Low-flow, Low-gradient Research Articles

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

Long-term outcomes of aortic stenosis patients with different flow/gradient patterns undergoing transcatheter aortic valve implantation

Abstract Background Few data exist on the comparative long-term outcomes of severe aortic stenosis (AS) patients with different flow-gradient patterns undergoing transcatheter aortic valve implantation (TAVI). This study sought to evaluate the impact of the pre-TAVI flow-gradient pattern on long-term clinical outcomes after TAVI. Methods Consecutive patients with severe AS undergoing TAVI in our institution were screened and prospectively enrolled. Patients were divided into four subgroups according to pre-TAVI flow/gradient pattern: (i) low flow—low gradient (LF-LG): stroke volume indexed (SVi) ≤ 35 mL/m2 and mean gradient (MG) < 40 mmHg); (ii) normal flow—low gradient (NF-LG): SVi > 35 mL/m2 and MG < 40 mmHg; (iii) low flow—high gradient (LF-HG): Svi 35 mL/m2 and MG ≥ 40 mmHg and (iv) normal flow—high gradient (NF-HG): SVi > 35 mL/m2 and MG ≥ 40 mmHg. Clinical follow-up was obtained at 12 months, and yearly thereafter until 5-year follow-up was complete for all patients. Results A total of 272 patients with complete echocardiographic and clinical follow-up were included in our analysis. Their mean age was 80 ± 7 years and the majority of patients (N = 138, 50.8%) were women. 62 patients (22.8% of the study population) were distributed in the LF-LG group, 98 patients (36%) were LF-HG patients, 95 patients (34.9%) were NF-HG, and 17 patients (6.3%) were NF-LG. There was a greater prevalence of comorbidities among LF-LG AS patients. One-year all-cause mortality differed significantly between the four subgroups of AS patients (log-rank p: 0.022) and was more prevalent among LF-LG patients (25.8%) compared to LF-HG (11.3%), NF-HG (6.3%) and NF-LG patients (18.8%). At 5-year follow-up, global mortality remained persistently higher among LF-LG patients (64.5%) compared to LF-HG (47.9%), NF-HG (42.9%), and NF-LG patients (58.8%) (log-rank p: 0.029) (Figure 1). At multivariable Cox hazard regression analysis, baseline SVi (HR: 0.951, 95% C.I.; 0.918–0.984), the presence of at least moderate tricuspid regurgitation at baseline (HR: 3.091, 95% C.I: 1.645–5.809) and at least moderate paravalvular leak (PVL) post-TAVI (HR: 1.456, 95% C.I.: 1.106–1.792) were significant independent predictors of late global mortality. Conclusions Patients with LF-LG AS have acceptable 1-year outcomes, but exhibit exceedingly high 5-year mortality following TAVI. The presence of low transvalvular flow and at least moderate tricuspid regurgitation at baseline and significant paravalvular leak post-TAVI were associated with poorer long-term outcomes in the entire cohort of AS patients.

Phenotype of patients with severe aortic stenosis and small aortic annulus: how does it impact on hemodynamics and on transcatheter aortic valve implantation outcomes

Abstract Background Discordant grading of severe aortic stenosis can result from a tight aortic valve area (<1cm2) with a low transvalvular mean gradient (<40 mmHg). Small aortic annulus dimensions and low flow status may contribute to discordant grading of severe aortic stenosis. However, the frequency of patients with small aortic annulus and discordant grading, along with their characteristics and outcomes after intervention, remains unknown. Purpose To investigate the frequency of discordant grading severe aortic stenosis in patients with a small aortic annulus and to evaluate their clinical characteristics, as well as outcomes after transcatheter aortic valve implantation (TAVI). Methods Patients with an aortic annulus diameter < 23 mm determined by cardiac computed tomography who underwent TAVI between 2018 to 2023 were retrospectively evaluated. Patients were followed for the occurrence of the composite endpoint of of all-cause mortality, rehospitalizations for heart failure, non-fatal myocardial infarction, and non-fatal stroke. Results Among 230 patients with severe aortic stenosis and a small aortic annulus, 52 (23%) had discordant gradient (24 with low flow low gradient (LFLG) and 28 with normal flow low gradient (NFLG)) while 120 (52%) exhibited normal flow high gradient (NFHG) and 58 (25%) had low flow high gradient (LFHG). The majority of the patients were female (Table 1). Differences were noted among the three groups regarding aortic transvalvular gradients, stroke volume index and ejection fraction. During a median follow-up of 2 years, the composite endpoint occurred in 20% of the total cohort. Patients with discordant grading severe aortic stenosis experienced the worse outcome (Figure1). Conclusions Most patients with severe aortic stenosis and small annulus have high gradient and only 23% of patients presented discordant grading. Patients with discordant grading severe aortic stenosis showed worse outcomes, suggesting potential delays in referral due to challenges in diagnosing severe aortic stenosis among patients with small aortic annulus.Basal clinical characteristicsKaplan-Meier survival curves

A novel functional index, aortic-valve-coefficient, for assessing aortic-stenosis in patients undergoing TAVR: A prospective-pilot study

BackgroundEvaluating the severity of aortic stenosis (AS) can be challenging, particularly in patients with low-gradient (LG, Δp < 40 mmHg) AS. Objective: This study aims to improve the accuracy of assessing severity of AS using a novel functional index- Aortic Valve Coefficient (AVC). The AVC is defined as ratio of mean transvalvular pressure-drop (Δp) to the proximal dynamic pressure (1/2 × blood density × VLVOT2; VLVOT: left ventricular outflow tract peak velocity). Hypothesis: AVC, developed from fundamental fluid dynamic principles, is a better index for accessing AS severity as it incorporates square of VLVOT and downstream pressure recovery. MethodsThis pilot prospective study enrolled 47 patients undergoing TAVR for AS. Using cardiac-catheterization-measured Δp and echocardiography-Doppler-derived VLVOT, AVC was evaluated. Pre- and post-TAVR pressure-velocity measurements were obtained, resulting in a dataset with 78 data points, including 32 data points specifically linked to LG AS. Linear regression analysis was performed to correlate AVC with Δp, VLVOT and aortic-valve-area. Welch 2-sample t-test was carried out to compare the means of AVC against aortic-valve-area. ResultsModerate correlation (r = 0.85) was observed between AVC and aortic-valve-area indicating AVC could be a prospective index. However, correlation decreased (r = 0.75) in LG AS patients, indicating increased discordancy. Comparing AVC and aortic-valve-area in LG AS patients with left ventricular ejection fraction (LVEF) < 50 % and LVEF ≥50 %, t-test showed that AVC values are significantly different (p < 0.05) as compared to aortic-valve-area (p = 0.48). ConclusionAVC, a novel index, has the potential to improve assessment of AS severity and clinical decision making for treating patients with AS. Condensed abstractComplex hemodynamics, such as paradoxical “low-flow low-gradient (LG)” Aortic stenosis (AS) can be difficult to diagnose. Currently, mean transvalvular pressure-drop and flow-derived aortic-valve-area assess AS severity. Aortic valve coefficient (AVC) is a novel index which combines both pressure-drop and flow measurements to assess the severity of AS. A total of 47 patients (72 data points) were studied undergoing TAVR. In LG AS patients, t-test comparing left ventricular ejection fraction (LVEF) < 50 % and LVEF ≥50 % showed that AVC are significantly different (p < 0.05) as compared to aortic-valve-area (p = 0.48). Therefore, AVC could be a better index.

Transcatheter aortic valve replacement outcomes in patients with high gradient versus low ejection fraction low gradient severe aortic stenosis: A meta-analysis of randomized controlled trials

BackgroundThe outcome of Low Flow-Low Gradient (LF-LG) severe aortic stenosis (AS) patients who underwent Transcatheter Aortic Valve Replacement (TAVR) procedure is not well defined. We conducted a systematic review of the literature to compare the outcomes of TAVR in LF-LG AS patients to the more traditional high gradient (HG) aortic stenosis. MethodsWe comprehensively searched for controlled randomized and non-randomized studies from 4 online databases. We are presenting the data using risk ratios (95 % confidence intervals) and measuring heterogeneity using Higgins' I2 index. ResultsOur analysis included 4380 patients with 3425 HG patients and 955 LF-LG patients from 6 cohort (5 retrospective and 1 prospective) studies. When compared to LFLG; TAVR was associated with significantly lower 30 days mortality in HG patients (5.1 % vs 7.4 %; relative risk [RR]: 0.55; 95 % confidence interval [CI]: 0.35 to 0.86; p < 0.01). Similar findings were also observed in 12-month cardiovascular (CV) mortality (5.5 % vs. 10.4 %; RR: 0.47; 95 % CI: 0.38 to 0.60; p < 0.01 and 12-month all-cause mortality (15.9 % vs 20.9 %; RR: 0.70; 95 % CI: 0.49 to 1.00; p < 0.05). There was no significant difference in myocardial infarction (MI) after TAVR between HG and LF-LG at 30 days (0.16 % vs. 0.95 %; p < 0.09) or 12 months (0.43 % vs. 0.95 %; p = 0.20). Similarly, there was no difference in stroke rates at 30 days (2.9 % vs. 2.86 %) or at 12 months (3.6 % vs. 3.06 %). Conclusions and relevancePatients with LF-LG severe AS who underwent TAVR had worse 1-year all-cause mortality, 30-day all-cause, and 1-year CV mortality when compared to TAVR in HG severe AS. There was no difference in MI or stroke rates. Therefore, with heart team discussion and informed patient decision regarding the risk and benefit, TAVR would still offer better outcomes in LFLG AS compared to conservative medical management.

Prognostic Impact of High-Molecular-Weight von Willebrand Factor Multimer Ratio in Classical Low-Flow Low-Gradient Aortic Stenosis.

High-molecular-weight (HMW) von Willebrand factor (VWF) multimer deficiency occurs in classical low-flow, low-gradient (LF/LG) aortic stenosis (AS) due to shear force-induced proteolysis. The prognostic value of HMW VWF multimer deficiency is unknown. Therefore, we sought to evaluate the impact of HMW VWF multimer deficiency on clinical outcome. In this prospective research study, a total of 83 patients with classical LF/LG AS were included. All patients underwent dobutamine stress echocardiography to distinguish true-severe (TS) from pseudo-severe (PS) classical LF/LG AS. HMW VWF multimer ratio was calculated using densitometric Western blot band quantification. The primary endpoint was all-cause mortality. Mean age was 79 ± 9 years, and TS classical LF/LG AS was diagnosed in 73% (n = 61) and PS classical LF/LG AS in 27% (n = 22) of all patients. Forty-six patients underwent aortic valve replacement (AVR) and 37 were treated conservatively. During a mean follow-up of 27 ± 17 months, 47 deaths occurred. Major bleeding complications after AVR (10/46; 22%) were more common in patients with HMW VWF multimer ratio &lt;1 (8/17; 47%) in comparison to patients with a normal multimer pattern (2/29; 7%) at baseline (p = 0.003). In a multivariable Cox regression analysis, HMW VWF multimer deficiency was a predictor of all-cause mortality (HR: 3.02 [95% CI: 1.31-6.96], p = 0.009) in the entire cohort. This association was driven by higher mortality rates in the AVR group (multivariable-adjusted HR: 9.4; 95% CI 2.0-43.4, p = 0.004). This is the first study to demonstrate the predictive value of HMW VWF multimer ratio for risk stratification in patients with classical LF/LG AS. HMW VWF multimer deficiency was associated with an increased risk of all-cause mortality and major bleeding complications after AVR.

Long-Term Outcomes of Aortic Stenosis Patients with Different Flow/Gradient Patterns Undergoing Transcatheter Aortic Valve Implantation.

Background: Few data exist on the comparative long-term outcomes of severe aortic stenosis (AS) patients with different flow-gradient patterns undergoing transcatheter aortic valve implantation (TAVI). This study sought to evaluate the impact of the pre-TAVI flow-gradient pattern on long-term clinical outcomes after TAVI and assess changes in the left ventricular ejection fraction (LVEF) of different subtypes of AS patients following TAVI. Methods: Consecutive patients with severe AS undergoing TAVI in our institution were screened and prospectively enrolled. Patients were divided into four subgroups according to pre-TAVI flow/gradient pattern: (i) low flow-low gradient (LF-LG): stroke volume indexed (SVi) ≤ 35 mL/m2 and mean gradient (MG) < 40 mmHg); (ii) normal flow-low gradient (NF-LG): SVi > 35 mL/m2 and MG < 40 mmHg; (iii) low flow-high gradient (LF-HG): Svi 35 mL/m2 and MG ≥ 40 mmHg and (iv) normal flow-high gradient (NF-HG): SVi > 35 mL/m2 and MG ≥ 40 mmHg. Transthoracic echocardiography was repeated at 1-year follow-up. Clinical follow-up was obtained at 12 months, and yearly thereafter until 5-year follow-up was complete for all patients. Results: A total of 272 patients with complete echocardiographic and clinical follow-up were included in our analysis. Their mean age was 80 ± 7 years and the majority of patients (N = 138, 50.8%) were women. 62 patients (22.8% of the study population) were distributed in the LF-LG group, 98 patients (36%) were LF-HG patients, 95 patients (34.9%) were NF-HG, and 17 patients (6.3%) were NF-LG. There was a greater prevalence of comorbidities among LF-LG AS patients. One-year all-cause mortality differed significantly between the four subgroups of AS patients (log-rank p: 0.022) and was more prevalent among LF-LG patients (25.8%) compared to LF-HG (11.3%), NF-HG (6.3%) and NF-LG patients (18.8%). At 5-year follow-up, global mortality remained persistently higher among LF-LG patients (64.5%) compared to LF-HG (47.9%), NF-HG (42.9%), and NF-LG patients (58.8%) (log-rank p: 0.029). At multivariable Cox hazard regression analysis, baseline SVi (HR: 0.951, 95% C.I.; 0.918-0.984), the presence of at least moderate tricuspid regurgitation at baseline (HR: 3.091, 95% C.I: 1.645-5.809) and at least moderate paravalvular leak (PVL) post-TAVI (HR: 1.456, 95% C.I.: 1.106-1.792) were significant independent predictors of late global mortality. LF-LG patients and LF-HG patients exhibited a significant increase in LVEF at 1-year follow-up. A lower LVEF (p < 0.001) and a lower Svi (p < 0.001) at baseline were associated with LVEF improvement at 1-year. Conclusions: Patients with LF-LG AS have acceptable 1-year outcomes with significant improvement in LVEF at 1-year follow-up, but exhibit exceedingly high 5-year mortality following TAVI. The presence of low transvalvular flow and at least moderate tricuspid regurgitation at baseline and significant paravalvular leak post-TAVI were associated with poorer long-term outcomes in the entire cohort of AS patients. The presence of a low LVEF or a low SVi predicts LVEF improvement at 1-year.

Myocardial sodium-glucose cotransporter 2 expression and cardiac remodelling in patients with severe aortic stenosis: The BIO-AS study.

Cardiac remodelling plays a major role in the prognosis of patients with aortic stenosis (AS) and could impact the benefits of aortic valve replacement. 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. Gene expression and protein levels of main biomarkers of cardiac fibrosis (galectin-3, sST2, serpin-4, procollagen type I amino-terminal peptide, procollagen type I carboxy-terminal propeptide, collagen, transforming growth factor [TGF]-β), inflammation (growth differentiation factor-15, interleukin-6, nuclear factor-κB [NF-κB]), oxidative stress (superoxide dismutase 1 [SOD1] and 2 [SOD2]), and cardiac metabolism (sodium-hydrogen exchanger, peroxisome proliferator-activated receptor [PPAR]-α, PPAR-γ, glucose transporter 1 [GLUT1] and 4 [GLUT4]) were evaluated in blood samples and heart biopsies of 45 patients with AS. 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-β (r = 0.72, p < 0.001) and collagen (r = 0.73, p < 0.001) as markers of fibrosis; (ii) NF-κB (r = 0.36, p < 0.01) and myocardial interleukin-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-α (r = 0.36, p < 0.01) as markers of cardiac metabolism. In patients with LF-LG AS, SGLT2 gene and protein were hyper-expressed in cardiomyocytes and associated with myocardial fibrosis, inflammation, and oxidative stress.

Paradoxical low flow-low gradient aortic stenosis: lights and shadows

Paradoxical low flow-low gradient aortic valve stenosis (AVS) is an increasing phenotype in the general population, particularly after the seventh decade of life. It is an AVS in which, despite the preserved ejection fraction, the mean transvalvular gradient is not suggestive of severe AVS (<40 mmHg). The pathophysiology is often intertwined with conditions resulting in heart failure with preserved ejection fraction, such as arterial hypertension and cardiac amyloidosis. Its management is rather controversial about the diagnosis and therapeutic management. The aims of this focus are: to clarify the role and reliability of the main available diagnostic methods, the efficacy of surgical and percutaneous treatments, and to develop a diagnostic-therapeutic algorithm for managing this condition in clinical practice. This algorithm will involve a multi-parametric evaluation, integrating standard echocardiographic assessment with three-dimensional planimetric valve area calculation, determination of the energy loss index), and calcium score calculation by computed tomography scan. This approach aims to ascertain the severity of the stenosis and determine the appropriate therapeutic management.

Impact of route of access and stenosis subtype on outcome after transcatheter aortic valve replacement.

Previous analyses have reported the outcomes of transcatheter aortic valve replacement (TAVR) for patients with low-flow, low-gradient (LFLG) aortic stenosis (AS), without stratifying according to the route of access. Differences in mortality rates among access routes have been established for high-gradient (HG) patients and hypothesized to be even more pronounced in LFLG AS patients. This study aims to compare the outcomes of patients with LFLG or HG AS following transfemoral (TF) or transapical (TA) TAVR. A total of 910 patients, who underwent either TF or TA TAVR with a median follow-up of 2.22 (IQR: 1.22-4.03) years, were included in this multicenter cohort study. In total, 146 patients (16.04%) suffered from LFLG AS. The patients with HG and LFLG AS were stratified according to the route of access and compared statistically. The operative mortality rates of patients with HG and LFLG were found to be comparable following TF access. The operative mortality rate was significantly increased for patients who underwent TA access [odds ratio (OR): 2.91 (1.54-5.48), p = 0.001] and patients with LFLG AS [OR: 2.27 (1.13-4.56), p = 0.02], which could be corroborated in a propensity score-matched subanalysis. The observed increase in the risk of operative mortality demonstrated an additive effect [OR for TA LFLG: 5.45 (2.35-12.62), p < 0.001]. LFLG patients who underwent TA access had significantly higher operative mortality rates (17.78%) compared with TF LFLG (3.96%, p = 0.016) and TA HG patients (6.36%, p = 0.024). HG patients experienced a twofold increase in operative mortality rates following TA compared with TF access, while LFLG patients had a fivefold increase in operative mortality rates. TA TAVR appears suboptimal for patients with LFLG AS. Prospective studies should be conducted to evaluate alternative options in cases where TF is not possible.

Right-ventricular/pulmonary artery coupling predicts long-term mortality in aortic stenosis patients with different flow types

Abstract Background Right-ventricular (RV) dysfunction in aortic stenosis (AS) patients undergoing transcatheter aortic valve implantation (TAVI) has long been neglected. Right-ventricular to pulmonary artery coupling (RV/PAc), a parameter of RV function, can be determined by echocardiography (tricuspid annular plane systolic excursion over systolic pulmonary artery pressure). Its use for mortality prediction in contemporary AS patients warrants further evaluation, data for different flow types of AS are lacking. Purpose To assess the impact of pathological RV/PAc on long-term mortality in AS patients with different flow types. Methods All 1577 consecutive patients from our registry from 2018 to 2020 were assessed. Patients without tricuspid regurgitation (n=523) or inconclusive echocardiography images (n=111) were excluded. RV/PAc could be analysed in 862 patients. To dichotomize the cohort, a receiver operator curve (ROC) analysis for 2-year mortality was used. Primary endpoint was 2-year mortality. Patients were further analysed according to the Valve Academic Research Consortium (VARC) 3 endpoint definitions. Results By ROC analysis, 0.512 mm/mmHg was defined as a cut-off, dividing the cohort into 428 patients with physiological RV/PAc (above cut-off) and 434 patients with pathological RV/PAc. Patients with pathological RV/PAc were more often male, had more comorbidities, a lower ejection fraction (50% [40-55%] vs. 55% [53-58%], p&amp;lt;0.01) and a higher Society of Thoracic Surgeons (STS) score (4.0 [2.5-6.0] vs. 2.8 [2.0-4.0], p&amp;lt;0.01). Procedural outcomes according to VARC-3 were comparable: the composite endpoints technical failure and device failure at 30 days occurred in 3.9% and 3.5% (p=0.75) and 11.3% and 13.3% (p=0.42) in the pathological and physiological group, respectively. Clinical outcomes in terms of New York Heart Association functional class were comparable at follow-up, with an improvement by at least one class in 76.2% (pathological group) and 79.9% (physiological group, p=0.33). All-cause 2-year mortality was significantly higher in the pathological group (34.9% [30.2-39.2%] vs. 15.4% [11.9-18.8%], p&amp;lt;0.01, hazard ratio, HR, 2.5 [1.9-3.4], Figure 1). The result persisted when adjusted for STS score (HR 2.3 [1.7-3.1]) or in a multivariate Cox regression. Cardiovascular mortality was increased too (pathological, 23.7% [19.3-27.8%], vs. physiological, 8.5% [5.8-11.2%], HR 2.9 [2.0-4.2], p&amp;lt;0.01). The fraction of patients with pathological RV/PAc differed significantly across the AS flow types (high-gradient, 40.3%, classical low-flow low-gradient (LFLG), 73.9%, paradoxical LFLG, 58.9%, and normal-flow low-gradient, 36.6%, p&amp;lt;0.01). Mortality differences persisted in high-gradient and LFLG groups (Figure 2A-D), which was consistent after statistical adjustment. Conclusions RV dysfunction defined as low RV/PAc is a strong predictor for long-term mortality in TAVI patients, with a strong prognostic value also in LFLG AS.

The potential role of the aortic valve calcium score by computed tomography scan in the diagnosis of concomitant cardiac amyloidosis in patients with severe aortic stenosis

Abstract Background Cardiac amyloidosis (CA) and aortic stenosis (AS) are two related, but the diagnosis of both these condition is challenging because of the common phenotype. Different predictors of CA in AS have been proposed in the last years. Purpose To identify a new red-flag of concomitant CA in patients with severe AS analyzing aortic valve calcium burden using calcium score, calcium mass and calcium volume by computed tomography scan (CT). Methods 55 patients with severe AS and suspicion of concomitant CA were retrospectively enrolled from 2009 to 2022. 5 Patients with a bicuspid aortic valve, previous aortic valve replacement, or an incomplete diagnostic workup for CA were excluded. 50 patients underwent CT-scan and were included in the final analysis. Results Of the 50 patients, 21 patients (AS-CA) had positive 99m Tc-DPD bone scintigraphy (19 with score 2 and 2 with score 3), none of the patients presented laboratory suspicion for AL amyloidosis, so all the patients had a diagnosis of transthyetin related CA. 29 patients (AS alone) had negative bone scintigraphy. AVA indexed were comparable between AS-CA and AS alone groups (0.3 mm2/m2, in both the group p: 0.88). Stroke volume, maximum and mean gradient were significatively lower in AS-CA group (29 vs 36 ml/m2, p: 0.01, 60 vs 72 mmHg, p: 0.016 and 34 vs 45 mmHg, p:0.01) with a higher percentage of low flow-low gradient aortic stenosis in AS-CA group (11 patients,52% vs 5 patients in AS-alone 17%, p: 0.014)ECG in AS-CA group showed atrial fibrillation in 12 patients (57%), versus 3 patients in the AS-alone group (10%), and lower QRS voltages (peripheral QRS score 44 mV vs 58 mV, p-value:0.017; total QRS score 120 mV versus 160 mV, p-value: 0.005). The echocardiogram showed a more thickened IVS and PW in AS-CA patients (17 versus 15 mm, p: 0.03 and 15 versus 14 mm, p: 0.01) with a decreases longitudinal systolic function (septal S wave at TDI 4.4 vs 5.1 cm/s, p: 0.011, lateral S wave 4.5 versus 5.6 cm/s, p: 0.014).CT- aortic valve calcium was quantified by an experienced operator. A statistically significant difference between AS-CA and AS-alone groups was observed in calcium score (3569 vs 4480 Agatston units, p: 0.017) calcium volume (2575 vs 3445 mm3, p: 0.012) and calcium mass (798 vs 1082 g, p: 0.016).At logistic regression analyses,confirmed perdictors of concomitant CA in AS were: AS low flow- low gradient (p:0.011), atrial fibrillation (p:0.001), lower QRS score periferical(p:0.004) and total (p:0.002) and a decreased longitudinal systolic function (p:0.028). Regarding the aortic valve calcium burden, calcium score( p:0.031) and calcium volume(p:0.026) were confirmed predictor of CA in AS. Conclusions This study shows that calcium burden at CT scan in patients with concomitant CA-AS is significatily lower than in patients with AS alone. Calcium burden at CT scan could be used in addition to the classical parameters as a potential red-flag of concomitant CA in AS severe.

Abstract 18349: The Impact of Concomitant Mitral Regurgitation on Aortic Valve Intervention Outcomes in Paradoxical Low-Flow Low-Gradient Severe Aortic Stenosis

Background: Patients with paradoxical low flow low gradient severe aortic stenosis (LFLGAS) exhibit low transvalvular flow rates due to reduced stroke volumes, while maintaining preserved left ventricular ejection fraction (LVEF). The presence of mitral regurgitation (MR) adds complexity to this already challenging diagnosis, by further lowering flow rate. However, the impact of aortic valve intervention in this patient population remains uncertain. Methods: A total of 1178 patients were included from an institutional echo database with adjudicated aortic valve area (AVA &lt;1.0 cm2), transaortic gradients (mean gradient&lt; 40 mmHg) and low flow rate (Q ≤210 ml/sec), to confirm the diagnosis of LFLGAS and preserved LVEF (&gt;50%). Subgroups were formed based on the presence of severe MR and subsequent surgical and transcatheter aortic valve intervention (SAVR/TAVR). Patients who underwent mitral valve intervention were censored. All-cause mortality was assessed as the primary outcome. Results: Patients with severe MR had significantly lower flow rates compared to patients w/o severe MR (166.5 ± 26.3 vs 174.7 ± 25, p=0.006). During a median follow up of 1.3 years, 745 deaths (62.2%) were identified, with a cumulative incidence significantly lower in the intervention groups (Figure). After multivariate propensity adjustment for age, sex, aortic valve area and comorbidities, aortic valve intervention showed a significant reduction in mortality risk in both intervention groups, which was more pronounced in the severe MR group compared to patients w/o severe MR (AdjHR 0.334, p=0.015 vs 0.436, p&lt;0.001, p for interaction =0.24). Conclusions: In paradoxical low-flow low-gradient severe aortic stenosis, aortic valve intervention results in a survival benefit, especially among patients with concomitant severe MR. Our findings highlight the importance of recognizing severe MR as a flow-diverting lesion that can impact outcomes in LFLGAS.

Outcomes of Transcatheter Aortic Valve Replacement Patients With Different Transvalvular Flow-Gradient Patterns

Low-flow low-gradient (LF-LG) aortic stenosis (AS) may occur with preserved or depressed left ventricular ejection fraction (LVEF). Both situations represent the most challenging subset of patients to manage and generally have a poor prognosis. Few and controversial data exist on the outcomes of these patients compared with normal flow-high gradient (NF-HG) AS after transcatheter aortic valve replacement (TAVR). We sought to characterize different transvalvular flow-gradient patterns and to examine their prognostic value after TAVR. We enrolled 1,208 patients with severe AS and categorized as follow: 976 patients NF-HG (mean aortic pressure gradient [MPG] ≥40mm Hg), 107 paradoxical LF-LG (pLF-LG, MPG <40mm Hg, LVEF ≥50%, stroke volume index <35ml/m2), and 125 classical LF-LG (cLF-LG) (MPG <40mm Hg, LVEF <50%, stroke volume index <35ml/m2). When compared with NF-HG and pLF-LG, cLF-LG had a worse symptomatic status (New York Heart Association III to IV 86% vs 62% and 67%, p <0.001), a higher prevalence of eccentric hypertrophy and a higher level of LV global afterload reflected by a higher valvuloarterial impedance. Valvular function after TAVR was excellent over time in all patients. While 30-day mortality (p=0.911) did not differ significantly among groups, cLF-LG had a lower 5-year survival rate (LF-LG 50% vs pLF-LG 62% and NF-HG 68%, p <0.05). cLF-LG was associated with a hazard ratio for mortality of 2.41 (95% confidence interval 1.65 to 3.52, p <0.001). In conclusion, TAVR is an effective procedure regardless of transvalvular flow-gradient patterns. However, special care should be given to characterized hemodynamic of AS, as patients with pLF-LG had similar survival rates than patients with NF-HG, whereas cLF-LG is associated with a twofold increased risk of mortality at 5-year follow-up.

Prognostic Implication of Pulmonary Hypertension in Low-Flow Low-Gradient Aortic Stenosis After Transcatheter Aortic Valve Replacement

Prognostic implications of pulmonary hypertension (PH) in low-flow low-gradient (LG) aortic stenosis (AS) after transcatheter aortic valve replacement (TAVR) remains unexplored. We aimed to investigate the impact of baseline and changes in PH after TAVR. In this single-center retrospective study, we included patients who underwent TAVR for low-flow LG AS. Patients were categorized into 2 groups: baseline pulmonary artery systolic pressure (PASP) <46mm Hg (no-to-mild PH) and PASP ≥46mm Hg (moderate-to-severe PH). On the basis of changes in PASP after TAVR, patients were stratified into increased (ΔPASP ≥+5 mm Hg), no change (-4 to +4 mm Hg), and decreased (≤ -5 mm Hg) groups. Primary end point was a composite of all-cause mortality and heart failure rehospitalization. In total, 210 patients were included, 148 in the no-to-mild PH group and 62 in the moderate-to-severe PH group. Median follow-up was 13.2 months. The moderate-to-severe PH group was at an increased risk of composite end point (adjusted hazard ratio [HR] 3.5, 95% confidence interval [CI] 1.8 to 6.9), all-cause mortality (HR 2.4, 95% CI 1.1 to 5.6), and heart failure rehospitalization (HR 8.3, 95% CI 2.9 to 23.7). There were no differences in clinical outcomes among those with increased (32%), no change (28%), and decreased (39%) PASP after TAVR. In conclusion, moderate-to-severe PH at baseline is an independent predictor of worse clinical outcomes in patients with low-flow LG AS who undergo TAVR, and this cohort of patients do not seem to derive the benefits of postoperative reduction of PASP.

Changes in echocardiographic parameters over time in paradoxical low-flow low-gradient aortic stenosis

Abstract Funding Acknowledgements Type of funding sources: None. Background Although paradoxical low-flow low-gradient (LFLG) aortic stenosis (AS) has been considered a more severe form of AS with a worse prognosis than high-gradient (HG) AS, data on the natural history of this entity are scant. Objectives To assess the progression of the disease and evolution of the main echocardiographic variables for quantifying AS in patients with severe LFLG AS compared to HG and normal-flow low-gradient (NFLG) AS. Methods A longitudinal, observational, multicenter study including consecutive asymptomatic patients with severe AS (AVA&amp;lt;1.0cm²) and normal LVEF (≥50%) was conducted. Patients were classified according to baseline echocardiography into one of three groups: HG (mean gradient≥40 mmHg), NFLG (mean gradient&amp;lt;40 mmHg, indexed systolic volume (SVi)&amp;gt;35ml/m²), or LFLG (mean gradient&amp;lt;40mmHg, SVi≤35ml/m²). AS progression was analyzed by comparing patients’ baseline measurements and their last follow-up measurements or those taken prior to aortic valve replacement (AVR). Results Of the 903 included patients, 401 (44.4%) were HG, 405 (44.9%) NFLG, and 97 (10.7%) LFLG. The median total follow-up time was 60.2 months (IQR 44.7–83.4). Progression of the mean gradient in a linear mixed regression model was greater in low-gradient groups: LFLG vs. HG (regression coefficient 0.124, p = 0.005) and NFLG vs. HG (regression coefficient 0.068, p = 0.018). No differences were observed between the LFLG and NFLG groups (regression coefficient 0.056, p = 0.195). However, aortic valve area (AVA) reduction was slower in the LFLG group compared to the NFLG (p&amp;lt;0.001). During follow-up, 19.1% (n=9) of LFLG patients evolved to having NFLG AS and 44.7% (n=21) to having HG AS. 58.0% of patients underwent AVR with HG AS (n=29). Conclusions LFLG AS shows an intermediate AVA and gradient progression compared to NFLG and HG AS. The majority of patients initially classified as having LFLG AS changed over time to having other severe forms of AS, and most of them received AVR with HG AS.

ABCDEG Stress Echocardiography in Aortic Stenosis.

Rest and stress echocardiography (SE) plays a pivotal role in the evaluation of valvular heart disease. The use of SE is recommended in valvular heart disease when there is a mismatch between resting transthoracic echocardiography findings and symptoms. In aortic stenosis (AS), rest echocardiographic analysis is a stepwise approach that begins with the evaluation of aortic valve morphology and proceeds to the measurement of the transvalvular aortic gradient and aortic valve area (AVA) using continuity equations or planimetry. The presence of the following three criteria suggests severe AS: AVA < 1.0 cm2, a peak velocity > 4.0 m/s, or a mean gradient > 40 mmHg. However, in approximately one in three cases, we can observe a discordant AVA < 1 cm2 with a peak velocity < 4.0 m/s or a mean gradient <40 mmHg. This is due to reduced transvalvular flow associated with LV systolic dysfunction (LVEF < 50%) defined as "classical" low-flow low-gradient (LFLG) AS or normal LVEF "paradoxical" LFLG AS. SE has an established role in evaluating LV contractile reserve (CR) patients with reduced LVEF. In classical LFLG AS, LV CR distinguished pseudo-severe AS from truly severe AS. Some observational data suggest that long-term prognosis in asymptomatic severe AS may not be as favorable as previously thought, offering a window of opportunity for intervention prior to the onset of symptoms. Therefore, guidelines recommend evaluating asymptomatic AS with exercise stress in physically active patients, particularly those younger than 70 years, and symptomatic classical LFLG severe AS with low-dose dobutamine SE. A comprehensive SE assessment includes evaluating valve function (gradients), the global systolic function of the LV, and pulmonary congestion. This assessment integrates considerations of blood pressure response, chronotropic reserve, and symptoms. StressEcho 2030 is a prospective, large-scale study that employs a comprehensive protocol (ABCDEG) to analyze the clinical and echocardiographic phenotypes of AS, capturing various vulnerability sources which support stress echo-driven treatment strategies.

Changes in echocardiographic parameters over time in paradoxical low-flow low-gradient aortic stenosis.

To assess the progression of the disease and evolution of the main echocardiographic variables for quantifying AS in patients with severe low-flow low-gradient (LFLG) AS compared to other severe AS subtypes. Longitudinal, observational, multicenter study including consecutive asymptomatic patients with severe AS (aortic valve area, AVA < 1.0 cm²) and normal left ventricle ejection fraction (LVEF ≥ 50%). Patients were classified according to baseline echocardiography into: HG (high gradient; mean gradient ≥ 40 mmHg), NFLG (normal-flow low-gradient; mean gradient < 40 mmHg, indexed systolic volume (SVi) > 35mL/m2), or LFLG (mean gradient < 40 mmHg, SVi ≤ 35 mL/m²). AS progression was analyzed by comparing patients' baseline measurements and their last follow-up measurements or those taken prior to aortic valve replacement (AVR). Of the 903 included patients, 401 (44.4%) were HG, 405 (44.9%) NFLG, and 97 (10.7%) LFLG. Progression of the mean gradient in a linear mixed regression model was greater in low-gradient groups: LFLG vs. HG (regression coefficient 0.124, P = 0.005) and NFLG vs. HG (regression coefficient 0.068, P = 0.018). No differences were observed between the LFLG and NFLG groups (regression coefficient 0.056, P = 0.195). However, AVA reduction was slower in the LFLG group compared to the NFLG (P < 0.001). During follow-up, in conservatively-managed patients, 19.1% (n = 9) of LFLG patients evolved to having NFLG AS and 44.7% (n = 21) to having HG AS. In patients undergoing AVR, 58.0% (n = 29) of LFLG baseline patients received AVR with a HG AS. LFLG AS shows an intermediate AVA and gradient progression compared to NFLG and HG AS. The majority of patients initially classified as having LFLG AS changed over time to having other severe forms of AS, and most of them received AVR with a HG AS.

Quantification of physical activity with prospective activity tracking after transfemoral aortic valve replacement

BackgroundTranscatheter aortic valve replacement (TAVR) is a well-established, safe and effective therapy for severe symptomatic aortic stenosis (AS). The aim of this study was to objectively quantify improvement of physical activity after TAVR, with consideration of different low-gradient AS subtypes. Methods and resultsAll patients undergoing TAVR for severe AS were screened. Participants received a wearable activity tracker (Fitbit®) at hospital discharge following TAVR and 6 months thereafter. The difference of median daily steps was defined as surrogate outcome for physical activity. For analysis, patients were grouped into high-gradient (HG) AS (dPmean ≥40 mmHg), classical low-flow low-gradient (LFLG) AS (dPmean <40 mmHg, EF <50%), paradoxical LFLG-AS (dPmean <40 mmHg, EF ≥50%, SVi ≤35 ml/m2) and normal-flow low-gradient (NFLG) AS (dPmean <40 mmHg, EF ≥50%, SVi >35 ml/m2) according to mean transvalvular pressure gradient (dPmean), stroke volume index (SVi) and left-ventricular ejection fraction (LVEF). Results and conclusionsThe analysis is based on 230 patients. The median daily step count was 4409 [IQR 2581–7487] after hospital discharge and 5326 [IQR 3045–8668] 6 months thereafter. Median difference of daily steps was ∆529 [IQR -702-2152]). Patients with HG-AS and paradoxical LFLG-AS showed a significant improvement of daily steps (∆951 [IQR -378-2323], p <0.001 and (∆1392 [IQR -609-4444], p = 0.02, respectively). Patients with classical LFLG-AS showed no statistically relevant improvement of daily steps (∆192 [IQR -687-770], p = 0.79). Patients with NFLG-AS showed a numerical decline in daily steps without statistical significance (∆-300 [IQR -1334-1406], p = 0.67).This first prospective study of this sample size shows significant improvement of physical activity after TAVR with an objective and reproducible method. This was mainly driven by an improvement in patients with HG-AS and paradoxical LFLG-AS.

High Prevalence of Cardiac Amyloidosis in Clinically Significant Aortic Stenosis: A Meta-Analysis.

There is growing evidence of coexistence of aortic stenosis (AS) and transthyretin cardiac amyloidosis (CA). Not screening AS patients at the time of hospital/clinic visit for CA represents a lost opportunity. We surveyed studies that reported the prevalence of CA among AS patients. Studies that compared patients with aortic stenosis with cardiac amyloidosis (AS-CA) and AS alone were further analyzed, and meta-regression was performed. We identified nine studies with 1,321 patients of AS, of which 131 patients had concomitant CA, with a prevalence of 11%. When compared to AS-alone, the patients with AS-CA were older, more likely to be males, had higher prevalence of carpal tunnel syndrome, right bundle branch block. On echocardiogram, patients with AS-CA had thicker interventricular septum, higher left ventricular mass index (LVMI), lower myocardial contraction fraction, and lower stroke volume index. Classical low-flow low-gradient (LFLG) physiology was more common among patients with AS-CA. Patients with AS-CA had higher all-cause mortality than patients with AS alone (33% vs. 22%, P = 0.02) in a follow-up period of at least 1 year. CA has a high prevalence in patients with AS and is associated with worse clinical, imaging, and biochemical parameters than patients with AS alone.