ± 19 mmHg; mean indexed aortic valve area 0.4 ± 0.01 cm2/m2; mean LV ejection fraction by TTE 58 ± 9%). Overall, a significant number of patients still showed sign of structural cardiac damage after surgery – 14 vs. 10 on stage 1, 44 vs. 39 on stage 2, 1 vs. 1 on stage 3 and 4 vs. 4 on stage 4 after AVR- figure 1. However, a statistically significant improvement in the number of patients at stage 0 after surgery (4 vs. 11, paired McNemar test p=0.016) was observed, as well as a significant improvement in GLS (mean GLS pre and post AVR -14.8 ± 3.6% vs. -16.6 ± 3.3%, respectively; 45 vs. 21% patients with abnormal GLS before and after AVR, p=0.001). Conclusion Extravalvular cardiac damage is common in a selected cohort of severe AS and potentially reversible after SAVR. A significant improvement in GLS, although not a part of the previously established staging system, was observed after AVR. Whether or not these findings may correlate with long-term patient prognosis or if additional favorable cardiac remodeling is seen on a longer-term follow-up remains to be determined.

Human calcified aortic valves release procoagulant microparticles inducing endothelial dysfunction and thrombogenicity: Role of the AT1R/NADPH oxidases/SGLT2 pro-oxidant pathway

Abstract Background Aortic stenosis (AS) pathogenesis is a dynamic process with interplay between the hemostatic system and the valve leading to inflammation, oxidative stress, endothelial dysfunction, and calcification. Within the pathological valve, mechanical strain induces the release of cell-derived microparticles (MPs) that promote mineralization and carry a pro-oxidant activator signal. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) showed cardiovascular benefit and anti-inflammatory responses in patients with heart failure. Oxidative stress has been shown to trigger SGLT2 expression in endothelial cells (ECs) to induce endothelial dysfunction. Therefore, this study evaluated calcified AS valves and the effect of AS-derived MPs on ECs and, if so, the role of the SGLT2. Methods Pathological valves were collected from 90 AS and 15 aortic insufficiency (AI) patients. MPs were extracted from human pathological valves, and quantified through their prothrombinase activity. Primary cultures of porcine valvular endothelial cells (VECs) were treated with MPs (10 nM) or thrombin (1 U/ml). Protein expression levels were assessed by Western blot analysis and immunofluorescence staining, mRNA levels by RT-qPCR, oxidative stress using dihydroethidium, and nitric oxide (NO) generation by DAF-FM diacetate. THP1 cells were used to evaluate the adhesiveness of VECs, and the generation of thrombin using a specific chromogenic substrate. Results Calcified AS valves showed increased levels of thrombogenic (TF, PAI-1), adhesive (VCAM-1, ICAM-1) and inflammatory markers (CD68, p-p65 NF-κB) and SGLT2 compared to non-calcified valves. These responses were associated with a higher level of oxidative stress that was reduced by inhibitors of the angiotensin system (ACEi, AT1R) and SGLT2, and an increased release of procoagulant MPs. Exposure of VECs to AS-MPs increased the expression of markers of the angiotensin system (ACE, p67 phox), inflammation (CXCL10, CCL11, CXCL8), thrombogenicity (TF, PAI-1), angiogenesis (VEGFR2, ANGPTL4), matrix remodeling (BMP-2, MMP-1), and SGLT2 and caused the down-regulation of eNOS. These responses were associated with a sustained pro-oxidant response, the nuclear translocation of NF-kB and blunted bradykinin-induced NO formation, which were prevented by inhibition of AT1R, NADPH oxidases, SGLT2, and NF-kB. AS-MPs-treated VECs showed also increased adhesion of THP-1 cells, and generation of thrombin. Conclusions Calcified AS valve is a potent reservoir of MPs, acting as a pro-thrombogenic source per se and prompting valvular endothelial cells dysfunction through activation of the AT1R/NADPH oxidases/SGLT2 pro-oxidant pathway. The observed protective effect of empagliflozin suggests SGLT2 inhibitors as a novel therapeutic option to curb valve dysfunction.

RAAS inhibitors in patients undergoing transcatheter aortic valve implantation: insights from the EffecTAVI registry

Abstract Background Aortic Stenosis (AS) is the most common heart disease in western countries, with a prevalence that is increasing in tandem with life expectancy. Renin-angiotensin-aldosterone system (RAAS) activation participates to myocardial fibrosis and worse clinical consequences. Purpose The association between baseline treatment with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) and cardiovascular (CV) mortality was evaluated in hypertensive patients with severe AS undergoing transcatheter aortic valve implantation (TAVI). Methods We retrospectively examined hypertensive patients with AS who had undergone TAVI at 2-year follow-up. Univariable and multivariable Cox regression models were built according to baseline RAAS inhibitors (RAASi) therapy status and a second analysis was undertaken by categorizing patients in ARBs (n= 110), ACEi (n= 112) and other antihypertensive meds (n= 105). As a sensitivity analysis, survival-time data were converted to case-control data in order to conduct a case–control study nested in the observational study. Results The present analysis included 327 hypertensive patients with severe AS undergoing TAVI. During the 2-year follow-up 43 patients died for CV death. In univariable Cox regression, the rate of the 2-year CV mortality was significantly lower in patients taking RAASi at baseline (HR=0.44, 95% CI 0.23-0.81 p=0.009), however after multivariable adjustment for significant confounders baseline treatment with RAASi was no more significant. Patients were then grouped based on ARBs/ACEIs/other antihypertensive therapy (Figure 1). In the univariate regression analysis ARBs therapy was associated with 65% reduction in CV mortality (HR=0.35, 95% CI 0.15-0.78 p=0.011) significantly lower than other anti-hypertensive meds (figure 1). The results were confirmed in multivariate analysis adjusted for significant confounders (HR=0.34, 95% CI 0.14-0.85 p=0.021). To reduce the risk of bias and better evaluate the stability of the results, a case–control study nested in the observational study was performed. Based on preliminary analysis, patients exposed to ARBs were selected as the case group, those not exposed as the control group, matching controls and cases in a 1:1 manner and balancing for sex, chronic kidney disease, atrial fibrillation and type 2 diabetes mellitus. Multivariable logistic regression analyses were conducted to determine the possible risk factors for CV mortality. After adjusting for the effect of significant confounders, the use of ARBs was found to be associated with a significant reduced risk of CV mortality (OR 0.30, 95% CI 0.11 – 0.82, p=0.019) (Figure 2). Conclusion In patients with severe AS undergoing TAVI, baseline treatment with ARBs was associated with reduced risk of CV mortality over 2 years of follow-up compared to the use of other antihypertensive drugs. The results were also confirmed by the nested, balanced, case-control analysis.KM curves grouped for ACEI/ARBs/otherAdjusted odds-ratio in the nested case-c

The prognostic value of aortic stenosis and aortic sclerosis in patients with heart failure with reduced ejection fraction

Abstract Background Aortic stenosis (AS) and aortic valve sclerosis (AVS) as assessed by Doppler echocardiography have been associated with adverse clinical outcomes in patients with heart failure with reduced ejection fraction (HFrEF). However, further clarification of the role of AV and AVS in the HFrEF population is warranted. Methods A total of 873 patients with stable HFrEF were included in this retrospective cohort study. At referral, the patients had a left ventricular ejection fraction (LVEF) of 45% or lower Baseline clinical and echocardiographic data were retrieved from the heart failure outpatient clinic's database, and the patients were followed through a nationwide register for the outcome of all-cause mortality. The presence of AS and AVS was assessed using Doppler-derived pressure gradients of the aortic valve (AV) from the echocardiogram. Cox-regression models were used to determine the association between AV peak gradient and mortality. Multivariable models were adjusted for demographic, clinical, and echocardiographic parameters (age, sex, diabetes (DM), ischemic heart disease (IHD), BMI, heart rate, mean arterial pressure, total cholesterol and atrial fibrillation (AF), LVEF, left atrial volume index (LAVi), left ventricular mass index (LVMi), E/e’). Results Seventy-four percent of patients were male, and mean age was 66.8 ± 11.4 years. In total, 13% had DM, 57% had IHD, 38% had NYHA III-IV, 8% had implantable cardiac device (including pacemaker, ICD, and CRT), and 15.9% had AF. Mean LVEF was 27.3 ± 9.4% with a mean LVMi of 120.2 g/m2 ± 38.2. Mean AV peak velocity was 1.4 m/s ± 0.5 and median AV peak gradient was 6.3 mmHg (IQR 4.7; 8.9). During a median follow-up of 3.3 years (IQR 1.9 – 4.7 years), 143 patients (16.4 %) reached the outcome. In univariable analysis, AV peak gradient was associated with all-cause mortality (HR 1.23 per 10 mmHg increase, 95% CI 1.05-1.44, p = 0.012). LVEF modified the prognostic value of AV peak gradient (p = 0.026 for interaction). After stratifying the population by the median value of LVEF (cut-off = 28%), AV peak gradient remained prognostic only in patients with LVEF above the median (HR 1.58 per 10 mmHg increase, 95% CI 1.30-1.91, p < 0.001), whereas AV peak gradient was not significantly associated with mortality amongst the patients with LVEF below the median level (HR 1.03 per 10 mmHg increase, 95% CI 0.83-1.37, p = 0.827). After multivariable adjustment, AV peak gradient remained an independent predictor of the outcome in patients in the higher median of LVEF (HR 1.32 per 10 mmHg increase, 95% CI 1.02-1.70, p = 0.035) (Figure 1). Conclusion Presence of AS and AVS (derived by AV peak gradient Doppler echocardiography) is an independent predictor of all-cause mortality amongst HFrEF patients. However, presence of AS and AVS only entails prognostic information amongst the HFrEF patients without severely reduced LVEF.Incidence rates of all-cause mortality

Introducing a novel ex-vivo calcification model for human aortic valves

Abstract Background Aortic stenosis (AS) is a narrowing of the aortic valve opening due to calcification and thickening of the leaflets. There are currently no effective pharmacological treatments for AS, and surgery or percutaneous interventions are the only therapeutic options. The cellular and molecular mechanisms underlying AS are complex and not fully understood due to the complexity and multi-factorial nature of AS and the absence of suitable test systems. In the current in-vitro models to study valvular calcification, isolated valvular interstitial cells (VICs) are cultured in 2D and in the absence of its native extracellular matrix. In addition, other cell types like valvular endothelial cells (VECs) and macrophages, which have been shown to impact the behavior of VICs, are absent. Purpose Our goal is to establish an ex-vivo calcification model for human aortic valves which maintains the original valve structure and cellular components. Methods Diseased aortic valves were harvested from patients undergoing aortic valve replacement. A 5mm x 7mm piece of this aortic valve tissue was dissected and embedded in agarose, then cut into 300 mm slices using a vibratome (Figure 1). In this way VICs remained in their valvular environment allowing the most native response of VICs to stimuli. The use of multiple slices from a single patient ensured proper internal controls. The slices were placed on a cell culture insert and cultured for 14 days. To induce calcification, the slices were cultured in the presence of 3 mM phosphate (n=23). As a control, valvular slices were cultured in the absence of 3mM phosphate (n=12). To validate if the calcification induced in the ex vivo culture system can be molecularly modulated the glucocorticoid dexamethasone was added to cultures containing 3mM phosphate (n=8). The slices were assessed for the presence of calcification using Alizarin Red staining and for the presence of osteogenic and inflammatory markers using (Immuno) histochemistry. Results In the presence of 3mM Phosphate, 74% of the slices demonstrated calcification, whereas no calcification was observed in all slices cultured without 3mM Phosphate (p<0.0001; Figure 2a). Furthermore, osteogenic genes such as Runx and alkaline phosphatase-1, as well as the inflammation marker NFkb were expressed in the calcified slices (Figure 2a). Dexamethason inhibited the calcification in the slices treated with 3 mM phosphate (Figure 2b). Conclusions We developed a novel ex-vivo calcification model for human aortic valves in which the initiation and progression of aortic valve calcification can be studied. In addition, the calcification can be modulated at a molecular level providing a unique opportunity to uncover the molecular signaling pathways involved in valvular calcification and to test compounds facilitating pre-clinical translational studies.Figure 1Figure 2

Changes in global longitudinal strain after TAVI: additional prognostic value over cardiac damage staging in severe aortic stenosis

Abstract Background Aortic stenosis (AS) is the most prevalent valvular heart disease in the aging population and has significant impact on cardiac function. In these patients, previous studies proposed an extra-valvular cardiac damage staging, which demonstrated a strong prognostic value. Left ventricular global longitudinal strain (LVGLS) has also been shown to be a better measure of LV performance in AS patients, and when impaired to be a robust predictor of adverse outcomes. Transcatheter aortic valve implantation (TAVI) can improve both cardiac damage stage and LVGLS significantly, but little is known about their prognostic value when measured after TAVI. Purpose To evaluate the changes and prognostic value in the extra-valvular cardiac damage staging and in LVGLS from baseline to 6 months follow-up after TAVI. Methods Patients with severe AS undergoing TAVI were analyzed retrospectively. Echocardiography was performed and measured before and 6 month after TAVI. Patients were hierarchically classified in a cardiac damage stage (worst stage) if at least one of the proposed criteria was met. The staging included: stage 0 = no signs of cardiac damage; stage 1 = LV ejection fraction < 50% and/or E/e´> 14 and/or LV mass index > 115 g/m2 (male) or > 95 g/m2 (female); stage 2 = Significant mitral regurgitation and/or Left atrial volume index > 34 mL/m2; stage 3 = Pulmonary artery systolic pressure ≥ 60 mmHg and/or Significant tricuspid regurgitation; stage 4 = Tricuspid annular planar systolic pressure < 16 mm. GLS was measured at baseline and follow-up. The primary endpoint was all-cause mortality. Results In total, 620 patients were included for paired analysis. At baseline, 4% of patients were classified as stage 0, 11% as stage 1, 30% as stage 2, 31% as stage 3, and 24% as stage 4, distinctly. At 6 months follow-up, 3% of the patients were classified as stage 0, 19% as stage 1, 49% as stage 2, 20% as stage 3, and 9% as stage 4. At 6 months follow-up, LVGLS significantly improved in the overall population (13.6% versus 16.3%, p<0.0001), and the improvement in LVGLS was similar among each baseline cardiac damage stage (Figure 1). Follow-up LVGLS values were divided in quantiles and implemented in the definition of follow-up cardiac damage stages, leading to a reclassification of 308 patients. Kaplan-Meier curve showed that survival rates in patients stratified by the new cardiac damage stage, including LVGLS, was significantly different (Figure 2). Multivariate Cox regression models showed that follow-up LVGLS and the re-classified cardiac damage stage (including LVGLS) had significant incremental prognostic value as compared to baseline variables. (Figure 2). Conclusions LVGLS improves at follow-up after TAVI independently of the cardiac damage stage at baseline; assessment of LV GLS and cardiac damage stage (also when combined for patient classification) is of additional prognostic value as compared to baseline assessment alone.Changes in LV GLS by each stageKM curve and Multivariate Cox regression

Prognostic role of extracardiac incidentalomas detected with computed tomography in patients with severe aortic stenosis candidates for transcatheter aortic valve replacement

Abstract Background Aortic stenosis is one of the most common valvular heart diseases worldwide, especially among older individuals. According to the latest guidelines for the management of valvular heart disease, in patient with high surgical risk and aged 75 years and older, transcatheter aortic valve replacement (TAVR) is the first therapeutic option to be considered (1). Every patient undergoing TAVR should perform a computed tomography (CT) scan before percutaneous procedure. An incidentaloma is defined as an unexpected finding on a CT scan performed for another clinical reason. Purpose The purpose of this study is to determine the prognostic role of incidentalomas found on CT scan performed pre-TAVR procedure in elderly patients with severe aortic stenosis. Methods We performed a monocentric retrospective observational study of 284 patients with severe aortic stenosis evaluated for TAVR from January 2016 to December 2022. All data were collected retrospectively and processed anonymously. Patients' clinical data (past medical history, cardiovascular risk factors, comorbidities, echocardiogram and coronary artery angiography findings) were collected, and all CT scans were reviewed for the presence of incidentalomas. An incidentaloma was considered clinically relevant only if further investigations were required following its diagnosis. Statistical analyses were performed using Mann-Whitney test, uni- and multivariate Cox regression models. Only variables with p<0,05 on univariate analysis were included in multivariate models. The primary endpoint of the study was delay in TAVR implantation. The secondary endpoint was death. Results We analyzed 284 patients’ data with a median age of 87 (83-90) years. The median follow-up was 713 (464-1130) days in which 165 (58%) patients underwent TAVR and 83 (29%) deceased. Among the patients, 43 incidentalomas were diagnosed (Table 1). About primary endpoint, within patients who underwent TAVR, median delay to the procedure was 217 (160-284) days and there was not statically difference in delay between patients with or without incidentalomas (Mann-Whitney test p=0,08) (Figure 1). Furthermore, about the secondary endpoint, incidentalomas were not associated with death on univariate analysis (p=0,38) (Figure 2). Atrial fibrillation, chronic kidney disease (CKD), dilatation of left ventricle, left ventricular ejection fraction (LVEF) and TAVR were statistically significant among patients survived or not. LVEF was not associated with outcome (p=0,06) on univariate Cox regression analysis. In multivariate model (Table 2) TAVR reduced risk of death, instead CKD and dilated left ventricle increased risk. Conclusion Between patients with severe aortic stenosis candidates for TAVR presence of clinically relevant incidentalomas on CT scan was not associated with significant delay in procedure or death. Further studies are needed to prospectively confirm these results on a larger cohort of patients.Table 1 and Table 2Figure 1 and Figure 2

Clinical outcomes and myocardial recovery in energetics, perfusion and contractile function after valve replacement surgery in severe aortic stenosis patients with diabetes comorbidity

Abstract Background Aortic stenosis (AS) and type 2 diabetes mellitus (DM) are increasingly frequent comorbidities in aging populations, and diabetes is associated with increased morbidity and mortality after aortic valve replacement (AVR). Although distinct pathological entities, AS and DM share common features of impaired myocardial energetics and coronary microvascular dysfunction (CMD). The mechanisms for the adverse prognostic association between AS and DM are incompletely understood. Purpose Utilising 31phosphorus magnetic resonance spectroscopy (31P-MRS) and CMR, we tested the hypotheses that the collective impact of severe AS and DM on the myocardium aggravates the impairment in energetics, function and perfusion. Methods Eighty-eight severe AS patients with (AS-DM) and without DM (Iso-AS) undergoing AVR and 15 healthy volunteers were recruited. Patients with coronary artery disease were excluded. Participants with AS underwent 31P-MRS and comprehensive CMR imaging 1 month prior to and 6 months after AVR. Results Demographic, biochemical and CMR/31P-MRS data are shown in Table-1. All groups were matched for age and sex distribution, with AS groups matched for surgical scores and frailty scores. NTproBNP levels were similarly elevated in AS groups. Left ventricular (LV) volumes and ejection fraction (EF) were similar between the groups, with no significant difference in LV mass or wall thickness between the AS groups. The baseline differences in myocardial energetics, stress myocardial blood flow (MBF) and global longitudinal strain (GLS) are shown in the Figure. AS-DM patients showed greater reductions in myocardial energetics (p<0.0001), global stress MBF (p<0.0001) and more significant reductions in GLS (p=0.001) than the Iso-AS patients. At 6 month post AVR both AS groups showed significant improvements in stress MBF and GLS. However, only the Iso-AS patients showed significant improvement in myocardial energetics. AS patients were followed up for a median of 12 months. Cumulative incidence of the clinical events post AVR (composite of cardiovascular death, stroke, heart failure admission, infective endocarditis) were significantly higher in the AS-DM group than the Iso-AS group (Hazard Ratio: 3.35; 95% CI: 0.97–11.6; p=0.02). Conclusion Diabetes was associated with increased morbidity and mortality after AVR. We showed for the first time that the collective impact of T2DM and AS on the myocardium aggravates energetic impairment, CMD and contractile dysfunction. While myocardial recovery following AVR was associated with similar improvements in perfusion and contractile function in severe AS patients with and without T2DM, improvements in energetics were only detected in isolated AS patients. However, despite the significant improvements in contractile function and perfusion following AVR in diabetes patients, these parameters remained lower in the group with diabetes comorbidity compared to isolated AS patients. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Wellcome Trust

High-sensitive Troponin T is not associated with the progression of asymptomatic mild to moderate aortic stenosis: a post hoc substudy of the SEAS trial

Abstract Background Aortic stenosis (AS) and coronary artery disease (CAD) share pathophysiological pathways, as reflected by frequent concomitant revascularization in patients undergoing aortic valve replacement (AVR). High-sensitive Troponin T (hsTnT) is a proven biomarker of cardiomyocyte overload and injury, and predicts postoperative mortality after AVR. However, it is unknown if hsTnT can predict AVR, mortality or ischemic coronary events (ICE) in asymptomatic AS patients. Purpose To investigate the hypothesis that increased hsTnT is associated with more severe AS and a higher risk of adverse outcomes in asymptomatic AS patients without overt CAD. Methods hsTnT concentrations were examined at baseline and after 1-year follow-up in 1739 asymptomatic AS patients enrolled in the randomized, double-blind Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. The main inclusion criteria were: left ventricular (LV) ejection fraction >55%, transaortic maximal velocity between 2.5–4.0 m/s, and no history of CAD. The primary exposure variable was increased hsTnT (>14 pg/mL according to the assay manufacturer, Roche). This study's primary endpoint was a composite of competing risk outcomes: all-cause mortality as the first event, AVR without revascularization, and ICE (defined as myocardial infarction before AVR, PCI before or combined with AVR, or any CABG). Multivariable regression examined associations between hsTnT and clinical variables. Cox proportional hazards regression models were adjusted for age, sex, creatinine, LV mass index, mean aortic pressure gradient (Pmean) and stratified by center and lipid-lowering treatment. We analyzed outcomes during 5-year follow-up from baseline. Results At baseline, 453 (26.0%) patients had increased hsTnT and 302 (17.4%) had moderate-severe AS with a mean (SD) aortic valve area of 0.8 (0.2) cm2 and Pmean of 33.2 (8.8) mmHg. The median annual hsTnT change from baseline to year 1 was 0.8 pg/mL (IQR, −0.4 to 2.3), regardless of AS severity (P=0.08). In adjusted models, log(hsTnT at baseline) was associated with age, sex, creatinine, and LV mass index (all P<0.05), but not with AS severity (P=0.36). The incidence rate ratio for ICE (Figure 1) in patients with increased vs normal baseline hsTnT concentrations was 2.32 (95% CI, 1.72–3.11, P<0.001). In adjusted Cox regression, increased hsTnT was associated with an increased 5-year ICE risk (HR 1.64; 95% CI, 1.18–2.29, P=0.003), but neither with AVR without revascularization nor death (Figure 1). Conclusion In these asymptomatic AS patients without overt CAD, hsTnT is often normal and remains stable during 1 year of follow-up regardless of AS severity. Increased hsTnT is associated with CAD-related events, but neither to AS severity nor AVR without concomitant revascularization. This analysis does not support routine hsTnT measurement in asymptomatic AS to predict AVR related to AS progression, although hsTnT could improve the risk assessment for ICE. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Main sponsor (SEAS): Merck & Co Inc, Whitehouse Station, New JerseyBlood analysis sponsor: Roche Diagnostics International Ltd, Switzerland

Higher long-term mortality in patients with concomitant acute coronary syndrome and aortic stenosis

Abstract Background Aortic stenosis (AS) and acute coronary syndrome (ACS) share similar cardiovascular risk factors, and their concomitant presentation is increasing in incidence with the aging population. Yet literature regarding the prognosis of patients with concomitant ACS and AS remains scarce. Methods This retrospective cohort study examined consecutive patients presenting with ACS (ST-segment elevation myocardial infarction [STEMI] and non-STEMI [NSTEMI]) and concomitant AS between 1 January 2011 and 31 March 2021 in a tertiary hospital. The cohort was divided into mild, moderate and severe AS based on index echocardiogram. The primary outcome was all-cause mortality. Kaplan-Meier curves were constructed to compare all-cause mortality among the three groups of patients, based on ACS type and left ventricular ejection fraction (LVEF). Multivariable Cox regression was performed to identify independent predictors of all-cause mortality. Results Of a total of 563 patients, 264 had mild (46.9%), 193 moderate (34.3%) and 106 severe AS (18.8%). The mean follow-up duration was 2.5 (± 2.4) years. Majority of patients (72.5%) presented with NSTEMI. Patients with moderate and severe AS had higher rates of all-cause mortality compared to those with mild AS (49.7% vs. 51.4% vs. 35.6% respectively, p=0.002). Concomitant moderate (HR 1.439, 95% CI 1.012–2.048, p=0.043) and severe AS (HR 1.844, 95% CI 1.159–2.933, p=0.010) were independent predictors of all-cause mortality after adjusting for age, gender, LVEF, ACS type, chronic kidney disease, diabetes, hypertension, coronary artery bypass grafting and aortic valve replacement as a time-dependent variable. The Kaplan-Meier curves demonstrated excess mortality in moderate and severe AS, compared to the mild AS group (p<0.001), with similar survival trends observed in the STEMI and the NSTEMI groups, as well as those with preserved LVEF. Conclusion Regardless of the ACS presentation type, long-term excess mortality in those with concomitant moderate or severe AS was observed. The adverse prognosis typically observed in patients with concomitant severe AS, in the setting of ACS, extends to patients with moderate AS. Funding Acknowledgement Type of funding sources: None.

Enrichment in procoagulant microparticles in calcified human aortic valve – role in valvular endothelium alterations and enhanced thrombogenicity

Abstract Background Aortic stenosis (AS) is characterized by endothelial dysfunction (ED), inflammatory cell infiltration, myofibroblastic and osteoblastic differentiation. Subclinical leaflet thrombosis was recently linked to higher rates of stroke and transient ischemic attack after transcatheter aortic valve implantation (TAVI). Procoagulant microparticles (MPs) are associated with ED, inflammation and clot formation. There is limited evidence regarding intra-valvular MPs content and their potential biological effects. This question is particularly relevant in TAVI in which the residing native valve could constitute a source of thrombotic activity enhancing leaflet thrombosis and valve dysfunction. Purpose Therefore, we hypothesized that MPs trapped within the native aortic valve contribute to valvular dysfunction including enhanced thrombogenicity. Methods Human valves were collected from patients undergoing surgical valve replacement for AS or aortic insufficiency (AI). Pro-thrombotic, pro-inflammatory, and ED markers were identified in the calcified vs non-calcified part of the valves by Western-blot. Calcium content was measured through colorimetric method. MPs were extracted from human pathological valves, and quantified through their prothrombinase activity. Primary cultures of porcine valvular endothelial cells (VEC) were treated with the MPs (10 nmol/L) or thrombin (1U/ml) for 24hrs. Phenotypic change was appreciated through gene expression pattern assessed by RT-qPCR. IL-8 secretion was measured by ELISA. Results The phenotype of the AS valve was characterized through increased expression of thrombogenic (tissue factor, thrombomodulin, PAI-1), adhesive (VCAM-1, ICAM-1) and inflammatory (COX-1, COX-2) molecules in the calcified part of the valve. Moreover, MPs content was increased in the calcified vs non-calcified part of the valve or AI valves. MPs levels was correlated with valvular calcium content (R=0.3862: p<0.001). Tissue factor was increased in MPs extracted from AS vs AI. The biological effect of MPs was tested on VEC in-vitro. Results showed dramatic increase in expression of inflammatory cytokines (CXCL10, CCL11, CXCL8, MCP1) adhesion molecules (VCAM-1, ICAM-1, SELP, SELE) and proangiogenic factors (VEGFR2, ANGPTL4) in VEC exposed to MPs (24h) from AS vs AI. Enhanced secretory phenotype was evidenced through IL-8 determination in the supernatant of VEC stimulated with MPs from AS valve. Conclusion Calcified aortic valve is a potent reservoir of MPs, acting as a pro-thrombogenic source per se and promoting a switch of VEC phenotype toward prothrombotic, proinflammatory and proangiogenic pattern. These data suggest that MPs released from the native valve constitute an important source of mediators involved in enhanced thrombogenicity and valvular remodeling. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): GERCA-Groupe Etudes Reali Commercia Avignon

Novel assay for quantifying the cholesterol crystal dissolution capacity of serum predicts outcomes in patients with severe aortic stenosis undergoing TAVR

Abstract Background Aortic stenosis (AS) is the most common valvular heart disease (VHD) in developed countries. The pathophysiology of calcific AS has several clinical and pathobiological findings in common with atherosclerosis including chronic inflammation and lipoprotein deposition. Histopathological examination has revealed atherosclerosis-like lesions, that mainly contain cholesterol crystals (CC) in resected calcific aortic valve cusps. Previous studies have demonstrated that CCs can activate the NLRP3 inflammasome, resulting in an IL-1 driven systemic inflammation, that leads to the development of atherosclerotic plaques. Purpose In this study, we sought to validate a novel assay for measuring the serum capacity to dissolve cholesterol crystals (CCDC) in patients with AS and to examine whether this biomarker may be associated with clinical outcomes. Methods Our study cohort included 348 patients with AS undergoing transcatheter aortic valve replacement. The CCDC was measured using flow cytometry to enumerate CC, that were added to a 50% serum solution, at baseline and after two hours of incubation. The dissolution capacity was indicated as percentage change in CC count at baseline and after incubation. The study cohort was stratified according to the median CCDC into high and low CC dissolvers. Results The study population was 47.7% female and had a mean age of 80.9±6.2 years. The primary end point, a composite of one-year all-cause mortality and major vascular complication occurred less frequently in the high CCDC group (7.0%) as compared with the low CCDC group (15.3%, p=0.01). This was mainly driven by lower rates of one-year mortality in patients with a high CCDC (7.0% vs 13.6%, p=0.05), as presented in Figure 1. Furthermore, unplanned endovascular interventions were significantly less frequent in high CC dissolvers in contrast to low CC dissolvers (12.2% vs 20.5%, p=0.04). Although LDL cholesterol (101.8±37.3 mg/dL vs 97.9±37.6 mg/dL, p=0.35) and total cholesterol levels (158.1±43.8 mg/dL vs 154.1±40.2, p=0.41) were comparable in the high and low CCDC group, only patients with a low CCDC showed a benefit from statin treatment (Figure 2). In multivariate analysis, only low CCDC (OR: 2.51 [95% CI: 1.02–6.15], p=0.05) and Albumin (OR: 0.88 [95% CI: 0.79–0.98], p=0.03) were independently associated with one-year all-cause mortality Conclusion The CCDC is a novel biomarker associated with clinical outcome in patients with AS undergoing TAVR. It may provide new insights into patient's preventative anti-inflammatory capacity and additional prognostic information to identify vulnerable patients beyond classic risk assessment. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation).

Early intervention versus conservative management of asymptomatic severe aortic stenosis: a systematic review and meta-analysis

Abstract Background Aortic stenosis (AS) is the most common valvular disease in developed countries. However, the specific timing of intervention for asymptomatic patients with severe AS remains controversial. Purpose To compare the outcomes of early aortic valve replacement (AVR) versus watchful waiting (WW) in asymptomatic patients with AS. Methods We systematically searched PubMed, Embase and Cochrane databases, in December 2021, for both interventional or observational studies comparing early AVR with WW in the treatment of asymptomatic severe AS. Random-effects meta-analysis was performed. Results Thirteen studies were included in which two were randomised clinical trials. A total of 4,679 patients were included, providing a 1,268 pooled death events (327 in early AVR and 941 in WW). Our meta-analysis showed a significantly lower all-cause mortality for the early-AVR compared with WW group, although with a moderate amount of heterogeneity between studies in the magnitude of the effect (pooled odds ratio [OR], 0.41; 95% confidence interval [CI] 0.34, 0.50, P<0.01; I2=60%). An early surgery strategy displayed a significantly lower cardiovascular mortality (pooled OR, 0.33; 95% CI [0.19, 0.56], P<0.01; I 2=64%) and heart failure hospitalisations (pooled OR 0.19; 95% CI [0.10, 0.39], P<0.01, I2=7%). However, both groups had similar rates of stroke (pooled OR 1.30; 95% CI [0.73, 2.29], P=0.36, I2=0%) and myocardial infarction (pooled OR 0.49; 95% CI [0.19, 1.27], P=0.14, I2=0%). Conclusions Our pooled data suggest that an early-AVR strategy is preferable for asymptomatic patients with severe AS. Funding Acknowledgement Type of funding sources: None.

Prevalence and prognostic impact of cardiac amyloidosis in patients with severe aortic stenosis undergoing transcatheter aortic valve implantation. AMY-TAVI study

Abstract Background Aortic stenosis (AS) and cardiac transthyretin amyloidosis (CTTRA) are two diseases that are typically associated with aging. In both cases, dyspnea is the main symptom, so the diagnosis of CTTRA in patients with AS is underestimated. Purpose To determine the real prevalence of CTTRA in patients with AS and its influence on prognosis. Methods After implantation, and before hospital discharge, CTTRA screening was carried out by performing a scintigraphy with 99mTc-3,3-diphosphono-1,2-propanedicarboxylic acid, and monoclonal peak in peripheral blood and urine was excluded to rule out CA-AL.According to Perugini's classification, CATTR grades 1, 2 and 3 were established and grade 0 as the absence of CATTR. Result 325 patients were included. The incidence of CTTRA was 11.7% (38 patients). Grade 1 39.4% (15 patients), grade 2 34.2% (13 patients) and grade 3 26.3% (10 patients). Patients with CATTR were more frequently male (female 36.8% vs 54%, p=0.046), had a lower mean transvalvular gradient (43.2±14.0 mmHg vs 50.9±14.7 mmHg, p=0.003), and greater thickness of the interventricular septum (15.4±2.3 mm vs 14.4±2.7 mm, p=0.038). There were no differences in the rest of the clinical or analytical variables, including functional class or NT proBNP levels (3663.3±4343.9 vs 3815.4±7901.7, p=0.912). According to the Valve Academic Research Consortium-3 classification, there were no differences in in-hospital complications between the two groups, stroke (3.1% vs 2.6%, p=0.866), greater bleeding (7.3% vs 15.8%, p=0.202), acute kidney injury stage 3 (2.1% vs 0.9, p=0.566), permanet pacemaker implantation (19.2% vs 13.2%, p=0.370), acute myocardial infarction (0.3% vs 0%), acute heart failure (4.2% vs 2.6%, p=0.647).Mean follow-up time was 19.0±7.4 months (median: 19.2, IQR 12.5–25.7 months). During this time, there was no difference in the appearance of MACE, defined as all-cause mortality, heart failure, acute myocardial infraction and stroke, between patients with and without CTTRA (Figure 1A). Nor when we analyze these events separately. Finally, the evolution in functional class and NT proBNP values six months after implantation were analyzed. Although there was an improvement in functional class in all groups, this was not significant in patients with CTTRA grade 3, going from 30% of patients in NYHA class III–IV at baseline to 22.2% at 6 months (p=0.556). Regarding the NT proBNP values, these decreased in all the groups but they only did so significantly in the patients without CTTRA (Figure 2). Conclusion The coexistence of AS and CTTRA in patients undergoing TAVR is relatively frequent. Although there are no more in-hospital or mid-term follow-up complications than in patients without CTTRA, the degree of symptomatic improvement and normalization of natriuretic peptides is lower in these patients, especially in the more advanced stages, where it will be necessary to assess whether the procedure will be futile or not. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Pfizer

Global longitudinal strain as a potential marker for earlier treatment referral for severe aortic stenosis

Abstract Background Aortic stenosis (AS) is the most prevalent valvular disease in the developed countries. The disease progression is long and It is of greatest importance to choose the optimal intervention timing and to secure best long term prognosis. Purpose To establish left ventricular strain as independent predictor for left ventricular function improvement after AVR which could be used for treatment decision making. Methods In this prospective, crossectional study 76 patients were included that fulfilled the criteria for severe aortic stenosis according to the guidelines from professional associations. In all patients before the AVR detailed clinical, functional, angiographic examination was performed as well as transthoracic echocardiography using Philips Epique 7. With 2D TTE the left ventricular systolic and diastolic function was assessed and with speckle tracking echocardiography global longitudinal strain (GLS %) was evaluated. Same TTE evaluation was performed 4 months after AVR. Measurements were analyzed using QLAB 7.1. Statistical analysis was performed using SPSS 25.0. Results Surgical treatment of the aortic valve significantly reduced aortic stenosis severity in all patients. Age didn't have any impact on change of left ventricular function after AVR. In both genders there was significant reduction in disease severity as well as improvement in systolic and diastolic function of the left ventricle (Figure 1) with greater improvement of GLS values in the female gender. Analysis of GLS changes after AVR in patients divided by EF showed significant improvement of GLS in patients no matter the value of preoperative EF (Figure 2). For EF improvement after AVR independent predictors were: left ventricular systolic dimension and GLS. Analysis of our cohort before AVR showed significant correlation of impaired GLS with male gender, obesity, more severe AS, larger LVD dimension and wall thickness, as well as LV systolic and diastolic volumes, higher LVMI, lower EF and lower stroke index, reduced MAPSE and s'TDI, higher wall motion score index, higher Zva and lower left atrial EF. After AVR there was significant improvement of GLS in all patient, however patients with reduced preoperative EF had significantly worse GLS after AVR. In the patients with preserved EF ≥50%, GLS before AVR was independent predictor for postoperative improvement of EF and number of segment with LS less than 13% was independent predictor for positive remodeling only in patients with low flow. Conclusions Impairment of LV GLS is of particular significance in the wide variety of patients with preserved EF that vary in ratio between flow and gradient were worse values of GLS imply worse prognosis. The results from our study support promotion of LV GLS as a marker for decision on AVR timing in respect of its prognostic implications. It is our expectation that GLS evaluation would find its place in future guidelines for diagnosis and treatment of patients with AS. Funding Acknowledgement Type of funding sources: None.

Early aortic valve replacement in asymptomatic severe aortic stenosis with preserved ejection fraction

Abstract Background Aortic stenosis (AS) is the most common valvular disease in developed countries. Specific timing of intervention for asymptomatic patients with severe aortic stenosis and preserved ejection fraction remains controversial. Purpose To compare the outcomes of early aortic valve replacement (AVR) versus watchful waiting (WW) in asymptomatic AS patients with preserved ejection. Methods We systematically searched PubMed, Embase and Cochrane databases, in November 2021, for both interventional or observational studies comparing early-AVR with WW in the treatment of asymptomatic severeAS with preserved ejection fraction criteria. Random-effects meta-analysis was performed. Results Eight studies were included in which two were randomized clinical trials. A total of 2672 patients were included, providing a 642 pooled death events (327 in early-AVR and 941 in watchful waiting). In our meta-analysis, early-AVR revealed a significant lower all-cause mortality (pooled OR, 0.39; 95% CI [0.30, 0.51], P<0.01; I2=47%). Additionally, the early-AVR group presented a lower rate of cardiovascular mortality (pooled OR, 0.33; 95% CI [0.19, 0.56], P<0.01; I2=64%). Both strategies had similar rate of stroke (pooled OR, 1.30; 95% CI [0.39, 4.27], P=0.67; I2=0%) and myocardial infarction (pooled OR, 0.49; 95% CI [0.14, 1.78], P=0.28; I2=0%). Heart Failure hospitalizations presented a lower trend early-AVR group (pooled OR, 0.22; 95% CI [0.05, 1.08], P=0.36; I2=36%). Conclusion Our pooled data suggests that early-AVR strategy is preferable for asymptomatic severe AS patients with preserved ejection fraction. Funding Acknowledgement Type of funding sources: None.