Aortic Stenosis Research Articles

Impact of body mass index on aortic valve stenosis and its clinical outcomes in early adulthood: a long-term study of young men

Abstract Aims Studies investigating associations between body mass index (BMI), incidence of aortic valve stenosis (AVS), and clinical outcomes in AVS patients are scarce. Purpose To investigate the relationship between BMI in youth and subsequent diagnosis of AVS. A secondary aim was to determine the role of obesity in clinical outcomes in individuals diagnosed with AVS. Methods This was a nationwide, register-based cohort study of 1 701 390 men (mean age, 18.3 ±0.8 years) enrolled in compulsory conscription for military service in Sweden from 1969 through 2005. Anthropometrics, blood pressure, fitness, muscle strength and IQ were recorded at baseline. AVS cases and cardiovascular outcomes were identified according to the International Classification of Diseases (ICD)-10 registered in the National patient register and Cause of Death Register through the Swedish 12-digit personal identification number. BMI (kg/m2) was categorized as <18.5, 18.5–<20, 20–<22.5, 22.5–<25, 25–<27.5, 27.5 <30, 30–<35, and 35–<50 kg/m2. Cox proportional hazard models were used to estimate the association between adolescent BMI and future hospitalization for AVS while adjusting for potential confounders. The BMI reference was set as 20–<22.5. Those who developed AVS formed a subcohort that was followed until a first clinical cardiovascular outcome of death, cardiovascular mortality, Heart failure, Atrial fibrillation, myocardial infarction, or ischaemic stroke. Results During a median follow-up of 32 years (IQR, 24-41 years), 5766 cases (mean age 54.7±9.4 years) of AVS were diagnosed. After adjustment, underweight subjects with a BMI of <18.5 kg/m2, compared to those with a low-normal BMI (20.0–<22.5 kg/m2) showed lower risk (HR 0.70; 95% CI 0.61–0.80) of AVS. The multivariable-adjusted HR for AVS increased from HR 1.28; 95% CI 1.17–1.39 for BMI 22.5–<25 kg/m2 to HR 1.91; 95% CI 1.12–3.25 for those with BMI 35–50 kg/m2. Further on, individuals diagnosed with AVS were followed for a median of ~5.5 years. The multivariable-adjusted HR for all-cause mortality, cardiovascular mortality, and heart failure for obese (BMI 30–50 kg/m2), compared to BMI <20.0 kg/m2 in men diagnosed with AVS, were 4.69 (95% CI 2.61–8.44), 4.09 (95% CI 1.72–9.73), and 2.76 (95% CI, 1.36–5.60), respectively. Conclusions Elevated BMI in youth, even within the normal range, is associated with increased risk of developing AVS, while subnormal BMI was protective. Excess weight in youth diagnosed with AVS is associated with higher risk of subsequent clinical outcomes. These findings are novel, generating new questions as to potential mechanisms and implying more vigilant monitoring of patients with AVS and a history of obesity in youth.Figure 1Figure 2

An artificial intelligence-based landmark model for early detection of aortic stenosis in Cardiac MRI

Abstract Background The utilisation of ratiometric intensity measures from cardiac magnetic resonance imaging (CMR) offers a promising biomarker for the diagnosis of aortic stenosis (AS)[1]. The Ao:LV ratio, an approximation of AS severity, is determined by comparing the relative blood signal intensity in the aorta and left ventricle (LV) within three-chamber (3Ch) cine sequences[1]. In patients with AS, the blood signal intensity of aortic blood above the valve is diminished compared to that within the LV in steady-state free precession (SSFP) 3Ch CMR cine. Although the Ao:LV ratio serves as a reliable indicator of AS severity, manual computation of this ratio may encounter difficulties due to visual obstructions caused by small LV cavities or prominent papillary muscles. Purpose This study aims to leverage artificial intelligence (AI) to automate the Ao:LV ratio analysis from 3Ch SSFP cine images and introduce the Ao:LA (aorta to left atrium) ratio, thus enhancing the diagnostic accuracy for AS severity. Methods Our methodology extends the ratiometric analysis to include both Ao:LV and Ao:LA ratios in three main steps: first, developing an AI-based algorithm for automated detection and tracking of cardiac landmarks; second, using these landmarks to automatically compute regions of interest (ROIs) in the cardiac chambers; and third, training and validating classification models with 5-fold cross-validation to select the most effective for AS severity classification. The final model's performance is assessed on a holdout test set. Data for model training and evaluation were sourced from CMR scans across three hospitals and two scanner types. Results We analysed 220 patients of which 78 patients had no AS and 122 had AS (mild AS, n = 29; moderate AS; n = 35, severe AS; n = 78). Our model yielded high efficacy in classifying AS, particularly in differentiating any grade of AS from a normal classification, which is clinically relevant. The Ao:LA ratio demonstrated a stronger correlation with AS severity class than Ao:LV, suggesting a more reliable biomarker. The proposed model demonstrated robust performance in AS classification, achieving an Area Under the Curve (AUC) of 0.845 in the automated binary classification of AS at any grade. The model exhibited a precision of 0.889, recall of 0.865, and an F1 score of 0.877 on a holdout set. Conclusion By the integration of AI in automating the analysis of CMR images through a novel ratiometric approach that includes Ao:LV and Ao:LA ratios, our model significantly improves the accuracy of early AS detection. This advancement enhances imaging strategies for AS evaluation, promoting more efficient and effective use of cardiac MRI sequences as a diagnostic tool for aortic stenosis. It has the potential to be implemented in real-time scanning protocols as a clinical decision support system.AI-inferred cardiac landmarks.ROC curve delineating AS prediction.

Invasive hemodynamic response to exercise in hemodynamically significant aortic stenosis with preserved left ventricular ejection fraction

Abstract Background Guidelines acknowledge that discordant low-gradient (LG) aortic stenosis (AS) may be severe, but verifying this can be challenging. Right heart catheterization during exercise is considered the gold standard evaluating ventricular hemodynamics. No invasive studies have compared the hemodynamic response of discordant LG and severe AS during exercise. Purpose To describe exercise hemodynamics in patients with asymptomatic discordant AS and left ventricular ejection fraction ≥50%, and to identify the variables associated with the steepness of the pulmonary capillary wedge pressure (PCWP)/cardiac output (CO) slope defined as (peak exercise PCWP-rest PCWP)/(peak exercise CO-rest CO). Methods Patients with aortic valve area (AVA) ≤1.5 cm² underwent right heart catheterization at rest and during maximal exercise measuring pulmonary artery pressures, PCWP, CO and PCWP/CO slope. Patients were stratified in three groups: 1) discordant LG AS (AVA ≤1.0 cm² and mean gradient <40 mmHg); 2) moderate AS (AVA >1.0 cm²) and 3) high-gradient severe AS (AVA ≤1.0 cm² and mean gradient ≥40 mmHg). Results Among 86 patients, 17 (20%) had discordant LG, 49 (57%) moderate, and 20 (23%) high-gradient severe AS. The PCWP/CO slope was significantly steeper in discordant LG: median 3.3 mmHg/L/min (interquartile range: 2.2 mmHg/L/min) and high-gradient severe AS: 2.7 mmHg/L/min (1.5 mmHg/L/min) compared to moderate AS: 1.9 mmHg/L/min (2.0 mmHg/L/min), p=0.004. In a linear regression model adjusted for age, sex and rest PCWP, systemic arterial compliance and AS severity were significantly associated with the PCWP/CO slope. Furthermore, patients with discordant LG AS had a leftward and upward shift in the PCWP/CO slope. Conclusions Discordant LG and high-gradient severe AS had similar hemodynamic response to exercise with steeper PCWP/CO slope than in moderate AS, suggesting that discordant LG AS is a severe form of AS. In addition, the left-upward shift in PCWP/CO slope for discordant LG compared to high-gradient severe AS indicates that, this group also has latent heart failure with preserved ejection fraction physiology.

Aortic valve stenosis augments long noncoding RNA H19 to govern angiogenic responses and phenotypes of valvular endothelial cell through endothelial to mesenchymal transition

Abstract Background Long noncoding RNAs (lncRNAs) have emerged as important regulators of cardiovascular disease, including aortic valve stenosis (AVS). Although several recent studies have reported that lncRNAs are dysregulated and might play a crucial role in (Endothelial to mesenchymal transition) EndMT, no specific role of lncRNA was reported in AVS pathogenesis. Here, we sought to investigate the role of H19 in EndMT during the pathogenesis of AVS. Methods and results High-throughput lncRNA sequencing of human aortic valve tissue explanted from patients with AVS due to severe stenosis during surgical aortic valve replacement (SAVR) demonstrated that certain lncRNAs [H19, AGAP2-AS1 (PUNISHER), GAS5, MALAT1] are significantly dysregulated compared to patients without AVS. To validate the RNA-seq data, 60 patients with AVS (n=30) or without AVS (n=30) were prospectively investigated. Among these, H19 (p=0.002), AGAP2-AS1 (p=0.002), and GAS5 (0.02) were significantly upregulated in patients with AVS, compared to non-AVS patients. Aortic valvular endothelial cells (VECs) were isolated from explanted valve tissue from AVS patients or obtained commercially. In vitro EndMT-promoting stimuli (TNFα or TGFß+IL1ß) were used for VEC stimulation for 5 days. RT-qPCR was used to quantify the expression of EndMT markers (EC markers, vWF, and NOS3, and mesenchymal markers, αSMA, SM22, Vimentin, and SNAI2). Loss of H19 led to dysregulation of the EC gene network and protein expression patterns that were analyzed by qRT-PCR, immunoblotting, and immunofluorescence, respectively. Further experiments show that silencing of H19 affects migration and proliferation, and promotes EndMT in EC. Functional assays suggested that H19 is a critical regulator of angiogenic properties. The molecular signature of angiogenesis was investigated using a RT-qPCR-based angiogenesis array to identify the regulation of angiogenesis with 84-angiogenesis-related genes. Mechanistically, the angiogenesis array revealed that H19 regulates Jagged Canonical Notch Ligand 1 (JAG1) (4.43-fold vs. control EC), an important regulator of NOTCH1 signaling, and pro-angiogenic factor in EC. Accordingly, EndMT marker expressions were dysregulated upon H19 depletion. A high-throughput luciferase reporter array demonstrated STAT3 activation upon H19 knockdown. Depletion of H19 increased the phosphorylation of STAT3 at TYR705 and pharmacological inhibition of STAT3 activation abolished the effects of H19 silencing on EndMT marker expression as well as on angiogenesis. Overexpression of H19 in VEC abrogated the H19-mediated promotion of JAG1- and VEGFA gene- and protein expression. Our data suggest that H19 might play a role in EC angiogenic gene expression and EndMT. The data reveal a pivotal role of H19 in controlling EndMT in AVS via regulation of the JAG1-NOTCH axis, which could potentially be therapeutically targeted to halt EndMT during AVS.

Prevalence of amyloidosis among patients with mild to severe aortic stenosis. Validation of screening parameters

Abstract Background Cardiac amyloidosis (CA) is an increasingly recognized cause of human heart failure. Up to 16% of patients with severe aortic stenosis (AS) undergoing transcatheter valve replacement have been reported to suffer concomitant transthyretin CA (ATTR). Since the diagnosis of CA implies distinct therapies with prognostic relevance, early diagnosis of CA is crucial. Different parameters have been described to improve screening accuracy for detection of CA, but it is unknown whether these parameters are valid, and the prevalence of CA is stable throughout the spectrum of AS. Purpose To validate screening parameters for the detection of CA in mild, moderate and severe AS. Methods Patient 65 years and above undergoing echocardiography with mild to severe AS, defined as calculated valve orifice area <2 cm2 by velocity-time-integral, and an intraventricular septum thickness > 11mm, fulfilling at least one of two additional criteria (Sokolow-Lyon-Index to left ventricular mass index ratio < 1.5 or stroke volume index < 35 ml/m2) were prospectively included and screened for CA using bone scintigraphy and immunofixation in blood and urine. Results 57 patients were included and completed the diagnostic work-up. Mean age was 83 ± 0.7 years and 71% were male. Overall, 15 (26%) of patients were diagnosed with CA (12 with ATTR and 3 with light-chain CA, Figure1A). 17 patients had mild, 21 had moderate and 19 patients were diagnosed with severe AS. Among patients with mild AS 41% were diagnosed with CA, whereas only 24% of patients with moderate and 16% of patients with severe AS suffered CA (Figure 1B), these results did not show statistically significant differences (p= 0.2, by Chi-Square Quadrat test). Patients with CA were less likely to have NYHA classes I or II (20 vs. 57%, p= 0.03), had higher values of NT-proBNP (4572 [2323; 6044] vs. 817 [589; 2571], p< 0.001) and high-sensitive troponin (66 [47; 103.5] vs. 22.5 [17; 33.6], p< 0.001) and were more likely to have an atrioventricular block of any degree (60 vs. 26%, p=0.04). Conclusion Prevalence of CA among patients fulfilling the criteria of this screening algorithm seems to be high independent of AS severity. Clinicians should not only focus on patients with severe AS to detect CA early. Further research is needed to estimate the prevalence of CA among all patients with AS. Figure 1 A: Among patients with an age >65 years, IVS >11mm, AS and SLI/LVMMI >1.5 or SVI <35 ml/m2 26% (red area) of patients were diagnosed with CA (n= 57). B: In patients with mild AS 41% were diagnosed with CA, whereas in patients with moderate AS only 24% and in patients with severe AS 16% had CA. These differences did not show statistical significance (p= 0.2). IVS: intraventricular septum, AS: aortic stenosis, SLI: Skolow-Lyon-Index, LVMM= left ventricular myocardial mass index, SVI: stroke volume index, CA: cardiac-amyloidosis. (Statistics performed by chi-square test using GraphPad Prism 9.0).

The diagnostic accuracy of aortic valve calcium score in patients with low gradient and high gradient aortic stenosis

Abstract Introduction The standard imaging modality for diagnosing aortic stenosis (AS) is echocardiography (echo), by which the definition of severe AS is based on the transvalvular mean gradient (AMG) (>40 mmHg) and aortic valve area (AVA) (<1 cm2). However, in around one quarter of the cases, echo provides discordant findings (AVA<1 cm2, despite of an AMG <40 mmHg), complicating clinical decision making. Computed tomography aortic valve calcium scoring (CT- AVCS) offers an alternative diagnostic method. In cases with discordant echo measurements current guidelines recommend the use CT-AVCS to decide on severity. Purpose Our aim was to validate the sensitivity of the recommended AVCS thresholds within our patient population, as well as to identify any factors associated with below cut-off AVCS values despite confirmed severe AS (low AVCS). Methods Our retrospective study included 332 consecutive patients with severe AS (AVA ≤1 cm2), who underwent CT angiography (CTA) for transcatheter aortic valve implantation (TAVI) planning. Based on the AMG the patients were classified into high gradient (HG: AMG ≥ 40 mmHg) and low gradient (LG: AMG <40 mmHg) groups. In the LG group AS severity was assessed by a multiparametric algorithm. To specify the predictors of low AVCS among patients with HG-AS, logistic regression analysis was used. The patients were followed for 50 months. Cox proportional hazard model was used to assess the risk of death from any cause. Results The HG-AS group consisted of 244 and the LG-AS cohort of 88 patients. In the HG-AS population the sensitivity of AVCS to diagnose severe AS was 89%. Within the HG severe AS group, logistic regression analysis revealed an association between low AVCS and the AMG (OR 0.89, CI 0.83 – 0.95, p <0,001), whereas none of the other tested factors (age, sex, hypertension, diabetes, left ventricle function, renal function) showed any association. In the LG-AS group, contrary to the HG- AS patients, the sensitivity of AVCS to define severe LG AS was limited (53% in males and 67% in females). Over a median follow-up of 50 months, the prognosis of HG AS patients with low AVCS was more favourable than that of the high AVCS patient population (HR 0.41; CI 017 – 097; p=0.04), however, in the LG AS group, the prognosis was not different when stratifying the patients according to high or low AVCS (p=0.21). Conclusions Our results confirmed that among patients with HG AS, the recommended AVCS thresholds provide a good diagnostic sensitivity for severe AS. Nonetheless, the number of severe AS patients with low AVCS is not negligible, especially within the LG-AS population, where the diagnosis is the most challenging. Our findings underline that in patients with discordant echocardiographic findings, a personalized, multiparametric diagnostic approach is needed, instead basing the final diagnosis exclusively on AVCS.

Rare genetic variants in LDLR, APOB, and PCSK9 are associated with aortic stenosis

Abstract Background Aortic stenosis (AS) is the most common cardiac valvular disease in the developed world. Although AS is associated with substantial morbidity and mortality, current treatment options are limited to invasive procedures and reserved for severe symptomatic disease. Genetic studies have linked common variants near lipid genes to AS and cohort studies have linked diagnoses of familial hypercholesterolemia to AS. In contrast, randomized controlled trials have shown no benefit of lipid-lowering therapy in AS. Purpose We aimed to assess the impact on AS conferred by lifelong decreased or increased LDL levels, by studying rare genetic variation in three important lipid handling genes (LDLR, APOB, PCSK9) from a genome-first perspective. Methods We utilized sequencing data and electronic health records from the UK Biobank (UKB) and the All of Us Research Program (AllofUs). We used LOFTEE to identify carriers of truncating variants in LDLR (LDLRtv), APOB (APOBtv) and PCSK9 (PCSK9tv); we used AlphaMissense to identify predicted-damaging missense variants (LDLR-AM, APOB-AM, PCSK9-AM). Linear regression analyses were used to assess the impact of the variant groupings on LDL levels in the UK Biobank, adjusting for sex, age, age^2, and principal components of ancestry. We then conducted Firth’s logistic regression analyses in UK Biobank and AllofUs modelling AS as outcome and variant status as predictor, adjusting for the same covariates; we used an inverse-variance-weighted meta-analysis to combine results. Results We identified 421,058 unrelated participants (N=5,322 AS cases) in the UK Biobank, and 232,170 unrelated participants (N=1,087 AS cases) in AllofUs. Across both cohorts, we identified 198 LDLRtv carriers, 1095 LDLR-AM carriers, 662 APOBtv carriers, 1422 APOB-AM carriers, 712 PCSK9tv carriers and 794 PCSK9-AM carriers. In the UK Biobank LDL values were substantially elevated in LDLRtv (P=1.9x10-48) and LDLR-AM carriers (P=7.5e-200), while LDL levels were substantially decreased in APOBtv (P<1x10-200), APOB-AM (P=6.3x10-19), PCSK9tv (P=1.2x10-114) and PCSK9-AM carriers (P=9.9x10-73; Figure 1). Across UK Biobank and AllofUs, the risk of being diagnosed with AS was strongly increased in LDLRtv (odds ratio [OR]=9.2 [4.32–19.50], P=8e-9) and LDLR-AM carriers (OR=2.76 [1.75–4.35], P=1e-5; Figure 2). Directionally consistent with these effects, we observed a trend towards decreased AS risk among carriers of either APOBtv or PCSK9tv (OR=0.57, [0.30–1.08], P=0.08) and a significantly reduced risk among carriers of APOB-AM or PCSK9-AM (OR=0.46, [0.26-0.82], P=0.009). Conclusion Rare genetic variants that confer lifelong increased LDL levels are associated with substantially increased risk of AS, and vice versa. Our results support a causal role of LDL in AS pathogenesis. In the context of trials demonstrating no benefit in AS, our findings suggest that lipid-lowering may need to be initiated earlier to affect AS development.LDL levels in UK BiobankAS risk in UK Biobank and AllofUs

Wire injury induced moderate aortic valve stenosis in mice is accompanied by a chronic systemic inflammatory reaction

Abstract Background Patients with aortic valve stenosis (AS) have elevated serum levels of inflammation markers, and blood cytokine levels correlate with ventricular recovery after transcatheter aortic valve replacement. While presence of inflammatory processes in stenotic aortic valves is acknowledged, no systematic characterization of the systemic immune reaction upon AS has been performed, yet. Purpose Hypothesis of this study was that AS induces a systemic inflammatory reaction linked with local processes in the heart. Methods AS was induced by wire injury (WI) or sham surgery was performed in 3-4 months old male C57Bl/6J mice. AS severity, left ventricular (LV) function and hypertrophy indices were assessed with echocardiography (echo). After four weeks, explanted organs were weighted, and flow cytometry identified total leukocyte numbers in blood, heart, and peripheral immune organs (spleen, liver, lymph nodes) and uptake of Cy5-labelled perfluorocarbon nanoemulsions by whole blood leukocytes. Costimulatory molecules (flow cytometry, RT-qPCR) and cytokines (RT-qPCR, Multiplex Immunoassay) were analysed in heart, peripheral immune organs and blood. Results R-values were positive for spleen weight correlation with AS severity, cardiac function and mass suggesting cardiac hypertrophy to preserve heart function. Myocardial myeloid and T cell r-values were positive or negative, respectively, for correlation with spleen and liver weight, hinting at T cell recruitment from peripheral stores. Immune cell numbers in peripheral lymph nodes and spleen showed negative r-values for correlation with heart hypertrophy indices; number of liver myeloid cells correlated negatively with LV wall thickness (monocytes=-0.8571, p=0.0238) suggesting immune cell recruitment to hypertrophic hearts. Cytokine mRNA levels trended mainly towards increase in heart and regional lymph nodes and reduction in spleen and liver after WI. Correlation with echo was more homogeneous after WI, with r-values mainly positive, except of T cell activation markers, for aortic valves, but negative for myocardium, hinting at mechanisms preserving heart function. Correlating unchanged cytokine protein levels in myocardium and plasma with echo, r-values were mostly positive for myocardium, and were more positive than in sham for plasma. Echo and costimulatory molecule correlation showed a more homogeneous pattern in WI, with mostly positive r-values in myocardium and periphery, while most r-values were negative in sham. Together with reduced PFC-uptake by lymphatic cells, this hints at systemic immune cell activation in AS. Conclusion The results suggest that number and activation state of leukocytes in peripheral organs are directly linked to cardiac processes in AS. Considering the pathological value of inflammation, it is crucial to in future studies find out if modulation of the systemic inflammatory reaction relieves severity of AS and prevents development of heart failure.

Deep learning improves detection of aortic stenosis in b-mode ultrasound: results of a pivotal multicenter validation study using artificial intelligence

Abstract Background Aortic stenosis (AS) is a highly prevalent and morbid condition, with moderate or severe AS present in 9% of patients over 75 years. Despite improved diagnostic and therapeutic methods, AS remains underdiagnosed, particularly in Black patients and underserved communities. Echocardiography (echo) is effective for detecting AS but requires expertise to quantify and interpret valve gradients and valve area. We hypothesized that a deep learning (DL) algorithm could be trained to detect AS severity using B-mode (non-Doppler) echo alone, the modality most likely to be available in point-of-care ultrasound (POCUS) studies. Here, we present the results of a multicenter pivotal trial to test whether artificial intelligence (AI) can help increase the detection of AS from B-mode echoes. Methods A convolutional neural network (CNN) was trained to classify the severity of aortic stenosis from 3 B-mode echo views of the aortic valve (parasternal long- and short-axis and apical 5-chamber). The training dataset had over 500,000 cine loops from 29,527 echoes in 26,981 patients. A fully crossed multireader multicase study was conducted using 220 echoes never seen during algorithm development. 5 level II-trained cardiologists (referred to as POCUS readers as they only reviewed B-mode clips) were presented with these echoes twice at least a month apart, once with and again without AI interpretation of AS severity. Readers identified 2 dichotomous severity levels (either "suggestive of moderate to severe AS" or not), with ground truth established by 3 level III-trained cardiology echo experts. While experts had access to full studies (including Doppler) to adjudicate severity, POCUS readers had no Doppler or measurements of any kind available. Sensitivity and specificity were compared for the 5 POCUS readers when aided by the AI algorithm vs unaided, with similar tests of inter-reader agreement. Results There was a statistically significant improvement in sensitivity (+5.5%, 95% CI [1.5%, 9.5%], p=0.007) with stable specificity (-0.3%, 95% CI [-3.6%, 3.0%], p=NS) when the 5 POCUS readers received the assistance of the AI software. Fig 1 shows 2,500 bootstrapping assessments to better show consistency of these findings. In addition, the POCUS inter-reader agreement (overall percent agreement) improved by approximately 7% (p<0.001), becoming comparable to that of expert readers (Fig 2). Conclusions In a comprehensive multireader pivotal trial, an AI algorithm improved the performance of POCUS cardiologist readers to identify significant AS from limited B-mode echoes as might be obtained in screening or outreach settings. Sensitivity for detection of moderate-severe AS increased significantly by 5.5% with stable specificity. Inter-reader agreement improved to resemble that of expert cardiologists given access to full study information, including Doppler. AI may have a role in assisting detection of significant AS from limited B-mode echoes.Fig 1Fig 2

Progression of aortic stenosis in patients with diabetes mellitus type 2 compared with matched controls

Abstract Background Degenerative aortic stenosis (AS) and diabetes mellitus type 2 (DM) increase with age1,2 and their prevalence is expected to rise. Patients with DM have a higher risk to develop AS3 and the pathophysiological process leading from a normal aortic valve to AS involves factors associated with DM. AS develops over years, but it can evolve more rapidly. There is insufficient knowledge about risk factors for rapid progression in AS and monitoring strategies among patients at high risk for rapid progression. The aim of this project is to evaluate the AS progression towards combined outcome (incident heart failure, death, need for intervention) in patients with type 2 DM compared with matched controls. Methods From the Swedish National Diabetes Register (NDR) we identified all patients with type 2 DM between 01-01-2001- 31-12-2019 and for each patient 5 controls (matched for age, sex, region) from the Swedish Total Population Register. Afterwards we identified a cohort of individuals with AS from these two groups, by linking the NDR with the National Patient Register. The outcomes were: all- cause and cardiovascular mortality, and combined outcome (mortality, hospitalization for heart failure (HF) or aortic valve replacement (AVR)). We used Kaplan Meier survival curves to detect differences in all-cause mortality, cardiovascular mortality, time until AVR and combined outcome between cases and controls. Cox proportional hazards model adjusted for sex, age, obesity, renal failure, hyperparathyroidism, hypertension, hyperlipidemia was used to study the risk difference between the cases and controls for the combined outcome. Results We identified 16 144 individuals with type 2 DM and AS and 31 206 matched controls. The individuals with type 2 DM were predominately men (59% vs 53%), younger (mean age 70.6 vs 71.9), and had more comorbidities. In unadjusted analysis they were hospitalized for HF more often (8.2% vs 6.8%) and more often underwent AVR (surgically) (22.0% vs 19.0%) or transcatheter(6.6% vs 5.0%). Patients with AS and DM had higher all-cause and cardiovascular mortality and faster progression towards death, AVR or hospitalization for HF (see figure 1, A, B, C). The progression to AVR was significant, although the difference was small and not clinically relevant (plot D). In the adjusted model, the patients with AS and DM had 13% higher hazard to have the combined outcome compared with controls (see figure 2). Sex (female), hypertension and hyperlipidemia lowered the hazard for the combined event, while obesity, hyperparathyroidism and renal failure increased the hazard for the combined event. Conclusions Patients with concomitant AS and DM seem to have faster progression towards death (both all-cause and cardiovascular), and heart failure hospitalization or AVR compared with patients with AS without DM. Therefore, it might be appropriate to be more active regarding follow-up and intervention in these patients.Kaplan Meirer curvesForest plot for adjusted Cox model

Aortic valve tract dynamics in normal-flow low-gradient and normal-flow high-gradient severe aortic stenosis

Abstract Introduction Aortic stenosis (AS) is the most common valvular heart disease in developed countries. Severe AS is defined as a mean pressure gradient (MG) ≥ 40 mmHg, a maximum aortic jet velocity≥4 m/s and an aortic valve area (AVA)≤1 cm2. However, classification of AS severity may be challenging due to discordant results on echocardiography. The normal-flow low-gradient severe AS (NFLG-AS) is defined as AVA≤1 cm2, MG<40 mmHg, left ventricular ejection fraction ≥ 50%, and stroke volume index (SVi) ≥ 35 ml/m2, whereas in the presence of MG > 40mmHg the condition is described as normal-flow high-gradient AS (NFHG-AS). Purpose The purpose of this study was to seek differences in the dynamic changes of the aortic valve tract throughout the cardiac cycle between the two clinical entities: NFHG-AS (Group 1) and NFLG-AS (Group 2). Methods In total, 130 patients with normal flow severe AS who underwent TAVI and had 3D transoesophageal echocardiographic data sets were screened. 38 patients with NFHG-severe AS and 40 patients with NFLG-severe AS with matching clinical characteristics and aortic valve area were identified. A custom-made semi-automated application developed by SQ was used. The application allows tracking of the aortic valve tract surface throughout the cardiac cycle in 3D transoesophageal echocardiograms and provides measurements of the geometrical planes at 4 levels: left ventricular outflow tract (LVOT), aortic annulus (AoA), sinuses of Valsalva (SoV) and sinotubular junction (STJ). Results The echocardiographic characteristics and the dynamic changes of the aortic valve tract between the two groups are shown in Tables 1 and 2. Both groups had comparable echocardiographic characteristic apart from the mean aortic valve pressure gradient as expected. With regards to the aortic valve tract geometrical dynamic changes, the relative LVOT and AoA area changes were bigger in Group 1 (36.8±15.9% vs 29.1±11.9%; p=0.017 and 21.0±8.39% vs 17.1±6.6%; p=0.028). The SoV and STJ relative changes were similar between the two groups. The same applies to aortic stiffness parameters, namely compliance and distensibility of the ascending aorta, systemic arterial compliance, and valvulo-arterial impedance. Conclusion The LVOT and aortic annulus area demonstrate more prominent dynamic changes in patients with normal-flow high-gradient severe AS compared to individuals with normal-flow low-gradient severe AS. While the SoV and the STJ geometry does not change significantly through the cardiac cycle, a more elastic outflow tract allows larger expansion in systole and higher pressure gradients across the aortic valve, whereas a stiffer outflow tract and annulus result in lower pressure gradients, despite the presence of severe aortic stenosis (AVA<1.0cm2). These differences in dynamic LVOT and aortic annulus changes may explain the discrepancy between aortic valve area and pressure gradients in patients with normal-flow low-gradient AS.

Left ventricular absolute myocardial work measured by cardiovascular magnetic resonance: a proof-of-concept

Abstract Background Myocardial Work Index (MWI) is a load-independent and non-invasive method for assessing cardiac systolic function [1]. However, MWI does not directly measure absolute myocardial work (AMW), since it does not consider the effect of variations in left ventricular (LV) wall thickness and regional wall curvature. Therefore, a direct comparison of MWI results may be difficult. Cardiovascular magnetic resonance (CMR) is the gold standard for assessing the LV geometry and therefore can be used to directly measure the AMW by calculating the area of the stress-strain curve. Purpose This study aims to measure and compare CMR-based AMW in three groups with different work profiles: healthy subjects, patients with ST-elevation myocardial infarction (STEMI), and patients with severe aortic valve stenosis (AS). Additionally, it aims to compare AMW with strain to provide additional insights into remodelling. Methods A total of 78 participants were included in our study; 38 healthy subjects from the CENS study [2], 19 STEMI patients 3-7 days post-PCI from the ASSAIL study [3], and 21 patients with AS scheduled for operation. Collected data were not adjusted for age or sex. Stress was estimated using Laplace’s equation [4]. Intra-ventricular pressure was calculated from brachial cuff pressure as previously described [5]. Mid-ventricular circumferential strain was calculated using CMR-based tissue phase mapping [4]. AMW was calculated both as Myocardial Work per unit endocardial Surface (MWS, in J/m^2) and per unit Mass (MWM, in mJ/g), both serving as measurements of global circumferential systolic function. Results Mean circumferential strain did not differ significantly between the AS and the healthy groups (p=0.37), but it was significantly lower in the STEMI group compared to the healthy group (p<0.001). MWS was significantly higher in the AS group (p<0.001) and lower in the STEMI group (p<0.001) compared the healthy group. This suggests that each unit of endocardial surface in the myocardium performed, on average, more work in the AS group and less work in the STEMI group relative to the healthy group. MWM was not significantly different between the AS and the healthy group (p=0.74), while in the STEMI group, it was significantly lower (p=0.001) than in healthy subjects. Conclusion Our results indicate that in patients with AS, the myocardium did more work per unit surface, while each gram of the myocardium did the same amount of work. This is likely due to concentric hypertrophy and the increase of afterload. In contrast, in patients with STEMI, the myocardium did, on average, less work per unit surface and per mass. This is expected due to the direct loss of mechanical function in the infarcted myocardium. Our results indicate that AMW enhances traditional strain analysis, improves myocardial function evaluation, and may provide deeper insight into myocardial remodeling in diverse cardiac conditions.

The effect of the LPA gene on aortic valve calcification in a Portuguese population

Abstract Introduction Aortic valve calcium (AVC) deposition is one of the mechanisms behind aortic sclerosis and stenosis. There is a known association between LPA gene rs3798220 T>C polymorphism and the development of severe aortic stenosis. However, it is still unknown if it has been a driving factor since the early stages of the disease. Objective Investigate, in our population, the association between the LPA gene variant rs3798220 T>C and aortic valve calcification. Methods AVC was measured in 451 consecutive individuals from the prospective arm of the GENEMACOR study with a mean age of 63.4±9.7 years, 58.8% male. AVC score was performed by cardiac computed tomography and reported as Agatston units. Results were separated into two groups (Group A: AVC=0; Group B: AVC>0). Lp(a) levels were analyzed in the different groups. Each individual was genotyped for LPA rs3798220 T>C. This variant has a minor allele frequency (MAF)<2%; hence, the risk homozygous CC is a rare genotype, and we used the heterozygous CT in our analysis. The bivariate and multivariate logistic regression analysis evaluated the presence of AVC adjusting to traditional risk factors (TRFs) and the LPA heterozygous genotype (CT). Results LP(a) levels were higher in the CT allele versus the homozygous TT, but this difference did not reach a statistical significance. After multivariate analysis, the heterozygous LPA rs3798220 T>C polymorphism remained an independent risk factor for the presence of aortic valve calcification (OR=12.14, p=0.002) together with age (OR=1.13, p<0.0001), arterial hypertension (AHT) (OR=1.96, p=0.006) and alcohol consumption (OR=2.46, p=0.016). Conclusion The LPA gene variant rs3798220 T>C is associated with the presence of aortic valve calcification in a Portuguese population. In such an age-dependent disease as aortic stenosis, the inversion in the age pyramid will see a dramatic increase in the prevalence of aortic stenosis. The early identification of high-risk individuals might enable prompt traditional risk factors control and disease prevention. Larger population studies may help to determine if this difference is driven by Lp(a) levels.

Cardiac damage predicts the outcome of calcific aortic valve disease regardless of the severity of aortic stenosis

Abstract Title: Cardiac damage predicts the outcome of patients with calcific aortic valve disease in both mild and moderate aortic stenosis Background Although the burden of calcific aortic valve disease (CAVD) is increasing, there is no current universal consensus for prognostic prediction. A staging system based on cardiac damage has been proposed to better stratify risk and evaluate the benefit of aortic valve intervention (AVI). Purpose We sought to evaluate this staging system’s prognostic value in mild and moderate aortic stenosis (AS). Methods Data from clinically indicated echocardiograms performed between 2010 and 2018 in patients aged over 18 years were extracted and linked to national outcome data. A time to first event analysis was performed with a primary outcome of mortality or heart failure hospitalization. Stages were categorized as described in previous literature: no extravalvular damage (stage 0); left ventricular damage (stage 1); left atrial damage (stage 2); elevated right ventricular pressures (stage 3); or right ventricular damage (stage 4). Results Amongst 24,699 patients in the study cohort, 513 had moderate AS and 920 had mild AS. Associated cardiac damage in those with moderate AS was graded as follows: Stage 0 - 9.4%; Stage 1 - 53.7%; Stage 2 - 31.1%; Stage 3 - 3.2%; Stage 4 - 2.6%. Increasing severity of CAVD correlated closely with increased risk of the primary outcome in both moderate (HR 1.62 per stage; 95% CI 1.36 – 1.92) and mild AS (HR 1.93 per stage; 95% CI 1.69 – 2.21), whilst increasing stage of cardiac damage was associated with mortality when censoring at the time of AVI in both moderate (HR 1.97 per stage; 95% CI 1.66 – 2.34) and mild AS (HR 2.06 per stage; 95% CI 1.81 – 2.35). Conclusion Cardiac dysfunction predicts prognosis to a similar extent in both mild and moderate AS. These data suggest that adverse outcomes may not be fully attributable to the haemodynamic consequences of valve disease, and therefore may not be reversed by valve intervention. Strategies to treat cardiac dysfunction in parallel with management of the anatomical valve pathology may be required.Mortality in mild AS by CAVD stageMortality in moderate AS by CAVD stage

Long-term mortality outcomes of southeast asian patients with aortic stenosis

Abstract Background Limited data exists on mortality outcomes of aortic stenosis (AS) in Southeast Asians. Insights into this may confer prognostic benefits and affect therapeutic targets. Purpose Our study aims to provide insights into 10-year mortality outcomes and prognostic indicators of AS in this cohort. Methods Consecutive patients (n = 703) with echocardiographic diagnoses of AS at a tertiary academic hospital in Southeast Asia were studied. Demographics, co-morbidities and outcomes were collected. Multivariate Cox regression model was constructed. Results 55.2% (n = 388) of patients had mild AS, 29.3% (n = 206) had moderate AS, and 15.5% (n = 109) had severe AS. Out of 431 deaths, 35.8% (n = 86) of known cases were cardiovascular. The leading cause of cardiovascular mortality was coronary-linked in 20.8% (n = 50); 7.9% (n = 19) was valvular aortic stenosis; 2.5% (n = 6) was cardiac failure, 1.3% (n = 3) was sudden cardiac death, and 2.9% (n = 7) was ischaemic stroke. Of 154 (64.2%) non-cardiovascular mortality, sepsis caused 40% (n = 97) of deaths, malignancy in 11.7% (n = 28), renal failure in 5% (n = 12) and respiratory failure in 1.7% (n = 4). 44.3% (n = 191) of cases were unknown. Higher proportions of AS patients with cardiovascular death had hyperlipidaemia (p = 0.027) and coronary artery disease (p = 0.028). Multivariable Cox regression showed age (HR 1.041, 95% CI: 1.020-1.062, p < 0.001), anaemia (HR 2.121, 95% CI: 1.535-2.930, p < 0.001) and prior cardiovascular hospitalisation (HR 1.420, 95% CI: 1.040-1.938, p = 0.027) to be significant predictors of all-cause mortality. Aortic valve replacement was a significant protective factor of all-cause mortality after adjustments for age, gender, comorbidities, and echocardiographic findings (HR 0.313, 95% CI 0.131-0.747, p = 0.009). Conclusions Non-cardiovascular death was the leading cause of mortality in Southeast Asians with AS. Ischaemic heart disease was the commonest cause of cardiovascular mortality. Predictors of all-cause mortality included age, anaemia and prior cardiovascular hospitalisation. Valvular replacement was protective of all-cause mortality in AS.

Identifying missing tools in aortic systolic upstroke parameter for valvular aortic stenosis diagnosis

Abstract Background Echocardiography is a widely accepted method for diagnosing severe aortic stenosis (AS), but it has certain limitations. Alternative methods, such as the direct catheter-based crossing of the valves, carry a risk of stroke. Delayed aortic upstroke parameters might predict the severity of aortic stenosis. Objective This study aimed to investigate the diagnostic utility of measuring catheter-based aortic acceleration time with ejection (AT/ET) for the diagnosis of severe aortic stenosis, including low-gradient (LG) AS. Methods We included 139 patients who underwent cardiac catheterization at our hospital, including patients with varying degrees of AS. Patients with LGAS were classified byan algorithm according to ESC guideline. All patients received echocardiographicassessments and direct hemodynamic measurements of AT/ET. The association between AT/ET and AS severity and other conventional utilities was analyzed using logistic regression and ROC analysis. Results Among the 139 patients, 73 had severe AS (52.5%), and 20 also had low gradient (27.3%). The mean AT/ET was 0.33 in the severe AS group and 0.28, 0.24 in moderate, and mild-no AS patients, respectively. AT/ET was significantly correlated with conventional echocardiographic and hemodynamic parameters. Furthermore, AT/ET is the strongest predictor of severe aortic stenosis using the multivariable test with relevant variables (OR; 2.01, 95% CI 1.17-3.45). Using a cut-off value of 0.30, catheter-based AT/ET had a sensitivity of 80% and specificity of 92% for diagnosing severe AS (AUC 0.94, 95% CI 0.90-0.97), withconsistent results from subgroup LGAS (AUC 0.94, 95% CI 0.93-0.99). Conclusion This study supports the use of catheter-based AT/ET of greater than 0.30 as a complementary diagnostic tool for severe aortic stenosis across the spectrum of low-gradient AS. Further studies are needed to validate these findings in larger, multicenter studies with more diverse patient populations.

Myocardial remodelling in bicuspid aortic valve associated severe aortic stenosis and reverse remodelling after aortic valve replacement

Abstract Background Bicuspid aortic valve (BAV) is a common congenital heart disease and a major risk factor for aortic stenosis (AS). Myocardial remodelling response to AS plays an important prognostic role1. Cardiovascular magnetic resonance (CMR) can evaluate myocardial structure, function and perfusion in AS. Phosphorus magnetic resonance spectroscopy (31P-MRS) can also assess myocardial energetic consequences of AS2. Purpose Assess differences in myocardial remodelling between tricuspid aortic valve (TAV) and BAV-associated severe-AS, and their recovery 6 months post aortic valve replacement (AVR). Methods Eighty severe-AS patients (70[69-72]years) undergoing AVR (40 TAV, 40 BAV) and 21 demographically-matched controls were recruited. AS groups were matched for demographics, AS severity, surgical risk scores and comorbidities. One month before and 6 months post-AVR, patients underwent CMR and 31P-MRS for measuring left ventricular (LV) mass, concentricity-index (LV mass to LV end-diastolic volume ratio), global longitudinal shortening (GLS), rest and adenosine-stress myocardial blood flow (MBF), myocardial perfusion reserve (MPR) and energetics-index phosphocreatine to ATP ratio (PCr/ATP). Results Pre-AVR, there was no significant differences between the three cohorts when assessing LV ejection fraction, indexed LV end-diastolic volume and indexed end-systolic volume. Pre-AVR, both AS groups showed higher LV-concentricity (controls:0.53[0.51,0.60], TAV:0.95[0.82,1.07], BAV:0.92[0.82,1.08]g/ml;P<0.0001), higher mass-index (controls:45[39,50], TAV:73[67,78], BAV:74[68,80]g/m2;P<0.0001), impaired GLS (controls:18.8[16.5,19.5], TAV:12.6[11.3,13.9], BAV:13.6[10.9,16.6]%;P<0.0001). Reductions in both AS groups were also seen in PCr/ATP (controls:2.19[1.85,2.63], TAV:1.64[1.39,1.85], BAV:1.85[1.60,2.10];P=0.0004), stress-MBF (controls:2.16[1.88,2.27], TAV:1.35 [1.16,1.56], BAV:1.36[1.00,1.66]ml/min/g;P<0.0001), and MPR (controls:3.38[2.65,3.92], TAV:2.04 [1.78,2.46], BAV:1.83[1.58,2.78]ml/min/g;P<0.0001) against controls, with no significant differences between TAV and BAV. No significant difference was seen in the proportion of patients with TAV and BAV undergoing transcatheter or surgical AVR (table1). Post-AVR, the TAV and BAV groups experienced similar patterns of reverse LV-remodelling, with no significant differences in LV-concentricity (TAV:0.86[0.71,0.98], BAV:0.81[0.65,0.96];P=0.41), LV-mass-index (TAV:60[54,65], BAV:61[55,66];P=0.81), GLS (TAV 15.4[13.6,17.9], BAV 16.3[12.8,18.1];P=0.82. Perfusion and cardiac energetic improvements were also similar between the AS cohorts: PCr/ATP (TAV:1.96[1.68,2.26], BAV:1.96[1.79,2.13];P=0.91), stress-MBF (TAV:1.63[1.37,1.97], BAV:1.56[1.25,1.97];P=0.86), and MPR (TAV:2.64[1.91,3.26], BAV:2.55[2.07,3.28];P=0.70). Conclusions Patients with severe AS irrespective of BAV or TAV morphology, show a similar myocardial phenotype pre-AVR, with similar magnitudes of reverse remodelling post-AVR.

Sex differences in severe aortic stenosis undergoing surgical replacement

Abstract Background Aortic stenosis (AS) is the most common valvular heart disease in developed countries. Sex differences have been described in AS pathophysiology and left ventricular (LV) remodelling, as well as clinical presentation and response to therapies (1). However, sex differences in LV function parameters, namely global longitudinal strain (GLS), have been scarcely explored so far. Purpose To investigate sex differences, taking into account GLS, in patients with severe AS referred to surgical aortic valve replacement (SAVR). Methods The study population was from a single centre, prospective registry of patients with severe native valve AS who were referred for SAVR between June 2020 to October 2022. Severe AS was defined by standard guideline criteria (2). All patients underwent an echocardiogram immediately before and at least 3 months after surgery. Results Table 1 recapitulates sex differences in our population (n=119, 43% women). No differences in age or cardiovascular (CV) risk factors were noted. Clinical presentation and AS etiology were also similar. At baseline, women had lower EuroSCORE (p=0.039), creatinine (p <0.001), and haemoglobin levels (p=0.001). The echocardiogram showed a higher mean aortic valve gradient in women (Gmean, 62 vs. 50 mmHg, p=0.002). Women also had higher relative wall thickness (RWT, 0.49 vs. 0.42, p=0.037), despite lower LV mass index (124.9 vs. 136.6 g/m², p=0.037). Regarding LV function, women showed higher EF (64% vs. 60%, p=0.002) and GLS (16.5% vs. 14.6%, p=0.006) values. This is partially explained by the higher prevalence of concomitant coronary artery disease (CAD) in men, more frequently subjected to a concomitant coronary artery bypass graft than women (CABG, 38% vs. 8%, p <0.001). Post-operative complications had similar rates in men and women. After a median follow-up of 16 (6-18) months, death from any cause (6.0% vs. 1.5%, p=0.186) and rehospitalization for CV causes (14.0% vs. 4.0%, p=0.055) tended to be more frequent among women. When considering patients with severe AS alone (n=89), women had higher Gmean (64 vs. 53 mmHg, p=0.035) and EF (65% vs. 62%, p=0.045) but similar GLS (16.9% vs. 16.6%, p=0.230) as compared to men (Figure 2). At follow-up, EF and GLS failed to improve in both sexes and no differences were noted between women and men (EF 60% vs. 60%, p=0.476; GLS 15.9% vs. 16.0%, p=0.976). Conclusions In a population of all-comers patients with severe AS undergoing SAVR, women showed higher Gmean, EF, and GLS values. This is partially due to the higher prevalence of a concomitant CAD in men. When considering patients with AS alone, women still had higher EF and Gmean than men, despite a similar GLS. Future larger prospective studies with longer follow-up are needed in order to further characterize such differences and correlate them with specific outcomes.

Lipoprotein(a) cardiovascular disease risk not captured by low density lipoprotein cholesterol and apolipoprotein B

Abstract Background Elevated lipoprotein(a) affects 1 in 5 individuals and is considered a causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis (AVS). However, lipoprotein(a) measurements are not widely implemented in clinical practice. Low-density lipoprotein (LDL) cholesterol and apolipoprotein B (ApoB) measurements include contributions from lipoprotein(a), yet whether these measurements can replace measurements of lipoprotein(a) in assessing cardiovascular disease risk from this causal risk factor is unknown. Purpose We tested the hypotheses that lipoprotein(a) risk of ASCVD and AVS is captured by LDL cholesterol or ApoB. Methods We included 70,189 individuals from a prospective contemporary cohort study of the general population. Mediated risk by LDL cholesterol and ApoB in the association between lipoprotein(a) and risk of ASCVD and AVS was examined using four-way decomposition analyses stratified by statin treatment at baseline. Results During a median follow-up of 10.8 years, 7,127 developed ASCVD and 1,516 AVS. Per 50 mg/dL higher lipoprotein(a), multivariable adjusted hazard ratios were 1.22 (95% CI: 1.18-1.26) for ASCVD and 1.36 (1.28-1.46) for AVS. In individuals without statin use, LDL cholesterol mediated 19% (15%-24%) of the risk of ASCVD from lipoprotein(a) and 7.7% (1.5%-14%) of the risk of AVS from lipoprotein(a) (Figure 1). Corresponding values for ApoB were 14.0% (11%-18%) and 6.6% (2.8%-10%). In statin users (n=9,570), LDL cholesterol did not mediate risk of ASCVD from lipoprotein(a) but mediated 8.0% (0.8%-15%) of the risk of AVS from lipoprotein(a). Correspondingly, ApoB mediated 9.8% (2.2%-17%) of the risk of ASCVD and 4.2% (0.4%-8.0%) of the risk of AVS from lipoprotein(a). Conclusion Lipoprotein(a) risk of ASCVD and AVS is not adequately captured by LDL cholesterol and ApoB. Therefore, lipoprotein(a) measurement is needed in all individuals to capture the cardiovascular disease risk from this causal risk factor.

Myocardial SGLT2 expression and cardiac remodeling in patients with severe aortic stenosis: the BIO-AS Study

Abstract Background Cardiac remodeling plays a major role in the prognosis of patients with aortic stenosis (AS) and could impact the benefits of aortic valve replacement. Blood and tissue biomarkers have a differential pattern and expression level in patients with AS, which may retain a pathophysiological role in cardiac remodeling and metabolism. However, the data available are limited and contradictory. Aim Our study aimed to evaluate the expression of sodium-glucose cotransporter 2 (SGLT2) gene and protein in patients with severe AS stratified in high gradient (HG) and low flow-low gradient (LF-LG) AS and its association with cardiac functional impairments. Methods Gene expression and protein levels of main biomarkers of cardiac fibrosis (Galectin-3, sST2, Serpin-4, PINP, PICP, Collagen, TGF-b), inflammation (GDF-15, IL-6, NF-kB), oxidative stress (SOD1, SOD2), and cardiac metabolism (NHE, PPAR-a, PPAR-g, GLUT1, and GLUT4) were evaluated in blood samples and heart biopsies of 45 patients with AS. Results Our study showed SGLT2 gene and protein hyper-expression in patients with LF-LG AS, compared to controls and HG AS (p<0.05). These differences remained significant even after adjusting for age, gender, body mass index, history of diabetes mellitus, arterial hypertension, and coronary artery disease. SGLT2 gene expression was positively correlated with: i) TGF-b (r=0.72, p<0.001) and collagen (r=0.73, p<0.001) as markers of fibrosis; ii) NF-kB (r=0.36, p<0.01) and myocardial IL-6 (r=0.68, p<0.001) as markers of inflammation: iii) SOD2 (r=-0.38, p<0.006) as a marker of oxidative stress; iv) GLUT4 (r= 0.33, p<0.02) and PPAR-a (r=0.36, p<0.01) as markers of cardiac metabolism (Figure 1). Conclusion In patients with LF-LG AS, SGLT2 gene and protein were hyper-expressed in cardiomyocytes and associated with myocardial fibrosis, inflammation, and oxidative stress. The hyper-expression of the SGLT2 gene and protein in patients with LF-LG might pave the way for using SGLT2-Is in this subset population, with the potential to improve the outcomes of AVR and reduce the likelihood of re-hospitalization within one year.Figure 1