Wearable device-measured moderate to vigorous physical activity and risk of degenerative aortic valve stenosis.

BACKGROUND AND AIMS: Physical activity has proven effective in preventing atherosclerotic cardiovascular disease, but its role in preventing degenerative valvular heart disease (VHD) remains uncertain. This study aimed to explore the dose-response association between moderate to vigorous physical activity (MVPA) volume and the risk of degenerative VHD among middle-aged adults. METHODS: A full week of accelerometer-derived MVPA data from 87 248 UK Biobank participants (median age 63.3, female: 56.9%) between 2013 and 2015 were used for primary analysis. Questionnaire-derived MVPA data from 361 681 UK Biobank participants (median age 57.7, female: 52.7%) between 2006 and 2010 were used for secondary analysis. The primary outcome was the diagnosis of incident degenerative VHD, including aortic valve stenosis (AS), aortic valve regurgitation (AR), and mitral valve regurgitation (MR). The secondary outcome was VHD-related intervention or mortality. RESULTS: In the accelerometer-derived MVPA cohort, 555 incident AS, 201 incident AR, and 655 incident MR occurred during a median follow-up of 8.11 years. Increased MVPA volume showed a steady decline in AS risk and subsequent AS-related intervention or mortality risk, levelling off beyond approximately 300 min/week. In contrast, its association with AR or MR incidence was less apparent. The adjusted rates of AS incidence (95% confidence interval) across MVPA quartiles (Q1-Q4) were 11.60 (10.20, 13.20), 7.82 (6.63, 9.23), 5.74 (4.67, 7.08), and 5.91 (4.73, 7.39) per 10 000 person-years. The corresponding adjusted rates of AS-related intervention or mortality were 4.37 (3.52, 5.43), 2.81 (2.13, 3.71), 1.93 (1.36, 2.75), and 2.14 (1.50, 3.06) per 10 000 person-years, respectively. Aortic valve stenosis risk reduction was also observed with questionnaire-based MVPA data [adjusted absolute difference Q4 vs. Q1: AS incidence, -1.41 (-.67, -2.14) per 10 000 person-years; AS-related intervention or mortality, -.38 (-.04, -.88) per 10 000 person-years]. The beneficial association remained consistent in high-risk populations for AS, including patients with hypertension, obesity, dyslipidaemia, and chronic kidney disease. CONCLUSIONS: Higher MVPA volume was associated with a lower risk of developing AS and subsequent AS-related intervention or mortality. Future research needs to validate these findings in diverse populations with longer durations and repeated periods of activity monitoring.

Dobutamine Stress Echocardiography in Low-Gradient Aortic Stenosis.

IMPORTANCE: Guidelines recommend the use of Dobutamine stress echocardiography (DSE) in patients with low-gradient aortic stenosis (AS) and left ventricular ejection fraction (LVEF) <50%. However, a paucity exists in DSE data when LVEF>35%. OBJECTIVE: To examine the diagnostic accuracy of DSE, in patients with low-gradient AS with a wide range of LVEF and to examine the interaction between the diagnostic accuracy of DSE and LVEF. DESIGN, SETTING AND PARTICIPANTS: Patients with mean-gradient<40 mmHg, AVA<1.0 cm2, and stroke volume index≤35 mL/m2 undergoing DSE and Cardiac Computer Tomography (C-CT) were identified from three prospectively collected patient cohorts, and stratified according to LVEF; LVEF<35%, LVEF 35-50% & LVEF>50%. EXPOSURE: DSE and C-CT was performed on patients with low-gradient AS MAIN OUTCOMES AND MEASURES: Severe AS was defined as AVC score ≥2000 AU among men, and ≥1200 AU for women on C-CT. RESULTS: Of 221 patients included in the study, 78 (35%) presented with LVEF<35%, 67 (30%) with LVEF 35-50%, and 76 (34%) with LVEF>50%. Mean-gradient and Vmax during DSE showed significantly diagnostic heterogeneity between LVEF groups, being most precise when LVEF<35% (both AUC=0.90), albeit with optimal thresholds of 30 mmHg & 377 cm/s, and a limited diagnostic yield in patients with LVEF≥35% (AUC=0.67 & 0.66 in LVEF 35-50% and AUC=0.65 & 0.60 in LVEF≥50%). Using guideline thresholds led to a sensitivity/specificity of 49%/84% for all patients with LVEF<50%. CONCLUSION AND RELEVANCE: While DSE is safe and leads to an increase in stroke volume in patients with low-gradient AS regardless of LVEF, the association between DSE gradients and AS severity assessed by C-CT demonstrates important heterogeneity depending on LVEF, with highest accuracy in patients with LVEF<35%.

Durability of transcatheter aortic valve implantation.

Transcatheter aortic valve implantation (TAVI) is now utilised as a less invasive alternative to surgical aortic valve replacement (SAVR) across the whole spectrum of surgical risk. Long-term durability of the bioprosthetic valves has become a key goal of TAVI as this procedure is now considered for younger and lower-risk populations. The purpose of this article is to present a state-of-the-art overview on the definition, aetiology, risk factors, mechanisms, diagnosis, clinical impact, and management of bioprosthetic valve dysfunction (BVD) and failure (BVF) following TAVI with a comparative perspective versus SAVR. Structural valve deterioration (SVD) is the main factor limiting the durability of the bioprosthetic valves used for TAVI or SAVR, but non-structural BVD, such as prosthesis-patient mismatch and paravalvular regurgitation, as well as valve thrombosis or endocarditis may also lead to BVF. The incidence of BVF related to SVD or other causes is low (<5%) at midterm (5- to 8-year) follow-up and compares favourably with that of SAVR. The long-term follow-up data of randomised trials conducted with the first generations of transcatheter heart valves also suggest similar valve durability in TAVI versus SAVR at 10 years, but these trials suffer from major survivorship bias, and the long-term durability of TAVI will need to be confirmed by the analysis of the low-risk TAVI versus SAVR trials at 10 years.

Lipoprotein(a) and Calcific Aortic Valve Stenosis Progression: A Systematic Review and Meta-Analysis.

Importance: There are currently no pharmacological treatments available to slow hemodynamic progression of aortic stenosis. Plasma lipoprotein(a) concentrations predict incident aortic stenosis but its association with hemodynamic progression is controversial. Objective: To determine the association between plasma lipoprotein(a) concentrations and hemodynamic progression in patients with aortic stenosis. Design, Settings and Participants: The study included patients with aortic stenosis from 5 longitudinal clinical studies conducted from March 2001 to March 2023 in Canada and the UK. Of 757 total patients, data on plasma lipoprotein(a) concentrations and rates of hemodynamic progression assessed by echocardiography were available for 710, who were included in this analysis. Data were analyzed from March 2023 to April 2024. Exposure: Cohort-specific plasma lipoprotein(a) concentration tertiles. Main Outcomes and Measures: Hemodynamic aortic stenosis progression on echocardiography as assessed by annualized change in peak aortic jet velocity, mean transvalvular gradient, and aortic valve area. Results: Among the included patients, 497 (70%) were male and 213 (30%) were female. The mean (SD) age was 65.2 (13.1) years. Patients in the top lipoprotein(a) tertile demonstrated 41% (estimate, 1.41; 95% CI, 1.13-1.75) faster progression of peak aortic jet velocity and 57% (estimate, 1.57; 95% CI, 1.18-2.10) faster progression of mean transvalvular gradient than patients in the bottom tertile. There was no evidence of heterogeneity across the individual cohorts. Progression of aortic valve area was comparable between groups (estimate, 1.23; 95% CI, 0.71-2.12). Similar results were observed when plasma lipoprotein(a) concentrations were treated as a continuous variable. Conclusions and Relevance: In this study, higher plasma lipoprotein(a) concentrations were associated with faster rates of hemodynamic progression in patients with aortic stenosis. Lowering plasma lipoprotein(a) concentrations warrants further investigation in the prevention and treatment of aortic stenosis.

Late Outcomes After Transcatheter Aortic Valve Implantation with Balloon-Versus Self-Expandable Valves: Meta-Analysis of Reconstructed Time-To-Event Data.

Self-expanding valves (SEV) and balloon-expandable valves (BEV) for transcatheter aortic valve implantation (TAVI) have their own features. There is a growing interest in long-term outcomes with the adoption of lifetime management in younger patients. To evaluate late outcomes in TAVI with SEV versus BEV, we performed a study-level meta-analysis of reconstructed time-to-event data published by May 31, 2023. We found no statistically significant difference in all-cause death after TAVI with SEV versus BEV. Randomized controlled trials are warranted to validate our results.

Effect of Sex and Flow Status on Outcomes After Surgical or Transcatheter Aortic Valve Replacement.

Background: Low stroke volume index <35 ml/m2 despite preserved ejection fraction (paradoxical low flow [PLF]) is associated with adverse outcomes in patients with aortic stenosis undergoing transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (SAVR). However, whether the risk associated with PLF is similar in both sexes is unknown. Objectives: The purpose of this study was to analyze the risk associated with PLF in severe aortic stenosis for men and women randomized to TAVR or SAVR. Methods: Patients with ejection fraction ≥50% from the PARTNER (Placement of Aortic Transcatheter Valves) 2 and 3 trials were stratified by sex and treatment arm. The impact of PLF on the 2-year occurrence of the composite of death or heart failure hospitalization (primary endpoint) and of all-cause mortality alone (secondary endpoint) was analyzed. Analysis of variance was used to assess baseline differences between groups. Multivariate Cox regression analysis was used to identify predictors of the endpoint. Results: Out of 2,242 patients, PLF was present in 390 men and 239 women (30% vs 26%, P = 0.06). PLF was associated with a higher rate of NYHA functional class III to IV dyspnea (60% vs 54%, P < 0.001) and a higher prevalence of atrial fibrillation (39% vs 24%, P < 0.001). PLF was a significant predictor of the primary endpoint among women undergoing SAVR in multivariate analysis (adjusted HR: 2.25 [95% CI: 1.14-4.43], P = 0.02) but was not associated with a worse outcome in any of the other groups (all P > 0.05). Conclusions: In women with PLF, TAVR may improve outcomes compared to SAVR. PLF appears to have less impact on outcomes in men.

Multimarker Approach to Improve Risk Stratification of Patients Undergoing Transcatheter Aortic Valve Implantation.

Background: A blood multimarker approach may be useful to enhance risk stratification in patients undergoing TAVI. Objectives: The objective of this study was to determine the prognostic value of multiple blood biomarkers in transcatheter aortic valve implantation (TAVI) patients. Methods: In this prospective study, several blood biomarkers of cardiovascular function, inflammation, and renal function were measured in 362 patients who underwent TAVI. The cohort was divided into 3 groups according to the number of elevated blood biomarkers (ie, ≥ median value for the whole cohort) for each patient before the procedure. Survival analyses were conducted to evaluate the association between blood biomarkers and risk of adverse event following TAVI. Results: During a median follow-up of 2.5 (IQR: 1.9-3.2) years, 34 (9.4%) patients were rehospitalized for heart failure, 99 (27%) patients died, and 113 (31.2%) met the composite endpoint of all-cause mortality or heart failure rehospitalization. Compared to patients with 0 to 3 elevated biomarkers (referent group), those with 4 to 7 and 8 to 9 elevated biomarkers had a higher risk of all-cause mortality (HR: 1.54 [95% CI: 0.84-2.80], P = 0.16, and HR: 2.81 [95% CI: 1.53-5.15], P < 0.001, respectively) and of the composite endpoint (HR: 1.65 [95% CI: 0.95-2.84], P = 0.07, and HR: 2.67 [95% CI: 1.52-4.70] P < 0.001, respectively). Moreover, adding the number of elevated blood biomarkers into the clinical multivariable model provided significant incremental predictive value for all-cause mortality (Net Reclassification Index = 0.71, P < 0.001). Conclusions: An increasing number of elevated blood biomarkers is associated with higher risks of adverse clinical outcomes following TAVI. The blood multimarker approach may be helpful to enhance risk stratification in TAVI patients.

Cardiac Damage Staging Predicts Outcomes in Aortic Valve Stenosis After Aortic Valve Replacement: Meta-Analysis.

Background: The prognostic value of cardiac damage staging classification based on the extent of extravalvular damage has been proposed in moderate/severe aortic stenosis (AS). Objectives: The purpose of this study was to assess the association of cardiac damage staging with mortality across the spectrum of patients with AS following aortic surgical or transcatheter aortic valve replacement (AVR). Methods: We conducted a pooled meta-analysis of Kaplan-Meier-derived reconstructed time-to-event data from studies published through February 2023. Results: In total, 16 studies (n = 14,499) met our eligibility criteria and included 12,282 patients with symptomatic severe AS and 2,217 patients with asymptomatic severe/moderate AS. For patients with symptomatic severe AS, all-cause mortality was 24.0%, 27.7%, 38.0%, 56.3%, and 57.3% at 5 years in patients with cardiac damage stage 0, 1, 2, 3, and 4, respectively (stage 0 as reference; HR in stage 1: 1.30 [95% CI: 1.03-1.64]; P = 0.029; stage 2: 1.74 [95% CI: 1.41-2.16]; P < 0.001; stage 3: 2.92 [95% CI: 2.35-3.64]; P < 0.001, and stage 4: 3.51 [95% CI: 2.79-4.41]; P < 0.001). For patients with asymptomatic moderate/severe AS, all-cause mortality was 19.3%, 36.9%, 51.7%, and 67.8% at 8 years in patients with cardiac damage stage 0, 1, 2, and 3 to 4, respectively (HR in stage 1: 1.70 [95% CI: 1.21-2.38]; P = 0.002; stage 2: 2.20 [95% CI: 1.60-3.02]; P < 0.001; and stage 3 to 4: 3.90 [95% CI: 2.79-5.47]; P < 0.001). Conclusions: In patients undergoing AVR across the symptomatic and severity spectrum of AS, cardiac damage staging at baseline has important prognostic implications. This pooled meta-analysis in patients undergoing AVR suggests that staging of baseline cardiac damage could be considered for timing and selection of therapy in patients with moderate or severe AS to determine the need for earlier AVR or adjunctive pharmacotherapy to prevent irreversible cardiac damage and improve the long-term prognosis.

Prognostic Value of Aortic Valve Calcification in Nonsevere Aortic Stenosis with Preserved Ejection Fraction.

BACKGROUND: Aortic valve calcification(AVC) is prognostic in patients with aortic stenosis(AS). We assessed the AVC prognostic value in nonsevere AS patients. METHODS AND RESULTS: We conducted a retrospective study of 395 patients with nonsevere AS, LV ejection fraction ≥50%. The Agatston method was used for computed tomography AVC assessment. The log-rank test determined the best AVC cutoffs for survival under medical surveillance: 1185 AU in men and 850 in women, lower than the established-cutoffs for severe AS(2064AU in men and 1274 in women). Patients were divided into three AVC groups based on these cutoffs: low(<1185 AU men and <850 women), sub-severe(1185-2064AU men and 850-1274 women) and severe(>2064AU men and >1274 women). Of 395 patients(mean age 73 ± 12 years, 60.5% men, aortic valve area 1.23 ± 0.30cm2, mean pressure gradient 28 ± 8 mmHg), 218 underwent aortic valve intervention(AVI) and 158 deaths occurred during follow-up, 82 before AVI. Median survival time under medical surveillance was 2.1[0.7-4.9]years. Compared to the low AVC group, both sub-severe and severe AVC groups had higher risk for all-cause death under medical surveillance after comprehensive adjustment including echocardiographic AS severity and coronary artery calcium score(all p ≤ 0.006); while mortality risk was similar between sub-severe and severe AVC groups(all p ≥ 0.2). This mortality risk pattern persisted in the overall survival analysis after adjustment for AVI. AVI was protective of all-cause death in the sub-severe and severe AVC(all p ≤ 0.01), but not in the low AVC groups. CONCLUSIONS: Sub-severe AVC is a robust risk-stratification parameter in patients with nonsevere AS and may inform AVI timing.

Prevalence, Characteristics, and Impact on Prognosis of Aortic Stenosis in Patients With Cardiac Amyloidosis.

BACKGROUND: Cardiac amyloidosis (CA) is frequently found in older patients with aortic stenosis (AS). However, the prevalence of AS among patients with CA is unknown. The objective was to study the prevalence and prognostic impact of AS among patients with CA. METHODS AND RESULTS: We conducted a retrospective analysis of a prospective registry comprising 976 patients with native aortic valves who were confirmed with wild type transthyretin amyloid (ATTRwt), hereditary variant transthyretin amyloid (ATTRv), or immunoglobulin light-chain (AL) CA. CA patients' echocardiograms were re-analyzed focusing on the aortic valve. Multivariable Cox regression analysis was performed to assess the mortality risk associated with moderate or greater AS in ATTRwt CA. The crude prevalence of AS among patients with CA was 26% in ATTRwt, 8% in ATTRv, and 5% in AL. Compared with population-based controls, all types of CA had higher age- and sex-standardized rate ratios (SRRs) of having any degree of AS (AL: SRR, 2.62; 95% Confidence Interval (CI) [1.09-3.64]; ATTRv: SRR, 3.41; 95%CI [1.64-4.60]; ATTRwt: SRR, 10.8; 95%CI [5.25-14.53]). Compared with hospital controls, only ATTRwt had a higher SRR of having any degree of AS (AL: SRR, 0.97, 95%CI [0.56-1.14]; ATTRv: SRR, 1.27; 95%CI [0.85-1.44]; ATTRwt: SRR, 4.01; 95%CI [2.71-4.54]). Among patients with ATTRwt, moderate or greater AS was not associated with increased all-cause death after multivariable adjustment (hazard ratio, 0.71; 95%CI [0.42-1.19]; P=0.19). CONCLUSIONS: Among patients with CA, ATTRwt but not ATTRv or AL is associated with a higher prevalence of patients with AS compared with hospital controls without CA, even after adjusting for age and sex. In our population, having moderate or greater AS was not associated with a worse outcome in patients with ATTRwt.

Subclinical valve leaflet thrombosis following bioprosthetic aortic valve replacement.

PURPOSE OF REVIEW: Subclinical leaflet thrombosis (SLT) is often an incidental finding characterized by a thin layer of thrombus involving one, two or three leaflets, with typical appearance on multi-detector computed tomography (MDCT) of hypo-attenuating defect at the aortic side of the leaflet, also called hypo-attenuating leaflet thickening (HALT). SLT may occur following both transcatheter aortic replacement (TAVR) or biological surgical aortic valve replacement (SAVR). The aim of this review is to present an overview of the current state of knowledge on the incidence, diagnosis, clinical impact, and management of SLT following TAVR or SAVR. RECENT FINDINGS: SLT occurs in 10-20% of patients following TAVR and is somewhat more frequent than following SAVR (5-15%). SLT may regress spontaneously without treatment in about 50% of the cases but may also progress to clinically significant valve thrombosis in some cases. Oral anticoagulation with vitamin K antagonist is reasonable if SLT is detected by echocardiography and/or MDCT during follow-up and is generally efficient to reverse SLT. SLT is associated with mild increase in the risk of stroke but has no impact on survival. SLT has been linked with accelerated structural valve deterioration and may thus impact valve durability and long-term outcomes. SUMMARY: SLT is often an incidental finding on echocardiography or MDCT that occurs in 10-20% of patients following TAVR or 5-15% following biological SAVR and is associated with a mild increase in the risk of thrombo-embolic event with no significant impact on mortality but may be associated with reduced valve durability.

Left and Right Ventricular Longitudinal Systolic Function Following Aortic Valve Replacement in the PARTNER 2 Trial And Registry.

AIMS: Evaluation of left and right ventricular longitudinal systolic function may enhance risk stratification following aortic valve replacement (AVR). The study objective was to evaluate the changes in left and right ventricular longitudinal systolic function and RV-pulmonary artery (RV-PA) coupling from baseline to 30-days and 1-year after aortic valve replacement (AVR). METHODS AND RESULTS: LV longitudinal strain (LS), tricuspid annulus plane systolic excursion (TAPSE), and RV-PA coupling were evaluated in patients from the PARTNER-2A surgical AVR (SAVR) arm (n=985) and from the PARTNER-2 SAPIEN-3 registry (n=719). TAPSE and RV-PA coupling decreased significantly following SAVR, but remained stable following TAVR. Lower LV LS, TAPSE, or RV-PA coupling at baseline were associated with increased risk of the composite of death, hospitalization, and stroke at 5-years (Adjusted-HRs for LV LS<15%: 1.24 95%CI 1.05-1.45, p=0.001; TAPSE<14mm: 1.44 95%CI 1.21-1.73, p<0.001; RV/PA coupling<0.55mm/mmHg: 1.32 95% CI 1.07-1.63, p=0.011). Reduced TAPSE at baseline was the most powerful predictor of the composite endpoint at 5-years. Patients with LV ejection fraction <50% at baseline had increased risk of the primary endpoint with SAVR (HR: 1.34, 95%CI 1.08-1.68, p=0.009) but not with TAVR (HR: 1.12, 95%CI 0.88-1.42). Lower RV-PA coupling at 30-days showed the strongest association with cardiac mortality. CONCLUSION: SAVR but not TAVR was associated with a marked deterioration in RV longitudinal systolic function and RV-PA coupling. Lower TAPSE and RV-PA coupling at 30-days were associated with inferior clinical outcomes at 5-years. In patients with LVEF<50%, TAVR was associated with superior 5-year outcomes.

Aortic Valve Calcification Density Measured by MDCT in the Assessment of Aortic Stenosis Severity.

BACKGROUND: Aortic valve calcification (AVC) indexation to the aortic annulus (AA) area measured by Doppler echocardiography (AVCdEcho) provides powerful prognostic information in patients with aortic stenosis (AS). However, the indexation by AA measured by multidetector computed tomography (AVCdCT) has never been evaluated. The aim of this study was to compare AVC, AVCdCT, and AVCdEcho with regard to hemodynamic correlations and clinical outcomes in patients with AS. METHODS: Data from 889 patients, mainly White, with calcific AS who underwent Doppler echocardiography and multidetector computed tomography within the same episode of care were retrospectively analyzed. AA was measured both by Doppler echocardiography and multidetector computed tomography. AVCdCT severity thresholds were established using receiver operating characteristic curve analyses in men and women separately. The primary end point was the occurrence of all-cause mortality. RESULTS: Correlations between gradient/velocity and AVCd were stronger (both P≤0.005) using AVCdCT (r=0.68, P<0.001 and r=0.66, P<0.001) than AVC (r=0.61, P<0.001 and r=0.60, P<0.001) or AVCdEcho (r=0.61, P<0.001 and r=0.59, P<0.001). AVCdCT thresholds for the identification of severe AS were 334 Agatston units (AU)/cm2 for women and 467 AU/cm2 for men. On a median follow-up of 6.62 (6.19-9.69) years, AVCdCT ratio was superior to AVC ratio and AVCdEcho ratio to predict all-cause mortality in multivariate analyses (hazard ratio [HR], 1.59 [95% CI, 1.26-2.00]; P<0.001 versus HR, 1.53 [95% CI, 1.11-1.65]; P=0.003 versus HR, 1.27 [95% CI, 1.11-1.46]; P<0.001; all likelihood test P≤0.004). AVCdCT ratio was superior to AVC ratio and AVCdEcho ratio to predict survival under medical treatment in multivariate analyses (HR, 1.80 [95% CI, 1.27-1.58]; P<0.001 compared with HR, 1.55 [95% CI, 1.13-2.10]; P=0.007; HR, 1.28 [95% CI, 1.03-1.57]; P=0.01; all likelihood test P<0.03). AVCdCT ratio predicts mortality in all subgroups of patients with AS. CONCLUSIONS: AVCdCT appears to be equivalent or superior to AVC and AVCdEcho to assess AS severity and predict all-cause mortality. Thus, it should be used to evaluate AS severity in patients with nonconclusive echocardiographic evaluations with or without low-flow status. AVCdCT thresholds of 300 AU/cm2 for women and 500 AU/cm2 for men seem to be appropriate to identify severe AS. Further studies are needed to validate these thresholds, especially in diverse populations.

Moderate Aortic Valve Stenosis Is Associated With Increased Mortality Rate and Lifetime Loss: Systematic Review and Meta-Analysis of Reconstructed Time-to-Event Data of 409 680 Patients.

BACKGROUND: The mortality risk attributable to moderate aortic stenosis (AS) remains incompletely characterized and has historically been underestimated. We aim to evaluate the association between moderate AS and all-cause death, comparing it with no/mild AS (in a general referral population and in patients with heart failure with reduced ejection fraction). METHODS AND RESULTS: A systematic review and pooled meta-analysis of Kaplan-Meier-derived reconstructed time-to-event data of studies published by June 2023 was conducted to evaluate survival outcomes among patients with moderate AS in comparison with individuals with no/mild AS. Ten studies were included, encompassing a total of 409 680 patients (11 527 with moderate AS and 398 153 with no/mild AS). In the overall population, the 15-year overall survival rate was 23.3% (95% CI, 19.1%-28.3%) in patients with moderate AS and 58.9% (95% CI, 58.1%-59.7%) in patients with no/mild aortic stenosis (hazard ratio [HR], 2.55 [95% CI, 2.46-2.64]; P<0.001). In patients with heart failure with reduced ejection fraction, the 10-year overall survival rate was 15.5% (95% CI, 10.0%-24.0%) in patients with moderate AS and 37.3% (95% CI, 36.2%-38.5%) in patients with no/mild AS (HR, 1.83 [95% CI, 1.69-2.0]; P<0.001). In both populations (overall and heart failure with reduced ejection fraction), these differences correspond to significant lifetime loss associated with moderate AS during follow-up (4.4 years, P<0.001; and 1.9 years, P<0.001, respectively). A consistent pattern of elevated mortality rate associated with moderate AS in sensitivity analyses of matched studies was observed. CONCLUSIONS: Moderate AS was associated with higher risk of death and lifetime loss compared with patients with no/mild AS.

Transcatheter versus surgical aortic valve replacement for severe aortic valve stenosis: Meta-analysis with trial sequential analysis.

OBJECTIVES: Randomized controlled trials comparing transcatheter aortic valve implantation with surgical aortic valve replacement demonstrate conflicting evidence, particularly in low-risk patients. We aim to reevaluate the evidence using trial sequential analysis, balancing type I and II errors, and compare with conventional meta-analysis. METHODS: Databases were searched for randomized controlled trials, which were divided into higher-risk and lower-risk randomized controlled trials according to a pragmatic risk classification. Primary outcomes were death and a composite end point of death or disabling stroke assessed at 1 year and maximum follow-up. Conventional meta-analysis and trial sequential analysis were performed, and the required information size was calculated considering a type I error of 5% and a power of 90%. RESULTS: Eight randomized controlled trials (n = 5274 higher-risk and 3661 lower-risk patients) were included. Higher-risk trials showed no significant reduction in death at 1 year with transcatheter aortic valve implantation (relative risk, 0.93, 95% CI, 0.81-1.08, P = .345). Lower-risk trials suggested lower death risk on conventional meta-analysis (relative risk, 0.67, 95% CI, 0.47-0.96, P = .031), but trial sequential analysis indicated potential spurious evidence (P = .116), necessitating more data for conclusive benefit (required information size = 5944 [59.8%]). For death or disabling stroke at 1 year, higher-risk trials lacked evidence (relative risk, 0.90, 95% CI, 0.79-1.02, P = .108). In lower-risk trials, transcatheter aortic valve implantation indicated lower risk in conventional meta-analysis (relative risk, 0.68, 95% CI, 0.50-0.93, P = .014), but trial sequential analysis suggested potential spurious evidence (P = .053), necessitating more data for conclusive benefit (required information size = 5122 [69.4%]). Follow-up results provided inconclusive evidence for both primary outcomes across risk categories. CONCLUSIONS: Conventional meta-analysis methods may have prematurely declared an early reduction of negative outcomes after transcatheter aortic valve implantation when compared with surgical aortic valve replacement.

Integrative genomic analyses identify candidate causal genes for calcific aortic valve stenosis involving tissue-specific regulation.

There is currently no medical therapy to prevent calcific aortic valve stenosis (CAVS). Multi-omics approaches could lead to the identification of novel molecular targets. Here, we perform a genome-wide association study (GWAS) meta-analysis including 14,819 cases among 941,863 participants of European ancestry. We report 32 genomic loci, among which 20 are novel. RNA sequencing of 500 human aortic valves highlights an enrichment in expression regulation at these loci and prioritizes candidate causal genes. Homozygous genotype for a risk variant near TWIST1, a gene involved in endothelial-mesenchymal transition, has a profound impact on aortic valve transcriptomics. We identify five genes outside of GWAS loci by combining a transcriptome-wide association study, colocalization, and Mendelian randomization analyses. Using cross-phenotype and phenome-wide approaches, we highlight the role of circulating lipoproteins, blood pressure and inflammation in the disease process. Our findings pave the way for the development of novel therapies for CAVS.

Prevalence and Outcomes of Patients With Discordant High-Gradient Aortic Stenosis.

BACKGROUND: Conflicting prognostic results have been reported in patients with discordant high-gradient aortic stenosis ([DHG-AS] the combination of a mean pressure gradient ≥40 mm Hg and an aortic valve area [AVA] >1 cm2). Moreover, existing studies only included selected patients without concomitant aortic regurgitation. OBJECTIVES: The authors assessed the prevalence and survival of patients presenting with DHG-AS in an unselected group of consecutive patients presenting to the echocardiography laboratory of a tertiary referral center. METHODS: A total of 3,547 adult patients with AVA ≤1.5 cm2 and peak aortic jet velocity ≥2.5 m/s or mean gradient ≥25 mm Hg who presented between 2005 and 2015 were included. Baseline clinical and echocardiographic data, and, when available, aortic valve calcium (AVC) score were collected in an institutional database, with subsequent retrospective analysis. The primary endpoint was all-cause mortality during follow-up. RESULTS: DHG-AS was observed in 163 patients (11.6% of patients with a high gradient). After adjustment for potential confounders, overall mortality rate of patients with DHG-AS was similar to that of patients with concordant severe aortic stenosis (HR: 0.98 [95% CI: 0.66-1.44]; P = 0.91), and patients with discordant low-gradient aortic stenosis (HR: 0.85 [95% CI: 0.58-1.26]; P = 0.42), and higher than concordant moderate aortic stenosis (HR: 0.54 [95% CI: 0.36-0.81]; P = 0.003). After adjustment for aortic velocities, aortic regurgitation had no significant impact on survival. AVC was higher than in patients with concordant moderate aortic stenosis and discordant low-gradient aortic stenosis, and not significantly different from that of concordant severe aortic stenosis. CONCLUSIONS: DHG-AS is not uncommon. Whereas AVA >1.0 cm2 is often seen as moderate aortic stenosis, a high-pressure gradient conveys a poor prognosis, whatever the AVA and the severity of concomitant aortic regurgitation.

The Canadian Women's Heart Health Alliance ATLAS on the Epidemiology, Diagnosis, and Management of Cardiovascular Disease in Women - Chapter 8: Knowledge Gaps and Status of Existing Research Programs in Canada.

Despite significant progress in medical research and public health efforts, gaps in knowledge of women's heart health remain across epidemiology, presentation, management, outcomes, education, research, and publications. Historically, heart disease was viewed primarily as a condition in men and male individuals, leading to limited understanding of the unique risks and symptoms that women experience. These knowledge gaps are particularly problematic because globally heart disease is the leading cause of death for women. Until recently, sex and gender have not been addressed in cardiovascular research, including in preclinical and clinical research. Recruitment was often limited to male participants and individuals identifying as men, and data analysis according to sex or gender was not conducted, leading to a lack of data on how treatments and interventions might affect female patients and individuals who identify as women differently. This lack of data has led to suboptimal treatment and limitations in our understanding of the underlying mechanisms of heart disease in women, and is directly related to limited awareness and knowledge gaps in professional training and public education. Women are often unaware of their risk factors for heart disease or symptoms they might experience, leading to delays in diagnosis and treatments. Additionally, health care providers might not receive adequate training to diagnose and treat heart disease in women, leading to misdiagnosis or undertreatment. Addressing these knowledge gaps requires a multipronged approach, including education and policy change, built on evidence-based research. In this chapter we review the current state of existing cardiovascular research in Canada with a specific focus on women.

En dépit des avancées importantes de la recherche médicale et des efforts en santé publique, il reste des lacunes dans les connaissances sur la santé cardiaque des femmes sur les plans de l'épidémiologie, du tableau clinique, de la prise en charge, des résultats, de l'éducation, de la recherche et des publications. Du point de vue historique, la cardiopathie a d'abord été perçue comme une maladie qui touchait les hommes et les individus de sexe masculin. De ce fait, la compréhension des risques particuliers et des symptômes qu'éprouvent les femmes est limitée. Ces lacunes dans les connaissances posent particulièrement problème puisqu'à l'échelle mondiale la cardiopathie est la cause principale de décès chez les femmes. Jusqu'à récemment, la recherche en cardiologie, notamment la recherche préclinique et clinique, ne portait pas sur le sexe et le genre. Le recrutement souvent limité aux participants masculins et aux individus dont l'identité de genre correspond au sexe masculin et l'absence d'analyses de données en fonction du sexe ou du genre ont eu pour conséquence un manque de données sur la façon dont les traitements et les interventions nuisent aux patientes féminines et aux individus dont l'identité de genre correspond au sexe féminin, et ce, de façon différente. Cette absence de données a mené à un traitement sous-optimal et à des limites de notre compréhension des mécanismes sous-jacents de la cardiopathie chez les femmes, et est directement reliée à nos connaissances limitées, et à nos lacunes en formation professionnelle et en éducation du public. Le fait que les femmes ne connaissent souvent pas leurs facteurs de risque de maladies du cœur ou les symptômes qu'elles peuvent éprouver entraîne des retards de diagnostic et de traitements. De plus, le fait que les prestataires de soins de santé ne reçoivent pas la formation adéquate pour poser le diagnostic et traiter la cardiopathie chez les femmes les mène à poser un mauvais diagnostic ou à ne pas traiter suffisamment. Pour pallier ces lacunes de connaissances, il faut une approche à plusieurs volets, qui porte notamment sur l'éducation et les changements dans les politiques, et qui repose sur la recherche fondée sur des données probantes. Dans ce chapitre, nous passons en revue l'état actuel de la recherche existante sur les maladies cardiovasculaires au Canada, plus particulièrement chez les femmes.

Unique Aspects of Women's Valvular Heart Diseases: Impact for Diagnosis and Treatment.

Valvular heart diseases (VHDs) are a major cause of cardiovascular morbidity and mortality worldwide. As degenerative and functional mechanisms represent the main etiologies in high-income countries are degenerative and functional, while in low income countries etiologie is mostly rheumatic. Although therapeutic options have evolved considerably in recent years, women are consistently diagnosed at later stages of their disease, are delayed in receiving surgical referrals, and exhibit worse postoperative outcomes, compared to men. This difference is a result of the historical underrepresentation of women in studies from which current guidelines were developed. However, in recent years, important research, including more female patients, has been conducted and has highlighted substantial sex-specific differences in the etiology, diagnosis, and treatment of VHDs. Systematic consideration of these sex-specific differences in VHD patients is crucial for providing equitable healthcare and optimizing clinical outcomes in both female and male patients. Hence, this review aims to explore implications of sex-specific particularities for diagnosis, treatment options, and outcomes in women with VHDs.

Les valvulopathies sont une cause majeure de morbidité cardiovasculaire et de mortalité dans le monde. Les mécanismes dégénératifs et fonctionnels représentent maintenant les principales étiologies dans les pays à revenu élevé, mais la maladie valvulaire rhumatismale demeure très prévalente dans les pays à revenu faible. Par ailleurs, même si les options thérapeutiques ont évolué depuis quelques années, les femmes reçoivent systématiquement leur diagnostic à des stades plus avancés de la maladie, sont orientées plus tard en chirurgie et les issues postopératoires sont moins favorables par rapport aux hommes. Cette différence s'explique par une sous-représentation historique des femmes dans les études sur lesquelles reposent les lignes directrices actuelles. Cependant, des études importantes réalisées ces dernières années ont mis au jour des différences substantielles entre les sexes en ce qui a trait à l'étiologie, au diagnostic et au traitement des valvulopathies. Il est essentiel de tenir compte des différences selon le sexe chez les patients atteints d'une valvulopathie pour fournir des soins de santé équitables et optimiser l'issue clinique tant chez les femmes que chez les hommes. Cette analyse vise donc à explorer les implications des particularités selon le sexe en ce qui concerne le diagnostic, les options thérapeutiques et les issues chez les femmes atteintes de valvulopathies.