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Background: Oxidized phospholipids (OxPLs) are carried by apolipoprotein B-100-containing lipoproteins (OxPL-apoB) including lipoprotein(a) (Lp[a]). Both OxPL-apoB and Lp(a) have been associated with calcific aortic valve disease (CAVD)., Objectives: This study aimed to evaluate the associations between OxPL-apoB, Lp(a) and the prevalence, incidence, and progression of CAVD., Methods: OxPL-apoB and Lp(a) were evaluated in MESA (Multi-Ethnic Study of Atherosclerosis) and a participant-level meta-analysis of 4 randomized trials of participants with established aortic stenosis (AS). In MESA, the association of OxPL-apoB and Lp(a) with aortic valve calcium (AVC) at baseline and 9.5 years was evaluated using multivariable ordinal regression models. In the meta-analysis, the association between OxPL-apoB and Lp(a) with AS progression (annualized change in peak aortic valve jet velocity) was evaluated using multivariable linear regression models., Results: In MESA, both OxPL-apoB and Lp(a) were associated with prevalent AVC (OR per SD: 1.19 [95% CI: 1.07-1.32] and 1.13 [95% CI: 1.01-1.27], respectively) with a significant interaction between the two (P < 0.01). Both OxPL-apoB and Lp(a) were associated with incident AVC at 9.5 years when evaluated individually (interaction P < 0.01). The OxPL-apoB∗Lp(a) interaction demonstrated higher odds of prevalent and incident AVC for OxPL-apoB with increasing Lp(a) levels. In the meta-analysis, when analyzed separately, both OxPL-apoB and Lp(a) were associated with faster increase in peak aortic valve jet velocity, but when evaluated together, only OxPL-apoB remained significant (ß: 0.07; 95% CI: 0.01-0.12)., Conclusions: OxPL-apoB is a predictor of the presence, incidence, and progression of AVC and established AS, particularly in the setting of elevated Lp(a) levels, and may represent a novel therapeutic target for CAVD., Competing Interests: Funding Support and Author Disclosures Dr Bhatia is supported by National Institutes of Health (NIH) grants 1K08HL166962 and 1KL2TR001444. Dr Dweck is supported by the British Heart Foundation (FS/SCRF/21/32010) and is the recipient of the Sir Jules Thorn Award for Biomedical Research 2015 (15/JTA). Dr Craig is supported by the Medical Research Council (MR/Y009932/1). Dr Rikhi is supported by the National Heart, Lung, and Blood Institute (NHLBI) of NIH under Award Number T32HL076132. Dr Budoff was supported by R01 HL071739 and R01HL146666. Dr Thanassoulis was supported by NIH R01 HL128550-04 and is funded by the FRQS as a Senior Clinician Scientist. Dr Tsimikas is supported by NHLBI grants R01 HL159156 and HL170224. The MESA was supported by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 from NHLBI, and by grants UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420 from the National Center for Advancing Translational Sciences (NCATS). The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. Dr Bhatia has served on the scientific advisory boards for Novartis, Abbott, and Arrowhead; and has served as a consultant for Kaneka and Novartis. Dr Dweck has received speaker fees from Pfizer, Radcliffe Cardiology, Amarin, Bristol Myers Squibb, Edwards, and Novartis; and has received consultancy fees from Novartis, Jupiter Bioventures, AstraZeneca, Beren, and Silence therapeutics. Dr Capoulade has received an honorarium from Novartis. Dr Shapiro has received grants from Amgen, Boehringer Ingelheim, 89Bio, Esperion, Genentech, Novartis, Ionis, Merck, and New Amsterdam; has served on scientific advisory boards of Amgen, Agepha, Ionis, Novartis, Precision BioScience, and New Amsterdam; and has served as a consultant for Ionis, Novartis, Regeneron, Aidoc, Shanghai Pharma Biotherapeutics, Kaneka, and Novo Nordisk. Dr Budoff has received grant support from Amgen. Dr Tsimikas is a co-inventor and receives royalties from patents owned by the University of California-San Diego (UCSD); is a co-founder and has an equity interest in Oxitope and Kleanthi Diagnostics; is a consult to Novartis; and has a dual appointment at UCSD and Ionis Pharmaceuticals (the terms of this arrangement have been reviewed and approved by UCSD in accordance with its conflict-of-interest policies). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Neurohormonal modulation and afterload reduction are key for treatment of heart failure with reduced ejection fraction (HFrEF). In HFrEF patients with concomitant moderate aortic stenosis (AS), treatment with transcatheter aortic valve replacement (TAVR) may be complementary to guideline-directed medical therapy (GDMT)., Objectives: This study sought to determine whether TAVR for moderate AS provides clinical benefit in patients with HFrEF on top of GDMT., Methods: We performed an investigator-initiated, international, randomized controlled trial in patients with HFrEF on GDMT with moderate AS who were suitable for transfemoral TAVR with a balloon-expandable valve. Patients were randomized 1:1 to TAVR or clinical aortic stenosis surveillance (CASS) with aortic valve replacement upon progression to severe AS. The primary endpoint was the hierarchical occurrence of: 1) all-cause death; 2) disabling stroke; 3) disease-related hospitalizations and heart failure equivalents; and 4) change from baseline in the Kansas City Cardiomyopathy Questionnaire Overall Summary Score analyzed using the win ratio., Results: From January 2017 to December 2022, 178 patients were randomized to TAVR (n = 89) or AS surveillance (n = 89). The mean age was 77 years, 20.8% were female, and 55.6% were in NYHA functional class III or IV. The median follow-up duration was 23 months (Q1-Q3: 12-33 months). A total of 38 (43%) patients in the CASS group (of whom 35 had progressed to severe AS) underwent TAVR at a median of 12 months postrandomization. TAVR was associated with wins in 47.6% of pairs, compared with 36.6% in the CASS group, resulting in a win ratio of 1.31 (95% CI: 0.91-1.88; P = 0.14). At 1 year, TAVR resulted in a greater improvement in the Kansas City Cardiomyopathy Questionnaire Overall Summary Score compared with the CASS group (12.8 ± 21.9 points vs 3.2 ± 22.8 points; P = 0.018)., Conclusions: TAVR was not superior to AS surveillance for the primary hierarchical composite endpoint in patients with moderate AS and HFrEF on GDMT. Preemptive TAVR for moderate AS was safe and may provide clinically meaningful quality-of-life benefits., Competing Interests: Funding Support and Author Disclosures The TAVR UNLOAD trial was funded by an investigator-initiated grant from Edwards Lifesciences. The funder had no role in the study design, data collection or management, or the statistical analyses. The principal investigators had unrestricted access to the study data, wrote the manuscript, and vouched for the accuracy and completeness of the data and for the fidelity of the trial to the protocol. All the authors reviewed and approved the manuscript. Dr Van Mieghem has received grant support from Abbott Vascular, Boston Scientific, Edwards Lifesciences, and Medtronic; and has received advisory fees from Abbott, Boston Scientific, Pulse Cath BV, and Medtronic. Dr Elmariah has received research grants from Edwards Lifesciences and Medtronic; and has received consulting fees from Edwards Lifesciences. Dr Spitzer has held institutional contracts/grants for which he receives no direct compensation from Abbott, Biosensors Europe SA, Boston Scientific, Edwards Lifesciences, Medtronic, Mixin Medtech (Suzhou), Shanghai Microport Medical, NVT GmbH, Philips Healthcare, Pie Medical Imaging, Shanghai Shenqi Medical Technologies, and Siemens Healthcare GmbH. Dr Pibarot has received funding from Edwards Lifesciences, Pi-Cardia, and Cardiac Success for echocardiography core laboratory analyses in the field of transcatheter valve therapies and Medtronic for in vitro analyses, with no personal compensation. Dr Nazif has received consulting fees or honoraria from Medtronic, Boston Scientific, Teleflex, Encompass Technologies, and Opsens Medical; and has received institutional research grants from Edwards Lifesciences, Boston Scientific, Medtronic, and Abbott. Dr Bax has received speaker fees from Abbott and Edwards Lifesciences. Dr Hahn has received speaker fees from Abbott Structural, Baylis Medical, Edwards Lifesciences, Medtronic, Philips Healthcare, and Siemens Healthineers; has held institutional consulting contracts for which she receives no direct compensation from Abbott Structural, Edwards Lifesciences, Medtronic, and Novartis; and is Chief Scientific Officer for the Echocardiography Core Laboratory at the Cardiovascular Research Foundation for multiple industry-sponsored tricuspid valve trials, for which she receives no direct industry compensation. Dr Popma’s spouse is a Medtronic employee. Dr Ben-Yehuda has received consulting fees from Edwards Lifesciences, Medtronic, Cardiovalve, and Bioventrix. Dr Redfors has received consulting fees from Pfizer and Boehringer Ingelheim. Dr Kodali has received grant support, paid to his institution, from Medtronic, Boston Scientific, and Abbott Vascular; has received consulting fees from Abbott Vascular, Claret Medical, Admedus, and Meril Life Sciences; and holds equity options in BioTrace Medical, Dura Biotech, and Thubrikar Aortic Valve. Dr Hermanides has received lecture fees from Abbott Vascular, Amgen, and Novartis. Dr Cohen has received research grant support from Edwards Lifesciences, Abbott, Boston Scientific, Corvia Medical, Philips, Brain-Q, Saranas, Zoll Medical, CathWorks, and ANCORA; and has received consulting fees from Medtronic, Edwards Lifesciences, Abbott, Boston Scientific, Corvia Medical, Impulse Dynamics, AngioInsight, and HeartBeam. Dr Leon has received institutional clinical research grants from Abbott, Boston Scientific, Edwards, and Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The American College of Cardiology/American Heart Association guidelines recommend the assessment and grading of severity of aortic stenosis (AS) as mild, moderate, or severe, per echocardiogram, and recommend aortic valve replacement (AVR) when the AS is severe., Objectives: The authors sought to describe mortality rates across the entire spectrum of untreated AS from a contemporary, large, real-world database., Methods: We analyzed a deidentified real-world data set including 1,669,536 echocardiographic reports (1,085,850 patients) from 24 U.S. hospitals (egnite Database, egnite). Patients >18 years of age were classified by diagnosed AS severity. Untreated mortality and treatment rates were examined with Kaplan-Meier (KM) estimates, with results compared using the log-rank test. Multivariate hazards analysis was performed to assess associations with all-cause mortality., Results: Among 595,120 patients with available AS severity assessment, the KM-estimated 4-year unadjusted, untreated, all-cause mortality associated with AS diagnosis of none, mild, mild-to-moderate, moderate, moderate-to-severe, or severe was 13.5% (95% CI: 13.3%-13.7%), 25.0% (95% CI: 23.8%-26.1%), 29.7% (95% CI: 26.8%-32.5%), 33.5% (95% CI: 31.0%-35.8%), 45.7% (95% CI: 37.4%-52.8%), and 44.9% (95% CI: 39.9%-49.6%), respectively. Results were similar when adjusted for informative censoring caused by treatment. KM-estimated 4-year observed treatment rates were 0.2% (95% CI: 0.2%-0.2%), 1.0% (95% CI: 0.7%-1.3%), 4.2% (95% CI: 2.0%-6.3%), 11.4% (95% CI: 9.5%-13.3%), 36.7% (95% CI: 31.8%-41.2%), and 60.7% (95% CI: 58.0%-63.3%), respectively. After adjustment, all degrees of AS severity were associated with increased mortality., Conclusions: Patients with AS have high mortality risk across all levels of untreated AS severity. Aortic valve replacement rates remain low for patients with severe AS, suggesting that more research is needed to understand barriers to diagnosis and appropriate approach and timing for aortic valve replacement., Competing Interests: Funding Support and Author Disclosures Dr Généreux has served as a consultant for, an advisor for, and received speaker fees from Abbott Vascular, Abiomed, Edwards Lifesciences, and Medtronic; has served as a consultant for Boston Scientific, GE Healthcare, iRhythm Technologies, OpSens, Siemens, and Teleflex; has served as a consultant for and PI of the Eclipse Trial for Cardiovascular System Inc; has served as a proctor for, received research grants from, and served as PI for the EARLY-TAVR and PROGRESS trials for Edwards Lifesciences; has equity in and served as a consultant for Pi-Cardia, Puzzle Medical, Saranas, and Soundbite Medical Inc; has served as a consultant for and received speaker fees from Shockwave; has served as a consultant for and PI of the ALTA Valve Feasibility study for 4C Medical; and has served as a consultant and advisor for egnite, Inc. Dr Sharma has served as a consultant and advisor for Edwards Lifesciences, Boston Scientific, Abbott, Philips, Siemens, and egnite, Inc. Dr Cubeddu has served on the Speakers Bureau for Abbott Laboratories, Edwards Lifesciences, and Gore Medical. Dr Thourani has served on the advisory board for Edwards Lifesciences, Abbott Vascular, Atricure, Cryolife, JenaValve, Shockwave, and Boston Scientific. Dr Makkar has received grant support/research contracts from Edwards Lifesciences and St Jude Medical; and has received consultant fees/honoraria and served on the Speakers Bureaus of Abbott Vascular, Cordis Corporation, and Medtronic. Dr Cohen has received research grant support from Edwards Lifesciences, Boston Scientific, Abbott, Medtronic, Philips, Zoll Medical, iRhythm, and Corvia; and has served as a consultant for Edwards Lifesciences, Boston Scientific, Abbott, Medtronic, and Corvia. Mr Dobbles and Dr Kwon have equity, stock(s), and/or options in and are employees of egnite, Inc. Dr Barnhart has equity, stock(s), and/or options in and was employed at egnite, Inc at the time of the study. Dr Pibarot has received institutional funding from Edwards Lifesciences, Medtronic, Pi-Cardia, Cardiac Success, and Roche Diagnostics for echocardiography core laboratory analyses, blood biomarker analyses, and research studies in the field of interventional and pharmacologic treatment of valvular heart diseases, for which he received no personal compensation. Dr Leon has received institutional clinical research grants from Abbott, Boston Scientific, Edwards Lifesciences, and Medtronic. Dr Gillam has served as a consultant for Medtronic, Philips, Edwards Lifesciences, and egnite, Inc; and has core laboratory contracts (no direct compensation) with Edwards Lifesciences, Medtronic, and Abbott. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Valvular heart disease (VHD) is common and poses important challenges from the standpoints of diagnosis and therapeutic management. Clinical practice guidelines have been developed to help health care professionals to overcome these challenges and provide optimal management to patients with VHD. The American College of Cardiology, in collaboration with the American Heart Association, and the European Society of Cardiology, in collaboration with the European Association for Cardio-Thoracic Surgery, recently updated their guidelines on the management of VHD. Although these 2 sets of guidelines are generally concordant, there are some substantial differences between these guidelines, which may have significant implications for clinical practice. This review prepared on behalf of the EuroValve Consortium describes the consistencies and discrepancies between the guidelines and highlights the gaps in these guidelines and the future research perspectives to fill these gaps., Competing Interests: Funding Support and Author Disclosures Dr Garbi was The NICE Topic Adviser for the NICE Guidelines on heart valve disease presenting in adults: investigation and management. Dr Dahl has received speaker fees from Edwards. Dr Barbanti has served as a consultant for Edwards Lifesciences, Medtronic, and Boston Scientific. Dr Vannan has received research grants and a speaker honorarium (to Piedmont Heart Institute, not to self) from Abbott, Medtronic, and Edwards Lifesciences. Dr Vassiliou served as an advisor for the NICE Guidelines on valvular heart disease (NG208) referred to in this paper; and has received grants for investigator-initiated research by Medtronic and B Braun Ltd. Dr de Paulis has received royalties from Edwards for a mitral ring; and has received speaker fees from Edwards and Medtronic. Dr Pibarot has received institutional research grants from Edwards Lifesciences, Medtronic, Pi-Cardia, Cardiac Success, and Roche Diagnostics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Previous studies demonstrated transcatheter aortic valve replacement (TAVR) with an earlier generation balloon-expandable valve to be noninferior to surgical aortic valve replacement (SAVR) for death and disabling stroke in intermediate-risk patients with symptomatic, severe aortic stenosis at 5 years. However, limited long-term data are available with the more contemporary SAPIEN 3 (S3) bioprosthesis., Objectives: The aim of this study was to compare 5-year risk-adjusted outcomes in intermediate-risk patients undergoing S3 TAVR vs SAVR., Methods: Propensity score matching was performed to account for baseline differences in intermediate-risk patients undergoing S3 TAVR in the PARTNER 2 (Placement of Aortic Transcatheter Valves) S3 single-arm study and SAVR in the PARTNER 2A randomized clinical trial. The primary composite endpoint consisted of 5-year all-cause death and disabling stroke., Results: A total of 783 matched pairs of intermediate-risk patients with severe aortic stenosis were studied. There were no differences in the primary endpoint between S3 TAVR and SAVR at 5 years (40.2% vs 42.7%; HR: 0.87; 95% CI: 0.74-1.03; P = 0.10). The incidence of mild or greater paravalvular regurgitation was more common after S3 TAVR. There were no differences in structural valve deterioration-related stage 2 and 3 hemodynamic valve deterioration or bioprosthetic valve failure., Conclusions: In this propensity-matched analysis of intermediate-risk patients, 5-year rates of death and disabling stroke were similar between S3 TAVR and SAVR. Rates of structural valve deterioration-related hemodynamic valve deterioration were similar, but paravalvular regurgitation was more common after S3 TAVR. Longer-term follow-up is needed to further evaluate differences in late adverse clinical events and bioprosthetic valve durability. (PII S3i [PARTNER II Trial: Placement of Aortic Transcatheter Valves II - S3 Intermediate], NCT03222128; PII A (PARTNER II Trial: Placement of Aortic Transcatheter Valves II - XT Intermediate and High Risk], NCT01314313)., Competing Interests: Funding Support and Author Disclosures Dr Kodali has received institutional research grants from Edwards Lifesciences, Medtronic, Abbott Vascular, Boston Scientific, and JenaValve; has received consulting fees from Admedus, TriCares, TriFlo, X-Dot, Micro Interventional Devices, Supira, Adona, Tioga, Helix Valve Repair, and Moray Medical; and is a scientific advisory board member for Dura Biotech, Thubrikar Aortic Valve, Philips, Medtronic, and Boston Scientific. Dr Thourani is an advisory board member for Edwards Lifesciences, Abbott Vascular, Atricure, CryoLife, JenaValve, Shockwave, and Boston Scientific. Dr Makkar has received grant support from and has research contracts with Edwards Lifesciences and St Jude Medical; and has received consulting fees and honoraria from and is a Speakers Bureau member for Abbott Vascular, Cordis Corporation, and Medtronic. Dr Mack has served as co–primary investigator for the PARTNER trial for Edwards Lifesciences and the COAPT trial for Abbott; and has served as study chair for the APOLLO trial for Medtronic (all activities unpaid). Dr Webb is a consultant for Edwards Lifesciences. Dr Herrmann has received institutional research funding from Abbott Vascular, Ancora, Boston Scientific, Edwards Lifesciences, and Medtronic; and has received consulting fees from Abbott Vascular, Edwards Lifesciences, and Medtronic; and holds equity in Micro Interventional Devices. Dr Cohen has received institutional research grants from Edwards Lifesciences, Medtronic, Boston Scientific, and Abbott Vascular; and has received consulting fees from Edwards Lifesciences, Medtronic, Boston Scientific, and Abbott Vascular. Dr Pibarot has received funding from Edwards Lifesciences, Medtronic, Pi-Cardia, and Cardiac Phoenix for echocardiography core laboratory analyses and research studies in the field of transcatheter valve therapies, for which he received no personal compensation. Dr Hahn has received speaker fees from Abbott Vascular, Baylis Medical, and Edwards Lifesciences; has institutional consulting agreements for which she receives no direct compensation with Abbott Vascular, Boston Scientific, Edwards Lifesciences, Medtronic, and Novartis; holds equity with Navigate; and is the Chief Scientific Officer for the echocardiography core laboratory at the Cardiovascular Research Foundation. Dr Xu is an employee of Edwards Lifesciences. Dr Alu has received institutional funding (no direct compensation) from Edwards Lifesciences and Abbott. Dr Leon serves on the PARTNER trial executive committee for Edwards Lifesciences (unpaid); has received institutional research grants from and is an unpaid adviser for Abbott, Boston Scientific, and Medtronic; is an unpaid adviser for Sinomed; and holds equity in Medinol. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023. Published by Elsevier Inc.)

Background: The extent of extravalvular cardiac damage is associated with increased risk of adverse events among patients with severe aortic stenosis undergoing aortic valve replacement (AVR)., Objectives: The goal was to describe the association of cardiac damage on health status before and after AVR., Methods: Patients from the PARTNER (Placement of Aortic Transcatheter Valves) 2 and 3 trials were pooled and classified by echocardiographic cardiac damage stage at baseline and 1 year as previously described (stage 0-4). We examined the association between baseline cardiac damage and 1-year health status (assessed by the Kansas City Cardiomyopathy Questionnaire Overall Score [KCCQ-OS])., Results: Among 1,974 patients (794 surgical AVR, 1,180 transcatheter AVR), the extent of cardiac damage at baseline was associated with lower KCCQ scores both at baseline and at 1 year after AVR (P < 0.0001) and with increased rates of a poor outcome (death, KCCQ-OS <60, or a decrease in KCCQ-OS of ≥10 points) at 1 year (stages 0-4: 10.6% vs 19.6% vs 29.0% vs 44.7% vs 39.8%; P < 0.0001). In a multivariable model, each 1-stage increase in baseline cardiac damage was associated with a 24% increase in the odds of a poor outcome (95% CI: 9%-41%; P = 0.001). Change in stage of cardiac damage at 1 year after AVR was associated with the extent of improvement in KCCQ-OS over the same period (mean change in 1-year KCCQ-OS: improvement of ≥1 stage +26.8 [95% CI: 24.2-29.4] vs no change +21.4 [95% CI: 20.0-22.7] vs deterioration of ≥1 stage +17.5 [95% CI: 15.4-19.5]; P < 0.0001)., Conclusions: The extent of cardiac damage before AVR has an important impact on health status outcomes, both cross-sectionally and after AVR. (PARTNER II Trial: Placement of AoRTic TraNscathetER Valves II - XT Intermediate and High Risk (PII A), NCT01314313; The PARTNER II Trial: Placement of AoRTic TraNscathetER Valves - PII B [PARTNERII B], NCT02184442; PARTNER 3 Trial: Safety and Effectiveness of the SAPIEN 3 Transcatheter Heart Valve in Low Risk Patients With Aortic Stenosis [P3], NCT02675114)., Competing Interests: Funding Support And Author Disclosures The PARTNER 2 and PARTNER 3 Trials were sponsored by Edwards Lifesciences (Irvine, California). Dr Généreux has served as a consultant for Abbott Vascular, Abiomed, BioTrace Medical, Boston Scientific, CARANX Medical, Cardiovascular System Inc (PI Eclipse Trial), Edwards Lifesciences (PI EARLY-TAVR trial, PI PROGRESS trial), GE Healthcare, iRhythm Technologies, Medtronic, Opsens, Pi-Cardia, Puzzle Medical, Saranas, Shockwave, Siemens, Soundbite Medical Inc, Teleflex, and 4C Medical (PI feasibility study); has served as an advisor for Abbott Vascular, Abiomed, BioTrace Medical, Edwards Lifesciences, and Medtronic; has received speaker fees from Abbott Vascular, Abiomed, BioTrace Medical, Edwards Lifesciences, Medtronic, and Shockwave; has served as a proctor for and received an institutional research grant from Edwards Lifesciences; and has equity in Pi-Cardia, Puzzle Medical, Saranas, and Soundbite Medical Inc. Dr Pibarot has received funding from Edwards Lifesciences, Medtronic, Pi-Cardia, and Cardiac Phoenix for echocardiography core laboratory analyses and research studies in the field of transcatheter valve therapies, for which he received no personal compensation; and has received lecture fees from Edwards Lifesciences and Medtronic. The Cardiovascular Research Foundation (Drs Redfors, Cohen, Alu, Hahn, and Lyon) receives research funding from Edwards Lifesciences (no direct compensation). Dr Bax reports that the Department of Cardiology (LUMC, the Netherlands) has received research grants from Medtronic, Biotronik, Edwards Lifesciences, and Boston Scientific; and has received speaker fees from Abbott Vascular. Drs Zhao and Prince are employees of Edwards Lifesciences. Dr Makkar has received grant support/research contracts from Edwards Lifesciences and St Jude Medical; and has received consultant fees/honoraria from and served on the speaker’s bureau for Abbott Vascular, Cordis Corporation, and Medtronic. Dr Thourani is on the advisory board of Edwards Lifesciences, Abbott Vascular, Atricure, Cryolife, Jenavalve, Shockwave, and Boston Scientific. Dr Mack served as co-primary investigator for the PARTNER Trial for Edwards Lifesciences; served as co-primary investigator for the COAPT trial for Abbott; and served as study chair for the APOLLO trial for Medtronic (all activities unpaid). Dr Nazif is a consultant for Edwards Lifesciences, Medtronic, and Boston Scientific. Dr Lindman has served on the scientific advisory board for Roche Diagnostics; and has received research grants from Edwards Lifesciences and Roche Diagnostics. Dr Babaliaros has received consulting fees from Edwards Lifesciences and Abbott. Dr Russo has received grants from Edwards Lifesciences; and has served as a consultant for Abbott, Boston Scientific, and Edwards Lifesciences. Dr McCabe has served as a consultant for Edwards, Medtronic, Boston Scientific, and Cardiovascular System Inc; and has equity in ConKay Medical. Dr Gillam has served as a consultant for Edwards Lifesciences; and has core lab contracts with Edwards Lifesciences and Medtronic. Dr Hahn has received speaker fees from Abbott Vascular, Baylis Medical, and Edwards Lifescience; has institutional consulting agreements for which she receives no direct compensation with Abbott Vascular, Boston Scientific, Edwards Lifesciences, Medtronic, and Novartis; has equity with Navigate; and is the Chief Scientific Officer for the Echocardiography Core Laboratory at the Cardiovascular Research Foundation. Dr Webb is a consultant for Edwards Lifesciences. Dr Leon serves on the PARTNER Trial Executive Committee for Edwards Lifesciences (non-paid); and has received institutional research grants from and has served as a nonpaid advisor for Abbott, Boston Scientific, and Medtronic; has served as a nonpaid advisor for Sinomed; and has equity in Medinol. Dr Cohen has received research grant support and consulting income from Edwards Lifesciences, Medtronic, Boston Scientific, and Abbott. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The prognostic impact of left ventricular ejection fraction (LVEF) in patients with bicuspid aortic valve (BAV) disease has not been previously studied., Objectives: The purpose of this study was to determine the prognostic impact of LVEF in BAV patients according to the type of aortic valve dysfunction., Methods: We retrospectively analyzed the data collected in 2,672 patients included in an international registry of patients with BAV. Patients were classified according to the type of aortic valve dysfunction: isolated aortic stenosis (AS) (n = 749), isolated aortic regurgitation (AR) (n = 554), mixed aortic valve disease (MAVD) (n = 190), or no significant aortic valve dysfunction (n = 1,179; excluded from this analysis). The study population was divided according to LVEF strata to investigate its impact on clinical outcomes., Results: The risk of all-cause mortality and the composite endpoint of aortic valve replacement or repair (AVR) and all-cause mortality increased when LVEF was <60% in the whole cohort as well as in the AS and AR groups, and when LVEF was <55% in MAVD group. In multivariable analysis, LVEF strata were significantly associated with increased rate of mortality (LVEF 50%-59%: HR: 1.83 [95% CI: 1.09-3.07]; P = 0.022; LVEF 30%-49%: HR: 1.97 [95% CI: 1.13-3.41]; P = 0.016; LVEF <30%: HR: 4.20 [95% CI: 2.01-8.75]; P < 0.001; vs LVEF 60%-70%, reference group)., Conclusions: In BAV patients, the risk of adverse clinical outcomes increases significantly when the LVEF is <60%. These findings suggest that LVEF cutoff values proposed in the guidelines to indicate intervention should be raised from 50% to 60% in AS or AR and 55% in MAVD., Competing Interests: Funding Support and Author Disclosures The Department of Cardiology of the Leiden University Medical Center has received research grants from Abbott Vascular, Bioventrix, Medtronic, Biotronik, Boston Scientific, GE Healthcare, and Edwards Lifesciences. Dr Butcher has received funding from the European Society of Cardiology (ESC Research Grant App000080404). Drs Marsan and Bax have received speaker fees from Abbott Vascular. Dr Delgado has received speaker fees from Abbott Vascular, Medtronic, Edwards Lifesciences, Merck Sharp & Dohme, Novartis, and GE Healthcare. Dr Pibarot holds the Canada Research Chair in Valvular Heart Diseases, Canadian Institutes of Health Research; and has received funding from Edwards Lifesciences and Medtronic for echocardiography CoreLab analyses with no personal compensation. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The impact of aortic valve replacement (AVR) on progression/regression of extravalvular cardiac damage and its association with subsequent prognosis is unknown., Objectives: The purpose of this study was to describe the evolution of cardiac damage post-AVR and its association with outcomes., Methods: Patients undergoing transcatheter or surgical AVR from the PARTNER (Placement of Aortic Transcatheter Valves) 2 and 3 trials were pooled and classified by cardiac damage stage at baseline and 1 year (stage 0, no damage; stage 1, left ventricular damage; stage 2, left atrial or mitral valve damage; stage 3, pulmonary vasculature or tricuspid valve damage; and stage 4, right ventricular damage). Proportional hazards models determined association between change in cardiac damage post-AVR and 2-year outcomes., Results: Among 1,974 patients, 121 (6.1%) were stage 0, 287 (14.5%) stage 1, 1,014 (51.4%) stage 2, 412 (20.9%) stage 3, and 140 (7.1%) stage 4 pre-AVR. Two-year mortality was associated with extent of cardiac damage at baseline and 1 year. Compared with baseline, cardiac damage improved in ∼15%, remained unchanged in ∼60%, and worsened in ∼25% of patients at 1 year. The 1-year change in cardiac damage stage was independently associated with mortality (adjusted HR for improvement: 0.49; no change: 1.00; worsening: 1.95; P = 0.023) and composite of death or heart failure hospitalization (adjusted HR for improvement: 0.60; no change: 1.00; worsening: 2.25; P < 0.001) at 2 years., Conclusions: In patients undergoing AVR, extent of extravalvular cardiac damage at baseline and its change at 1 year have important prognostic implications. These findings suggest that earlier detection of aortic stenosis and intervention before development of irreversible cardiac damage may improve global cardiac function and prognosis. (PARTNER II Trial: Placement of AoRTic TraNscathetER Valves II - XT Intermediate and High Risk [PII A], NCT01314313; The PARTNER II Trial: Placement of AoRTic TraNscathetER Valves - PII B [PARTNERII B], NCT02184442; and PARTNER 3 Trial: Safety and Effectiveness of the SAPIEN 3 Transcatheter Heart Valve in Low Risk Patients With Aortic Stenosis [P3], NCT02675114)., Competing Interests: Funding Support and Author Disclosures The PARTNER II and PARTNER 3 Trials were Sponsored by Edwards Lifesciences. Dr Généreux has served as a consultant for, advisor for, and received speaker fees from Abbott Vascular, Abiomed, BioTrace Medical, and Medtronic; has served as a consultant for Boston Scientific, CARANX Medical, GE Healthcare, iRhythm Technologies, Opsens, Teleflex, and Siemens; has served as a consultant and PI for the Eclipse Trial for Cardiovascular System Inc; has served as a consultant, advisor, and proctor, and received speaker fees and institutional research grants for PI EARLY-TAVR and PI PROGRESS trials from Edwards Lifesciences; has received equity from and served as a consultant for Pi-Cardia, Puzzle Medical, Saranas, and Soundbite Medical Inc; has served as a consultant for and received speaker fees from Shockwave; and has served as consultant for and PI of the Feasibility study for 4C Medical. Dr Pibarot has received funding from Edwards Lifesciences, Medtronic, Pi-Cardia, and Cardiac Phoenix for echocardiography core laboratory analyses and research studies in the field of transcatheter valve therapies, for which he received no personal compensation; and has received lecture fees from Edwards Lifesciences and Medtronic. The Cardiovascular Research Foundation (Drs Redfors, Vincent, Alu, Hahn, Leon, and Cohen) receives research funding from Edwards Lifesciences (no direct compensation). Dr Bax’s department (Department of Cardiology, LUMC, the Netherlands) has received research grants from Medtronic, Biotronik, Edwards Lifesciences, and Boston Scientific; and he has received speaker fees from Abbott Vascular. Dr Zhao is an employee of Edwards Lifesciences. Dr Makkar has received grant support/research contracts from Edwards Lifesciences and St. Jude Medical; and has received consultant fees/honoraria from/served on the speaker's bureau for Abbott Vascular, Cordis Corporation, and Medtronic. Dr Thourani has served on the Advisory Board of Edwards Lifesciences, Abbott Vascular, Atricure, Cryolife, Jenavalve, Shockwave, and Boston Scientific. Dr Mack has served as coprimary investigator for the PARTNER Trial for Edwards Lifesciences and COAPT trial for Abbott; and has served as study chair for the APOLLO trial for Medtronic (all activities unpaid). Dr Nazif is a consultant for Edwards Lifesciences, Medtronic, and Boston Scientific. Dr Lindman has served on the Scientific Advisory Board for Roche Diagnostics; and has received research grants from Edwards Lifesciences and Roche Diagnostics. Dr Babaliaros has received consulting fees from Edwards Lifesciences and Abbott. Dr Russo has received grants from Edwards Lifesciences; and has served as a consultant for Abbott, Boston Scientific, and Edwards Lifesciences. Dr McCabe has served as a consultant for Edwards, Medtronic, Boston Scientific, and Cardiovascular System Inc; and has equity in ConKay Medical. Dr Gillam has served as a consultant for Edwards Lifesciences; and has received core laboratory contracts from Edwards Lifesciences and Medtronic. Dr Hahn has received speaker fees from Abbott Vascular, Baylis Medical, and Edwards Lifesciences; has institutional consulting agreements for which she receives no direct compensation with Abbott Vascular, Boston Scientific, Edwards Lifesciences, Medtronic, and Novartis; has equity with Navigate; and is the Chief Scientific Officer for the Echocardiography Core Laboratory at the Cardiovascular Research Foundation. Dr Webb is a consultant for Edwards Lifesciences. Dr Leon serves on the PARTNER Trial Executive Committee for Edwards Lifesciences (nonpaid); has received institutional research grants from and is a nonpaid advisor for Abbott, Boston Scientific, and Medtronic; has served as a nonpaid advisor for Sinomed; and has equity in Medinol. Dr Cohen has received research grant support and consulting income from Edwards Lifesciences, Medtronic, Boston Scientific, and Abbott. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The prognostic implications of discordant grading in severe aortic stenosis (AS) are well known. However, the prevalence of different flow-gradient patterns and their prognostic implications in moderate AS are unknown., Objectives: The purpose of this study was to investigate the occurrence and prognostic implications of different flow-gradient patterns in patients with moderate AS., Methods: Patients with moderate AS (aortic valve area >1.0 and ≤1.5 cm 2 ) were identified and divided in 4 groups based on transvalvular mean gradient (MG), stroke volume index (SVi), and left ventricular ejection fraction (LVEF): concordant moderate AS (MG ≥20 mm Hg) and discordant moderate AS including 3 subgroups: normal-flow, low-gradient moderate AS (MG <20 mm Hg, SVi ≥35 mL/m 2 , and LVEF ≥50%); "paradoxical" low-flow, low-gradient moderate AS (MG <20 mm Hg, SVi <35 mL/m 2 , and LVEF ≥50%) and "classical" low-flow, low-gradient moderate AS (MG <20 mm Hg and LVEF <50%). The primary endpoint was all-cause mortality., Results: Of 1,974 patients (age 73 ± 10 years, 51% men) with moderate AS, 788 (40%) had discordant grading, and these patients showed significantly higher mortality rates than patients with concordant moderate AS (P < 0.001). On multivariable analysis, "paradoxical" low-flow, low-gradient (HR: 1.458; 95% CI: 1.072-1.983; P = 0.014) and "classical" low-flow, low-gradient (HR: 1.710; 95% CI: 1.270-2.303; P < 0.001) patterns but not the normal-flow, low-gradient moderate AS pattern were independently associated with all-cause mortality., Conclusions: Discordant grading is frequently (40%) observed in patients with moderate AS. Low-flow, low-gradient patterns account for an important proportion of the discordant cases and are associated with increased mortality. These findings underline the need for better phenotyping patients with discordant moderate AS., Competing Interests: Funding Support and Author Disclosures The Department of Cardiology of the Leiden University Medical Centre has received unrestricted research grants from Abbott Vascular, Bayer, Biotronik, Bioventrix, Boston Scientific, Edwards Lifesciences, GE Healthcare, and Medtronic. Dr Stassen has received funding from the European Society of Cardiology (ESC Training Grant App000064741). Dr Butcher has received funding from the European Society of Cardiology (ESC Research Grant App000080404). Dr Pibarot has received funding from Edwards Lifesciences, Medtronic, Pi-Cardia, and Cardiac Phoenix for echocardiography core laboratory analyses and research studies in the field of transcatheter valve therapies, for which he received no personal compensation; and has received lecture fees from Edwards Lifesciences and Medtronic. Dr Delgado has received speaker fees from Abbott Vascular, Edwards Lifesciences, Merck Sharp and Dohme, and GE Healthcare. Dr Marsan has received speaker fees from Abbott Vascular and GE Healthcare. Dr Bax received speaker fees from Abbott Vascular. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Data comparing valve systems in the valve-in-valve transcatheter aortic valve replacement (ViV-TAVR) field have been obtained from retrospective studies., Objectives: The purpose of this study was to compare the hemodynamic results between the balloon-expandable valve (BEV) SAPIEN (3/ULTRA, Edwards Lifesciences) and self-expanding valve (SEV) Evolut (R/PRO/PRO+, Medtronic) in ViV-TAVR., Methods: Patients with a failed small (≤23 mm) surgical valve were randomized to receive a BEV or an SEV. The primary endpoint was valve hemodynamics (maximal/mean residual gradients, severe prosthesis patient mismatch [PPM], or moderate-severe aortic regurgitation) at 30 days as evaluated by Doppler echocardiography., Results: A total of 102 patients were randomized, and of these, 98 patients finally underwent a ViV-TAVR procedure (BEV: n = 46, SEV: n = 52). The procedure was successful in all cases, with no differences in clinical outcomes at 30 days between groups (no death or stroke events). Patients in the SEV group exhibited lower mean and maximal transvalvular gradient values (15 ± 8 mm Hg vs 23 ± 8 mm Hg; P ˂ 0.001; 28 ± 16 mm Hg vs 40 ± 13 mm Hg, P ˂ 0.001), and a tendency toward a lower rate of severe PPM (44% vs 64%; P = 0.07). There were no cases of moderate-severe aortic regurgitation. In total, 55 consecutive patients (SEV: n = 27; BEV: n = 28) underwent invasive valve hemodynamic evaluation during the procedure, with no differences in mean and peak transvalvular gradients between both groups (P = 0.41 and P = 0.70, respectively)., Conclusions: In patients with small failed aortic bioprostheses, ViV-TAVR with an SEV was associated with improved valve hemodynamics as evaluated by echocardiography. There were no differences between groups in intraprocedural invasive valve hemodynamics and 30-day clinical outcomes (Comparison of the Balloon-Expandable Edwards Valve and Self-Expandable CoreValve Evolut R or Evolut PRO System for the Treatment of Small, Severely Dysfunctional Surgical Aortic Bioprostheses. The 'LYTEN' Trial; NCT03520101)., Competing Interests: Funding Support and Author Disclosures Dr Rodés-Cabau holds the Research Chair “Fondation Famille Jacques Larivière” for the Development of Structural Heart Disease Interventions (Laval University); and has received institutional research grants from and is consultant for Edwards Lifesciences and Medtronic. Dr Abbas has received research grants and consulting fees from Edwards Lifesciences. Dr Nombela-Franco holds a research grant (INT19/00040 and CM21/00091) from the Spanish Ministry of Science and Inovation (Instituto de Salud Carlos III); and has received consulting fees from Edwards Lifesciences. Dr Conradi is a member of the Advisory Board of Medtronic, Abbott, JenaValve, and Neovase; and has received consulting fees from Edwards Lifesciences, Boston Scientific, New Valve Technology, and MicroInterventions. Dr Pibarot has received research grants from Edwards Lifesciences and Medtronic; and has received consulting fees from Edwards Lifesciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Ischemic mitral regurgitation (MR) is primarily caused by left ventricle deformation, but leaflet thickening with fibrotic changes are also observed in the valve. Increased levels of 5-hydroxytryptamine (5-HT; ie, serotonin) are described after myocardial infarction (MI); 5-HT can induce valve fibrosis through the 5-HT type 2B receptor (5-HT2BR)., Objectives: This study aims to test the hypothesis that post-MI treatment with cyproheptadine (5-HT2BR antagonist) can prevent ischemic MR by reducing the effect of serotonin on mitral biology., Methods: Thirty-six sheep were divided into 2 groups: inferior MI and inferior MI treated with cyproheptadine (0.5 mg/kg/d). Animals were followed for 90 days. Blood 5-HT, infarct size, left ventricular volume and function, MR fraction and mitral leaflet size were assessed. In a complementary in vitro study, valvular interstitial cells were exposed to pre-MI and post-MI serum collected from the experimental animals., Results: Increased 5-HT levels were observed after MI in nontreated animals, but not in the group treated with cyproheptadine. Infarct size was similar in both groups (11 ± 3 g vs 9 ± 5 g; P = 0.414). At 90 days, MR fraction was 16% ± 7% in the MI group vs 2% ± 6% in the cyproheptadine group (P = 0.0001). The increase in leaflet size following MI was larger in the cyproheptadine group (+40% ± 9% vs +22% ± 12%; P = 0.001). Mitral interstitial cells overexpressed extracellular matrix genes when treated with post-MI serum, but not when exposed to post-MI serum collected from treated animals., Conclusions: Cyproheptadine given after inferior MI reduces post-MI 5-HT levels, prevents valvular fibrotic remodeling, is associated with larger increase in mitral valve size and less MR., Competing Interests: Funding Support and Author Disclosures This work has been funded by the Canadian Institutes for Health Research (CIHR—grant #399323). Dr Clavel is supported by a New National Investigator from the Heart and Stroke Foundation of Canada and an Early Carrier Investigator Award from the CIHR. Dr Beaudoin is supported by the Fonds de Recherche du Québec-Santé (FRQS). The other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

A virtual workshop was organized by the Heart Valve Collaboratory to identify areas of expert consensus, areas of disagreement, and evidence gaps related to bioprosthetic aortic valve hemodynamics. Impaired functional performance of bioprosthetic aortic valve replacement is associated with adverse patient outcomes; however, this assessment is complicated by the lack of standardization for labelling, definitions, and measurement techniques, both after surgical and transcatheter valve replacement. Echocardiography remains the standard assessment methodology because of its ease of performance, widespread availability, ability to do serial measurements over time, and correlation with outcomes. Management of a high gradient after replacement requires integration of the patient's clinical status, physical examination, and multimodality imaging in addition to shared patient decisions regarding treatment options. Future priorities that are underway include efforts to standardize prosthesis sizing and labelling for both surgical and transcatheter valves as well as trials to characterize the consequences of adverse hemodynamics., Competing Interests: Funding Support and Author Disclosures Dr Herrmann has received institutional research funding from Abbott, Boston Scientific, Edwards Lifesciences, Highlife, Medtronic, and WL Gore; has received consulting fees from Edwards Lifesciences, Medtronic, Wells Fargo, and WL Gore; and has equity in Holistick Medical and Microinterventional Devices. Dr Pibarot has received funding from Edwards Lifesciences, Medtronic, Pi-Cardia, and Cardiac Phoenix for echocardiography core laboratory analyses and research studies in the field of transcatheter valve therapies, for which he received no personal compensation. Dr Hahn has received speaker fees from Abbott Structural and Edwards Lifesciences; has institutional consulting contracts for which she receives no direct compensation with Abbott Structural, Boston Scientific, Edwards Lifesciences, Medtronic, and Novartis; has served on the Scientific Advisory Board for Novartis; and has equity in Navigate. Dr Tang is a physician proctor and consultant for Medtronic; has served as a consultant and physician advisory board member for Abbott Structural Heart; has served as a consultant for NeoChord; and has served as a physician advisory board member for JenaValve. Dr Abbas has received research grants and consulting fees from Edwards Lifesciences. Dr Playford has received investigator-initiated research funding from Edwards Lifesciences, Pfizer, Novartis, Actelion, Bayer, and GlaxoSmithKline; is Chief Medical Advisor for Echo IQ; and has been a physician advisory board member for Edwards Lifesciences and AstraZeneca. Dr Ruel is a physician proctor for Medtronic (MICS CABG) and for Edwards Lifesciences (MICS AVR); has served as a steering committee member for Cryolife (PROACT Xa trial); and is a recipient of research funds from Medtronic (MIST trial). Dr Jilaihawi is a consultant to Boston Scientific, Edwards Lifesciences, and Medtronic; and has received grant/research support from Abbott Vascular, Edwards Lifesciences, and Medtronic. Dr Sathananthan is a consultant for and has received institutional research funding from Edwards Lifesciences and Medtronic; and has received speaker fees from NVT. Dr Wood is a consultant for and his institution (CCI-CIC) receives grant support from Edwards Lifesciences, Abbott Vascular, and Medtronic. Dr Bax’s institution (Department of Cardiology, LUMC, the Netherlands) has received research grants from Medtronic, Biotronik, Edwards Lifesciences, and Boston Scientific. Dr Rodes-Cabau has received institutional research grants from Edwards Lifesciences, Medtronic, and Boston Scientific. Dr Del Nido is cofounder of Autus Valve Technologies, Inc. Dr Dweck is a consultant to Edwards Lifesciences and Medtronic; has received research funding from Edwards Lifesciences and Medtronic; and has received speaker fees from NVT. Dr Kaneko is a consultant for Edwards, Medtronic, Abbott, and 4C Medical. Dr Latib is a consultant for Medtronic, Edwards Lifesciences, Boston Scientific, and Abbott. Dr Moat is a full-time employee of Abbott Structural Heart, Inc. Dr Modine has received research grants from Edwards Lifesciences and Medtronic; and is a consultant for Abbott, Edwards Lifesciences, Medtronic, and Microport. Dr Popma is a full-time employee of Medtronic, Inc. Dr Smith has received institutional grants from Edwards Lifesciences, Medtronic, Abbott, and Cryolife; has received advisory board fees from Edwards Lifesciences; and has received speaking honoraria from Medtronic, Cryolife, Abbott, and Edwards Lifesciences. Dr Thomas is a full-time employee of Edwards Lifesciences. Dr Yoganathan is a Principal Consultant to CardioMed Device Consultants LLC in the Structural Heart Valve area; is on the Scientific Advisory Board of Foldax Inc; and has served as Educational Consultant to Boston Scientific, Edwards Lifesciences, Abbott Cardiovascular, and Livanova. Dr Mack has served as a co-principal investigator for clinical trials for Abbott and Edwards Lifesciences; and has served as study chair for a trial for Medtronic; all roles were uncompensated. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Bioprosthetic valve dysfunction (BVD) and bioprosthetic valve failure (BVF) may be caused by structural or nonstructural valve dysfunction. Both surgical and transcatheter bioprosthetic valves have limited durability because of structural valve deterioration. The main objective of this summary of experts participating in a virtual workshop was to propose standardized definitions for nonstructural and structural BVD and BVF following aortic or mitral biological valve replacement with the goal of facilitating research reporting and implementation of these terms in clinical practice. Definitions of structural BVF, based on valve reintervention or death, underestimate the true incidence of BVF. However, definitions solely based on the presence of high transprosthetic gradient at a given echocardiogram during follow-up overestimate the incidence of structural BVD and BVF. Definitions of aortic or mitral structural BVD must therefore include the confirmation by imaging of permanent structural changes to the leaflets alongside evidence of deterioration in valve hemodynamic function at echocardiography follow-up., Competing Interests: Funding Support and Author Disclosures Dr Pibarot has received funding from Edwards Lifesciences, Medtronic, Pi-Cardia, and Cardiac Phoenix for echocardiography core laboratory analyses and research studies in the field of transcatheter valve therapies, for which he received no personal compensation; and has received lecture fees from Edwards Lifesciences and Medtronic. Dr Herrmann has received institutional research funding from Abbott, Boston Scientific, Edwards Lifesciences, Highlife, Medtronic, and WL Gore; has received consulting fees from Edwards Lifesciences, Medtronic, Wells Fargo, and WL Gore; and has equity in Holistick Medical and Microinterventional Devices. Dr Hahn has received speaker fees from Abbott Structural, Edwards Lifesciences, and Philips Healthcare; has institutional consulting contracts for which she receives no direct compensation with Abbott Structural, Boston Scientific, Edwards Lifesciences, Medtronic and Novartis; and has equity in Navigate. Dr Abbas has received research grants and consulting fees from Edwards Lifesciences. Dr Dweck has served as a consultant to Edwards Lifesciences and Medtronic; has received research funding from Edwards Lifesciences and Medtronic; and has received speaking fees from NVT. Dr Leipsic has served as a consultant for Circle CVI and MVRX; and has received institutional funding for CT core laboratory analyses from Edwards Lifesciences, Neovasc, Abbott, Medtronic, Boston Scientific, PI Cardia, and Conformal. Dr Rogers has served as a consultant and physician proctor for Edwards Lifesciences and Medtronic; has served as an advisory board member for Medtronic; and holds equity interest in Transmural Systems. Dr Sathananthan has served as a consultant to Edwards Lifesciences and Medtronic; has received research funding from Edwards Lifesciences and Medtronic; and has received speaking fees from NVT. Dr Guerrero has received institutional research grant support from Edwards Lifesciences. Dr Ternacle has served as a consultant for Philips Healthcare and Abbott Medical. Dr Barbanti has served as a consultant for Edwards Lifesciences and Boston Scientific. Dr Généreux has served as a consultant and advisor for and received speaker fees from Abbott Vascular, Abiomed, BioTrace Medical, and Medtronic; has served as a consultant for Boston Scientific, GE Healthcare, iRhythm Technologies, Opsens, Siemens, and Teleflex; has served as a consultant, PI Eclipse Trial, for Cardiovascular System Inc; has served as a consultant, advisor, and proctor for and received speaker fees and research grant from Edwards LifeSciences for the PI EARLY-TAVR and PI PROGRESS trials; has served as a consultant for and has equity in Pi-Cardia, Puzzle Medical, Saranas, and Soundbite Medical Inc; has served as a consultant for and received speaker fees from Shockwave; and has served as a consultant for the PI Feasibility study for 4C Medical. Dr Kaneko has served as a consultant for Edwards Lifesciences, Medtronic, and Abbott Structural. Dr Wood has served as a consultant to and his institution (CCI-CIC) receives grant support from Edwards Lifesciences, Abbott Vascular, and Medtronic. Dr Gillam has served as a consultant to Philips and Bracco; is an advisory board member for Edwards Lifesciences; and has core lab contracts with Edwards Lifesciences, Medtronic, and Abbott for which she receives no direct compensation. Dr Reardon has served as a consultant for Medtronic, Boston Scientific, Abbott Medical, and Gore Medical; all fees for such are to his department. Dr Rodes-Cabau has received institutional research grants from Edwards Lifesciences, Medtronic, and Boston Scientific. Dr Thourani has performed consulting/research for Abbott Vascular, Boston Scientific, Cryolife, Edwards Lifesciences, Medtronic, and Shockwave. Dr Bax’s institution (Department of Cardiology, LUMC, the Netherlands) has received research grants from Medtronic, Biotronik, Edwards Lifesciences, and Boston Scientific. Dr Mack has served as a co-principal investigator for clinical trials for Abbott and Edwards Lifesciences; and has served as study chair for a trial for Medtronic; all roles were uncompensated. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Despite numerous promising therapeutic targets, there are no proven medical treatments for calcific aortic stenosis (AS). Multiple stakeholders need to come together and several scientific, operational, and trial design challenges must be addressed to capitalize on the recent and emerging mechanistic insights into this prevalent heart valve disease. This review briefly discusses the pathobiology and most promising pharmacologic targets, screening, diagnosis and progression of AS, identification of subgroups that should be targeted in clinical trials, and the need to elicit the patient voice earlier rather than later in clinical trial design and implementation. Potential trial end points and tools for assessment and approaches to implementation and design of clinical trials are reviewed. The efficiencies and advantages offered by a clinical trial network and platform trial approach are highlighted. The objective is to provide practical guidance that will facilitate a series of trials to identify effective medical therapies for AS resulting in expansion of therapeutic options to complement mechanical solutions for late-stage disease., Competing Interests: Funding Support and Author Disclosures Dr Lindman has served on the scientific advisory board for Roche Diagnostics; and has received research grants from Edwards Lifesciences and Roche Diagnostics. Dr Madhavan has received support from an institutional grant by the National Institutes of Health/National Heart, Lung, and Blood Institute to Columbia University Irving Medical Center (grant T32 HL007854). Dr Arsenault has received investigator-initiated research contracts from Pfizer and Ionis Pharmaceuticals; and has served as a consultant for Novartis and Silence Therapeutics. Dr Coylewright has received research grants from Edwards Lifesciences and Boston Scientific; and has served on consulting/advisory boards for Abbott, Medtronic, and Alleviant. Dr Merryman has received support from the National Institutes of Health (grant R35-HL135790) and Fondation Leducq. Dr Harrell has received support from the Clinical and Translational Science Awards (award UL1 TR002243) from the National Center for Advancing Translational Sciences. Dr Mack has served as coprimary investigator for the PARTNER trial for Edwards Lifesciences and the COAPT trial for Abbott; and has served as study chair for the APOLLO trial for Medtronic. Dr Leon has received institutional research support from Edwards Lifesciences, Medtronic, Boston Scientific, and Abbott; and has served on consulting/advisory boards for Medtronic, Boston Scientific, Gore, Meril Lifescience, and Abbott. Dr Pibarot has received research grants from Edwards Lifesciences and Medtronic for echo core lab analyses in transcatheter aortic valve replacement. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Cardiovascular magnetic resonance (CMR) is increasingly used for risk stratification in aortic stenosis (AS). However, the relative prognostic power of CMR markers and their respective thresholds remains undefined., Objectives: Using machine learning, the study aimed to identify prognostically important CMR markers in AS and their thresholds of mortality., Methods: Patients with severe AS undergoing AVR (n = 440, derivation; n = 359, validation cohort) were prospectively enrolled across 13 international sites (median 3.8 years' follow-up). CMR was performed shortly before surgical or transcatheter AVR. A random survival forest model was built using 29 variables (13 CMR) with post-AVR death as the outcome., Results: There were 52 deaths in the derivation cohort and 51 deaths in the validation cohort. The 4 most predictive CMR markers were extracellular volume fraction, late gadolinium enhancement, indexed left ventricular end-diastolic volume (LVEDVi), and right ventricular ejection fraction. Across the whole cohort and in asymptomatic patients, risk-adjusted predicted mortality increased strongly once extracellular volume fraction exceeded 27%, while late gadolinium enhancement >2% showed persistent high risk. Increased mortality was also observed with both large (LVEDVi >80 mL/m 2 ) and small (LVEDVi ≤55 mL/m 2 ) ventricles, and with high (>80%) and low (≤50%) right ventricular ejection fraction. The predictability was improved when these 4 markers were added to clinical factors (3-year C-index: 0.778 vs 0.739). The prognostic thresholds and risk stratification by CMR variables were reproduced in the validation cohort., Conclusions: Machine learning identified myocardial fibrosis and biventricular remodeling markers as the top predictors of survival in AS and highlighted their nonlinear association with mortality. These markers may have potential in optimizing the decision of AVR., Competing Interests: Funding Support and Author Disclosures The work was supported by a National Research Foundation of Korea grant funded by the Korea government (Ministry of Science and ICT; No. 2019R1A2C2084099) and a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number HI18C2383). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)

Background: The study investigators previously reported that moderate aortic stenosis (AS) is associated with a poor prognosis in patients with heart failure (HF) with reduced left ventricular ejection fraction (LVEF) (HFrEF). However, the respective contribution of moderate AS versus HFrEF to the outcomes of these patients is unknown., Objectives: This study sought to determine the impact of moderate AS on outcomes in patients with HFrEF., Methods: The study included 262 patients with moderate AS (aortic valve area >1.0 and <1.5 cm 2 ; and peak aortic jet velocity >2 and <4 m/s, at rest or after dobutamine stress echocardiography) and HFrEF (LVEF <50%). These patients were matched 1:1 for sex, age, estimated glomerular filtration rate, New York Heart Association functional class III to IV, presence of diabetes, LVEF, and body mass index with patients with HFrEF but no AS (i.e., peak aortic jet velocity <2 m/s). The endpoints were all-cause mortality and the composite of death and HF hospitalization., Results: A total of 262 patients with HFrEF and moderate AS were matched with 262 patients with HFrEF and no AS. Mean follow-up was 2.9 ± 2.2 years. In the moderate AS group, mean aortic valve area was 1.2 ± 0.2 cm 2 , and mean gradient was 14.5 ± 4.7 mm Hg. Moderate AS was associated with an increased risk of mortality (hazard ratio [HR]: 2.98; 95% confidence interval [CI]: 2.08 to 4.31; p < 0.0001) and of the composite of HF hospitalization and mortality (HR: 2.34; 95% CI: 1. 72 to 3.21; p < 0.0001). In the moderate AS group, aortic valve replacement (AVR) performed in 44 patients at a median follow-up time of 10.9 ± 16 months during follow-up was associated with improved survival (HR: 0.59; 95% CI: 0.35 to 0.98; p = 0.04). Notably, surgical AVR was not significantly associated with improved survival (p = 0.92), whereas transcatheter AVR was (HR: 0.43; 95% CI: 0.18 to 1.00; p = 0.05)., Conclusions: In this series of patients with HFrEF, moderate AS was associated with a marked incremental risk of mortality. AVR, and especially transcatheter AVR during follow-up, was associated with improved survival in patients with HFrEF and moderate AS. These findings provide support to the realization of a randomized trial to assess the effect of early transcatheter AVR in patients with HFrEF and moderate AS., Competing Interests: Funding Support and Author Disclosures The Department of Cardiology of the Erasmus Medical Center Rotterdam has received research grants from Claret Medical, Boston Scientific, Medtronic, and Edwards Lifesciences. The Department of Cardiology of the Leiden University Medical Center has received research grants from Medtronic, Biotronik, Edwards Lifesciences, and Boston Scientific. Dr. Delgado has received speaker fees from Abbott Vascular. Dr. Pibarot has received research grants from Edwards Lifesciences; and has echocardiography core laboratory research contracts with Edwards Lifesciences and Medtronic. Dr. Van Mieghem has received research grants from Claret Medical, Boston Scientific, Medtronic, and Edwards Lifesciences. Dr. Clavel has a computed tomography core laboratory research contract with Edwards Lifesciences; and has received a research grant from Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: In low surgical risk patients with symptomatic severe aortic stenosis, the PARTNER 3 (Safety and Effectiveness of the SAPIEN 3 Transcatheter Heart Valve in Low Risk Patients With Aortic Stenosis) trial demonstrated superiority of transcatheter aortic valve replacement (TAVR) versus surgery for the primary endpoint of death, stroke, or re-hospitalization at 1 year., Objectives: This study determined both clinical and echocardiographic outcomes between 1 and 2 years in the PARTNER 3 trial., Methods: This study randomly assigned 1,000 patients (1:1) to transfemoral TAVR with the SAPIEN 3 valve versus surgery (mean Society of Thoracic Surgeons score: 1.9%; mean age: 73 years) with clinical and echocardiography follow-up at 30 days and at 1 and 2 years. This study assessed 2-year rates of the primary endpoint and several secondary endpoints (clinical, echocardiography, and quality-of-life measures) in this as-treated analysis., Results: Primary endpoint follow-up at 2 years was available in 96.5% of patients. The 2-year primary endpoint was significantly reduced after TAVR versus surgery (11.5% vs. 17.4%; hazard ratio: 0.63; 95% confidence interval: 0.45 to 0.88; p = 0.007). Differences in death and stroke favoring TAVR at 1 year were not statistically significant at 2 years (death: TAVR 2.4% vs. surgery 3.2%; p = 0.47; stroke: TAVR 2.4% vs. surgery 3.6%; p = 0.28). Valve thrombosis at 2 years was increased after TAVR (2.6%; 13 events) compared with surgery (0.7%; 3 events; p = 0.02). Disease-specific health status continued to be better after TAVR versus surgery through 2 years. Echocardiographic findings, including hemodynamic valve deterioration and bioprosthetic valve failure, were similar for TAVR and surgery at 2 years., Conclusions: At 2 years, the primary endpoint remained significantly lower with TAVR versus surgery, but initial differences in death and stroke favoring TAVR were diminished and patients who underwent TAVR had increased valve thrombosis. (Safety and Effectiveness of the SAPIEN 3 Transcatheter Heart Valve in Low Risk Patients With Aortic Stenosis [PARTNER 3]; NCT02675114)., Competing Interests: Funding Support and Author Disclosures The PARTNER 3 Trial was funded by Edwards Lifesciences. Dr. Leon has received grant support, paid to his institution, from Edwards Lifesciences, Medtronic, Abbott, and Boston Scientific; and has received advisory board fees from Medtronic, Abbott, Boston Scientific, Gore, and Meril Life Sciences. Dr. Mack has received consulting fees from Gore; has served as a trial coprimary investigator for Edwards Lifesciences and Abbott; and has served as a study chair for Medtronic. Dr. Hahn has received consulting fees from Abbott Vascular, Siemens Healthineers, Boston Scientific, Bayliss, Edwards Lifesciences, Philips Healthcare, 3Mensio, Medtronic, and Navigate. Dr. Thourani has received grant support and has served as an advisor for Edwards Lifesciences. Dr. Makkar has received grant support from Abbott and Edwards Lifesciences. Dr. Kodali holds equity in BioTrace Medical, Dura Biotech, and Thubrikar Aortic Valve; has received grant support from Medtronic and Boston Scientific; has received grant support and consulting fees from Abbott Vascular; and has received consulting fees from Claret Medical, Admedus, and Meril Life Sciences. Ms. Alu has received research funding, paid to her institution, from Edwards Lifesciences and Abbott. Dr. Russo has received consulting fees, lecture fees, and fees for serving as a proctor from Edwards Lifesciences; has received consulting fees and fees for serving as a proctor from Abbott; and has received consulting fees from Boston Scientific. Dr. Malaisrie has received consulting fees from Medtronic; and has received lecture fees from Abbott. Dr. Cohen has received grant support, paid to his institution, from Edwards Lifesciences, Medtronic, Boston Scientific, and Abbott Vascular; and has received consulting fees from Edwards Lifesciences and Medtronic. Dr. Blanke has received consulting fees from Edwards Lifesciences, Tendyne (Abbott), Circle Cardiovascular Imaging, Neovasc, and Gore. Dr. Leipsic has received grant support from Abbott and Medtronic; and has received consulting fees and holds stock options from Circle Cardiovascular Imaging. Dr. McCabe has received consulting fees from Edwards Lifesciences. Dr. Babaliaros has received lecture fees and consulting fees from Edwards Lifesciences and Abbott. Dr. Goldman has received advisory board fees from Edwards Lifesciences. Dr. Szeto has received lecture fees and has served as an investigator for Edwards Lifesciences. Dr. Genereux has received consulting fees and advisory board fees from Abbott Vascular, Boston Scientific, Cardiovascular Solutions, and Cordis; has received consulting fees and fees for serving as a proctor from Edwards Lifesciences; and has received consulting fees from Medtronic, Saranas, Pi-Cardia, and Sig.Num. Dr. Webb has received consulting fees and fees for serving as a proctor from Edwards Lifesciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Few studies have evaluated if diastolic function could predict outcomes in patients with aortic stenosis., Objectives: The authors aimed to assess the association between diastolic dysfunction (DD) and outcomes in patients with aortic stenosis undergoing transcatheter aortic valve replacement (TAVR)., Methods: Baseline, 30-day, and 1- and 2-year transthoracic echocardiograms from the PARTNER (Placement of Aortic Transcatheter Valves) 2 SAPIEN 3 registry were analyzed by a consortium of core laboratories and divided into the American Society of Echocardiography DD groups., Results: Among the 1,750 included, 682 (54.4%) had grade 1 DD, 352 (28.1%) had grade 2 DD, 168 (13.4%) had grade 3 DD, and 51 (4.1%) had indeterminate DD grade. Incremental baseline grades of DD were associated with an increase in combined 1- and 2-year cardiovascular (CV) death/rehospitalization (all p < 0.002) and all-cause death at 2 years (p = 0.01) but not at 1 year. Improvement in DD grade/grade 1 DD at 30 days post-TAVR was seen in 70.8% patients. Patients with improvement in ≥1 grade of DD/grade 1 DD had reduced 1-year CV death/rehospitalization (p < 0.001) and increased 2-year survival (p = 0.01). Baseline grade 3 DD was a predictor of 1-year CV death/rehospitalization (hazard ratio: 2.73; 95% confidence interval: 1.07 to 6.98; p = 0.04). Improvement in DD grade/grade 1 DD at 30 days was protective for 1-year CV death/rehospitalizations (hazard ratio: 0.39; 95% confidence interval: 0.19 to 0.83; p = 0.01)., Conclusions: In the PARTNER 2 SAPIEN 3 registry, baseline DD was a predictor of up to 2 years clinical outcomes in patients who underwent TAVR. Improvement in DD grade at 30 days was associated with improvement in short-term clinical outcomes. (The PARTNER II Trial: Placement of AoRTic TraNscathetER Valves II - PARTNER II - PARTNERII - S3 Intermediate [PARTNERII S3i]; NCT03222128; PARTNER II Trial: Placement of AoRTic TraNscathetER Valves II - High Risk and Nested Registry 7 [PII S3HR/NR7]; NCT03222141)., Competing Interests: Author Disclosures The PARTNER 2 trial was funded by Edwards Lifesciences. Drs. Pibarot, Weissman, Jaber, Douglas, and Hahn have echocardiographic core laboratory contracts with Edwards Lifesciences (no direct financial compensation). Dr. Makkar has received grant funding from Edwards Lifesciences and St. Jude Medical; and has received consulting fees/honoraria from Abbott Vascular, Cordis Corporation, and Medtronic. Dr. Kodali has received consulting fees/honoraria from Abbott Vascular, Merrill Lifesciences, and Claret Medical; and has served on the Scientific Advisory Boards of Thubrikar Aortic Valve Inc., Dura Biotech, and Biotrace Medical. Dr. Thourani serves on Advisory Boards for Edwards Lifesciences, Abbott Vascular, Gore Vascular, Bard Medical, JenaValve, and Boston Scientific. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: It is unknown whether transcatheter valves will have similar durability as surgical bioprosthetic valves. Definitions of structural valve deterioration (SVD), based on valve related reintervention or death, underestimate the incidence of SVD., Objectives: This study sought to determine and compare the 5-year incidence of SVD, using new standardized definitions based on echocardiographic follow-up of valve function, in intermediate-risk patients with severe aortic stenosis given transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (SAVR) in the PARTNER (Placement of Aortic Transcatheter Valves) 2A trial and registry., Methods: In the PARTNER 2A trial, patients were randomly assigned to receive either TAVR with the SAPIEN XT or SAVR, whereas in the SAPIEN 3 registry, patients were assigned to TAVR with the SAPIEN 3. The primary endpoint was the incidence of SVD, that is, the composite of SVD-related hemodynamic valve deterioration during echocardiographic follow-up and/or SVD-related bioprosthetic valve failure (BVF) at 5 years., Results: Compared with SAVR, the SAPIEN-XT TAVR cohort had a significantly higher 5-year exposure adjusted incidence rates (per 100 patient-years) of SVD (1.61 ± 0.24% vs. 0.63 ± 0.16%), SVD-related BVF (0.58 ± 0.14% vs. 0.12 ± 0.07%), and all-cause (structural or nonstructural) BVF (0.81 ± 0.16% vs. 0.27 ± 0.10%) (p ≤ 0.01 for all). The 5-year rates of SVD (0.68 ± 0.18% vs. 0.60 ± 0.17%; p = 0.71), SVD-related BVF (0.29 ± 0.12% vs. 0.14 ± 0.08%; p = 0.25), and all-cause BVF (0.60 ± 0.15% vs. 0.32 ± 0.11%; p = 0.32) in SAPIEN 3 TAVR were not significantly different to a propensity score matched SAVR cohort. The 5-year rates of SVD and SVD-related BVF were significantly lower in SAPIEN 3 versus SAPIEN XT TAVR matched cohorts., Conclusions: Compared with SAVR, the second-generation SAPIEN XT balloon-expandable valve has a higher 5-year rate of SVD, whereas the third-generation SAPIEN 3 has a rate of SVD that was not different from SAVR. (The PARTNER II Trial: Placement of AoRTic TraNscathetER Valves - PII A [PARTNERII A]; NCT01314313; The PARTNER II Trial: Placement of AoRTic TraNscathetER Valves II - PARTNER II - PARTNERII - S3 Intermediate [PARTNERII S3i]; NCT03222128)., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The prognostic value of aortic valve calcification (AVC) measured by using multidetector computed tomography imaging has been well validated in native aortic stenosis, and sex-specific thresholds have been proposed. However, few data are available regarding the impact of leaflet calcification on outcomes after biological aortic valve replacement (AVR)., Objectives: The goal of this study was to analyze the association of quantitative bioprosthetic leaflet AVC with hemodynamic and clinical outcomes, as well as its possible interaction with sex., Methods: From 2008 to 2010, a total of 204 patients were prospectively enrolled with a median of 7.0 years (interquartile range: 5.1 to 9.2 years) after biological surgical AVR. AVC measured by using the Agatston method was indexed to the cross-sectional area of aortic annulus measured by echocardiography to calculate the AVC density (AVCd). Presence of hemodynamic valve deterioration (HVD; increase in mean gradient [MG] ≥10 mm Hg and/or increase in transprosthetic regurgitation ≥1) was assessed by echocardiography in 137 patients at the 3-year follow-up. The primary clinical endpoint was mortality or aortic valve re-intervention., Results: There was no significant sex-related difference in the relationship between bioprosthetic AVCd and the progression of MG. Baseline AVCd showed an independent association with HVD at 3 years. During follow-up, there were 134 (65.7%) deaths (n = 100) or valve re-interventions (n = 47). AVCd ≥58 AU/cm 2 was independently associated with an increased risk of mortality or aortic valve re-intervention (adjusted hazard ratio: 2.23; 95% confidence interval: 1.44 to 3.35; p < 0.001). The AVCd threshold combined with an MG progression threshold of 10 mm Hg amplified the stratification of patients at risk (log-rank, p < 0.001). The addition of AVCd threshold into the prediction model including traditional risk factors improved outcome prediction (net classification improvement: 0.25, p = 0.04; likelihood ratio test, p < 0.001)., Conclusions: Aortic bioprosthetic leaflet calcification is strongly and independently associated with HVD and the risk of death or aortic valve re-intervention. As opposed to native aortic stenosis, there is no sex-related differences in the relationship between AVCd and hemodynamic or clinical outcomes., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Greater early left ventricular mass index (LVMi) regression is associated with fewer hospitalizations 1 year after transcatheter aortic valve replacement (TAVR). The association between LVMi regression and longer-term post-TAVR outcomes is unclear., Objectives: The purpose of this study was to determine the association between LVMi regression at 1-year post-TAVR and clinical outcomes between 1 and 5 years., Methods: Among intermediate- and high-risk patients who received TAVR in the PARTNER (Placement of Aortic Transcatheter Valves) I, II, and S3 trials or registries and were alive at 1 year, we included patients with baseline moderate or severe left ventricular hypertrophy (LVH) and paired measurements of LVMi at baseline and 1 year. The associations between LVMi regression (percent change between baseline and 1 year) and death or rehospitalization from 1 to 5 years were examined., Results: Among 1,434 patients, LVMi was 146 g/m 2 (interquartile range [IQR]: 133 to 168 g/m 2 ) at baseline and decreased 14.5% (IQR: 4.2% to 26.1%) to 126 g/m 2 (IQR: 106 to 148 g/m 2 ) at 1 year. After adjustment, greater LVMi regression at 1 year was associated with lower all-cause death (adjusted hazard ratio [aHR]: 0.95 per 10% decrease in LVMi; 95% confidence interval [CI]: 0.91 to 0.98; p = 0.004; aHR of the quartile with greatest vs. least LVMi regression: 0.61; 95% CI: 0.43 to 0.86; p = 0.005). Severe LVH at 1 year was observed in 39%, which was independently associated with increased all-cause death (aHR of severe LVH vs. no LVH: 1.71; 95% CI: 1.20 to 2.44; p = 0.003). Similar associations were found for rates of cardiovascular mortality and rehospitalization., Conclusions: Among patients with moderate or severe LVH treated with TAVR who are alive at 1 year, greater LVMi regression at 1 year is associated with lower death and hospitalization rates to 5 years. These findings may have implications for the timing of valve replacement and the role of adjunctive medical therapy after TAVR., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The respective impacts of transvalvular flow, gradient, sex, and their interactions on mortality in patients with severe aortic stenosis undergoing surgical aortic valve replacement (AVR) are unknown., Objectives: This study sought to compare the impact of pre-operative flow-gradient patterns on mortality after AVR and to examine whether there are sex differences., Methods: This study analyzed clinical, echocardiographic, and outcome data prospectively collected in 1,490 patients (544 women [37%]), with severe aortic stenosis and preserved left ventricular ejection fraction who underwent AVR., Results: In this cohort, 601 patients (40%) had normal flow (NF) with high gradient (HG), 405 (27%) NF with low gradient (LG), 246 (17%) paradoxical low flow (LF)/HG, and 238 (16%) LF/LG. During a median follow-up of 2.42 years (interquartile range: 1.04 to 4.29 years), 167 patients died. Patients with LF/HG exhibited the highest mortality after AVR (hazard ratio [HR]: 2.01; 95% confidence interval [CI]: 1.33 to 3.03; p < 0.01), which remained significant after multivariate adjustment (HR: 1.96; 95% CI: 1.29 to 2.98; p < 0.01). Both LF/LG and NF/LG patients had comparable outcome to NF/HG (p ≥ 0.47). Optimal thresholds of stroke volume index were obtained for men (40 ml/m 2 ) and women (32 ml/m 2 ). Using these sex-specific cutpoints, paradoxical LF was independently associated with increased mortality in both women (adjusted HR: 2.05; 95% CI: 1.21 to 3.47; p < 0.01) and men (adjusted HR: 1.54; 95% CI: 1.02 to 2.32; p = 0.042), whereas guidelines' threshold (35 ml/m 2 ) does not., Conclusions: Paradoxical LF/HG was associated with higher mortality following AVR, suggesting that a reduced flow is a marker of disease severity even in patients with HG aortic stenosis. Early surgical AVR (i.e., before gradient attains 40 mm Hg) might be preferable in these patients. Furthermore, the use of sex-specific thresholds (<40 ml/m 2 for men and <32 ml/m 2 for women) to define low-flow outperforms the guidelines' threshold of 35 ml/m 2 in risk stratification after AVR., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Aortic valve area (AVA) ≤1.0 cm 2 is a defining characteristic of severe aortic stenosis (AS). AVA can be underestimated at low transvalvular flow rate. Yet, the impact of flow rate on prognostic value of AVA ≤1.0 cm 2 is unknown and is not incorporated into AS assessment., Objectives: This study aimed to evaluate the effect of flow rate on prognostic value of AVA in AS., Methods: In total, 1,131 patients with moderate or severe AS and complete clinical follow-up were included as part of a longitudinal database. The effect of flow rate (ratio of stroke volume to ejection time) on prognostic value of AVA ≤1.0 cm 2 for time to death was evaluated, adjusting for confounders. Sensitivity analysis was performed to identify the optimal cutoff for prognostic threshold of AVA. The findings were validated in a separate external longitudinal cohort of 939 patients., Results: Flow rate had a significant effect on prognostic value of AVA. AVA ≤1.0 cm 2 was not prognostic for mortality (p = 0.15) if AVA was measured at flow rates below median (≤242 ml/s). In contrast, AVA ≤1.0 cm 2 was highly prognostic for mortality (p = 0.003) if AVA was measured at flow rates above median (>242 ml/s). Findings were irrespective of multivariable adjustment for age, sex, and surgical/transcatheter aortic valve replacement (as time-dependent covariates); comorbidities; medications; and echocardiographic features. AVA ≤1.0 cm 2 was also not an independent predictor of mortality below median flow rate in the validation cohort. The optimal flow rate cutoff for prognostic threshold was 210 ml/s., Conclusions: Transvalvular flow rate determines prognostic value of AVA in AS. AVA measured at low flow rate is not a good prognostic marker and therefore not a good diagnostic marker for truly severe AS. Flow rate assessment should be incorporated into clinical diagnosis, classification, and prognosis of AS., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: N-terminal pro-B-type natriuretic peptide (NT-proBNP) may reflect early prognosis in patients with valvular heart disease (VHD)., Objectives: The aim of this study was to examine the association between NT-proBNP and mortality in elderly patients with VHD., Methods: A total of 5,983 elderly patients (age ≥60 years) with moderate or severe VHD underwent echocardiography and NT-proBNP measurement. VHD examined included aortic stenosis, aortic regurgitation, mitral stenosis, mitral regurgitation, tricuspid regurgitation, and multivalvular heart disease. NT-proBNP ratio was defined as measured NT-proBNP relative to the maximal normal values specific to age and sex. Disease-specific thresholds were defined on the basis of penalized splines and maximally selected rank statistics., Results: The cohort had a mean age of 71.1 ± 7.6 years. At 1-year follow-up, 561 deaths (9.4%) had occurred. In penalized splines, relative hazards showed a monotonic increase with greater NT-proBNP ratio for death with different VHDs (p < 0.001 for all) except mitral stenosis. Higher NT-proBNP ratio, categorized by disease-specific thresholds, was independently associated with mortality (overall adjusted hazard ratio: 1.99; 95% confidence interval: 1.76 to 2.24; p < 0.001). Different subtypes of VHD all incurred excess mortality with elevated NT-proBNP ratio, with the strongest association detected for aortic stenosis (adjusted hazard ratio: 10.5; 95% confidence interval: 3.9 to 28.27; p < 0.001). The addition of NT-proBNP ratio to the prediction algorithm including traditional risk factors improved outcome prediction (overall net reclassification index = 0.28; 95% CI: 0.24 to 0.34; p < 0.001; likelihood ratio test p < 0.001). Results remained consistent in patients under medical care, with normal left ventricular ejection fractions, and with primary VHD., Conclusions: NT-proBNP provides incremental prognostic information for mortality in various VHDs. It could aid in risk stratification as a pragmatic and versatile biomarker in elderly patients., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Mitral leaflet enlargement has been identified as an adaptive mechanism to prevent mitral regurgitation in dilated left ventricles (LVs) caused by chronic aortic regurgitation (AR). This enlargement is deficient in patients with functional mitral regurgitation, which remains frequent in the population with ischemic cardiomyopathy. Maladaptive fibrotic changes have been identified in post-myocardial infarction (MI) mitral valves. It is unknown if these changes can interfere with valve growth and whether they are present in other valves., Objectives: This study sought to test the hypothesis that MI impairs leaflet growth, seen in AR, and induces fibrotic changes in mitral and tricuspid valves., Methods: Sheep models of AR, AR + MI, and controls were followed for 90 days. Cardiac magnetic resonance, echocardiography, and computed tomography were performed at baseline and 90 days to assess LV volume, LV function, mitral regurgitation and mitral leaflet size. Histopathology and molecular analyses were performed in excised valves., Results: Both experimental groups developed similar LV dilatation and dysfunction. At 90 days, mitral valve leaflet size was smaller in the AR + MI group (12.8 ± 1.3 cm 2 vs. 15.1 ± 1.6 cm 2 , p = 0.03). Mitral regurgitant fraction was 4% ± 7% in the AR group versus 19% ± 10% in the AR + MI group (p = 0.02). AR + MI leaflets were thicker compared with AR and control valves. Increased expression of extracellular matrix remodeling genes was found in both the mitral and tricuspid leaflets in the AR + MI group., Conclusions: In these animal models of AR, the presence of MI was associated with impaired adaptive valve growth and more functional mitral regurgitation, despite similar LV size and function. More pronounced extracellular remodeling was observed in mitral and tricuspid leaflets, suggesting systemic valvular remodeling after MI., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Myocardial fibrosis is a key mechanism of left ventricular decompensation in aortic stenosis and can be quantified using cardiovascular magnetic resonance (CMR) measures such as extracellular volume fraction (ECV%). Outcomes following aortic valve intervention may be linked to the presence and extent of myocardial fibrosis., Objectives: This study sought to determine associations between ECV% and markers of left ventricular decompensation and post-intervention clinical outcomes., Methods: Patients with severe aortic stenosis underwent CMR, including ECV% quantification using modified Look-Locker inversion recovery-based T1 mapping and late gadolinium enhancement before aortic valve intervention. A central core laboratory quantified CMR parameters., Results: Four-hundred forty patients (age 70 ± 10 years, 59% male) from 10 international centers underwent CMR a median of 15 days (IQR: 4 to 58 days) before aortic valve intervention. ECV% did not vary by scanner manufacturer, magnetic field strength, or T1 mapping sequence (all p > 0.20). ECV% correlated with markers of left ventricular decompensation including left ventricular mass, left atrial volume, New York Heart Association functional class III/IV, late gadolinium enhancement, and lower left ventricular ejection fraction (p < 0.05 for all), the latter 2 associations being independent of all other clinical variables (p = 0.035 and p < 0.001). After a median of 3.8 years (IQR: 2.8 to 4.6 years) of follow-up, 52 patients had died, 14 from adjudicated cardiovascular causes. A progressive increase in all-cause mortality was seen across tertiles of ECV% (17.3, 31.6, and 52.7 deaths per 1,000 patient-years; log-rank test; p = 0.009). Not only was ECV% associated with cardiovascular mortality (p = 0.003), but it was also independently associated with all-cause mortality following adjustment for age, sex, ejection fraction, and late gadolinium enhancement (hazard ratio per percent increase in ECV%: 1.10; 95% confidence interval [1.02 to 1.19]; p = 0.013)., Conclusions: In patients with severe aortic stenosis scheduled for aortic valve intervention, an increased ECV% is a measure of left ventricular decompensation and a powerful independent predictor of mortality., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The prevalence of calcific aortic stenosis (AS) and of cardiac amyloidosis (CA) increases with age, and their association is not uncommon in the elderly. The identification of CA is particularly challenging in patients with AS because these 2 conditions share several features. It is estimated that ≤15% of the AS population and ≤30% of the subset with low-flow, low-gradient pattern may have CA. In patients with AS, CA is associated with increased risk of heart failure, mortality, and treatment futility with aortic valve replacement. In case of suspicion of CA, it is thus crucial to confirm the diagnosis to guide therapeutic management of AS and eventually implement recently developed pharmacological treatment dedicated to transthyretin amyloidosis. Given the high surgical risk of patients with AS and concomitant CA, transcatheter aortic valve replacement may be preferred to surgery in these patients., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Several studies have demonstrated the benefits of transcatheter aortic valve replacement (TAVR) in patients with aortic stenosis, but the presence of persistent fibrosis and myocardial hypertrophy has been related to worse prognosis., Objectives: The aim of this study was to explore the potential benefits of renin-angiotensin system (RAS) inhibitors on left ventricular remodeling and major clinical outcomes following successful transcatheter aortic valve replacement (TAVR)., Methods: Patients from 10 institutions with severe aortic stenosis who underwent TAVR between August 2007 and August 2017 were included. All baseline data were prospectively recorded, and pre-specified follow-up was performed. Doses and types of RAS inhibitors at discharge were recorded, and matched comparison according to their prescription at discharge was performed., Results: A total of 2,785 patients were included. Patients treated with RAS inhibitors (n = 1,622) presented similar surgical risk scores but a higher rate of all cardiovascular risk factors, coronary disease, and myocardial infarction. After adjustment for these baseline differences, reduction of left ventricular volumes and hypertrophy was greater and cardiovascular mortality at 3-year follow-up was lower (odds ratio: 0.59; 95% confidence interval: 0.41 to 0.87; p = 0.007) in patients treated with RAS inhibitors. Moreover, RAS inhibitors demonstrated a global cardiovascular protective effect with significantly lower rates of new-onset atrial fibrillation, cerebrovascular events, and readmissions., Conclusions: Post-TAVR RAS inhibitors are associated with lower cardiac mortality at 3-year follow-up and offer a global cardiovascular protective effect that might be partially explained by a positive left ventricular remodeling. An ongoing randomized trial will help confirm these hypothesis-generating findings. (Renin-Angiotensin System Blockade Benefits in Clinical Evolution and Ventricular Remodeling After Transcatheter Aortic Valve Implantation [RASTAVI]; NCT03201185)., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The optimal timing of intervention in patients with asymptomatic severe aortic stenosis (AS) remains controversial., Objectives: This multicenter study sought to test and validate the prognostic value of the staging of cardiac damage in patients with asymptomatic moderate to severe AS., Methods: This study retrospectively analyzed the clinical, Doppler echocardiographic, and outcome data that were prospectively collected in 735 asymptomatic patients (71 ± 14 years of age; 60% men) with at least moderate AS (aortic valve area <1.5 cm 2 ) and preserved left ventricular ejection fraction (≥50%) followed in the heart valve clinics of 4 high-volume centers. Patients were classified according to the following staging classification: no cardiac damage associated with the valve stenosis (Stage 0), left ventricular damage (Stage 1), left atrial or mitral valve damage (Stage 2), pulmonary vasculature or tricuspid valve damage (Stage 3), or right ventricular damage or subclinical heart failure (Stage 4). The primary endpoint was all-cause mortality., Results: At baseline, 89 (12%) patients were classified in Stage 0, 200 (27%) in Stage 1, 341 (46%) in Stage 2, and 105 (14%) in Stage 3 or 4. Median follow-up was 2.6 years (interquartile range: 1.1 to 5.2 years). There was a stepwise increase in mortality rates according to staging: 13% in Stage 0, 25% in Stage 1, 44% in Stage 2, and 58% in Stages 3 to 4 (p < 0.0001). The staging was significantly associated with excess mortality in multivariable analysis adjusted for aortic valve replacement as a time-dependent variable (hazard ratio: 1.31 per each increase in stage; 95% CI: 1.06 to 1.61; p = 0.01), and showed incremental value to several clinical variables (net reclassification index = 0.34; p = 0.003)., Conclusions: The new staging system characterizing the extra-aortic valve cardiac damage provides incremental prognostic value in patients with asymptomatic moderate to severe AS. This staging classification may be helpful to identify asymptomatic AS patients who may benefit from elective aortic valve replacement., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: In severe aortic stenosis (AS), patients often show extra-aortic valvular injury. Recently, a new staging system for severe AS has been proposed on the basis of the extent of cardiac damage., Objectives: The present study evaluated the prevalence and prognostic impact of these different stages of cardiac damage in a large, real-world, multicenter cohort of symptomatic severe AS patients., Methods: From the ongoing registries from 2 academic institutions, a total of 1,189 symptomatic severe AS patients were selected and retrospectively analyzed. According to the extent of cardiac damage on echocardiography, patients were classified as Stage 0 (no cardiac damage), Stage 1 (left ventricular damage), Stage 2 (mitral valve or left atrial damage), Stage 3 (tricuspid valve or pulmonary artery vasculature damage), or Stage 4 (right ventricular damage). Patients were followed for all-cause mortality and combined endpoint (all-cause mortality, stroke, and cardiac-related hospitalization)., Results: On the basis of the proposed classification, 8% of patients were classified as Stage 0, 24% as Stage 1, 49% as Stage 2, 7% as Stage 3, and 12% as Stage 4. On multivariable analysis, cardiac damage was independently associated with all-cause mortality and combined outcome, although this was mainly determined by Stages 3 and 4., Conclusions: In this large multicenter cohort of symptomatic severe AS patients, stage of cardiac injury as classified by a novel staging system was independently associated with all-cause mortality and combined endpoint, although this seemed to be predominantly driven by tricuspid valve or pulmonary artery vasculature damage (Stage 3) and right ventricular dysfunction (Stage 4)., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Transcatheter aortic valve replacement (TAVR) for degenerated surgical bioprosthetic aortic valves is associated with favorable early outcomes. However, little is known about the durability and longer-term outcomes associated with this therapy., Objectives: The aim of this study was to examine late outcomes after valve-in-valve TAVR., Methods: Patients with symptomatic degeneration of surgical aortic bioprostheses at high risk (≥50% major morbidity or mortality) for reoperative surgery were prospectively enrolled in the multicenter PARTNER (Placement of Aortic Transcatheter Valves) 2 valve-in-valve and continued access registries. Three-year clinical and echocardiographic follow-up was obtained., Results: Valve-in-valve procedures were performed in 365 patients. The mean age was 78.9 ± 10.2 years, and the mean Society of Thoracic Surgeons score was 9.1 ± 4.7%. At 3 years, the overall Kaplan-Meier estimate of all-cause mortality was 32.7%. Aortic valve re-replacement was required in 1.9%. Mean transaortic gradient was 35.0 mm Hg at baseline, decreasing to 17.8 mm Hg at 30-day follow-up and 16.6 mm Hg at 3-year follow-up. Baseline effective orifice area was 0.93 cm 2 , increasing to 1.13 and 1.15 cm 2 at 30 days and 3 years, respectively. Moderate to severe aortic regurgitation was reduced from 45.1% at pre-TAVR baseline to 2.5% at 3 years. Importantly, moderate or severe mitral and tricuspid regurgitation also decreased (33.7% vs. 8.6% [p < 0.0001] and 29.7% vs. 18.8% [p = 0.002], respectively). Baseline left ventricular ejection fraction was 50.7%, increasing to 54.7% at 3 years (p < 0.0001), while left ventricular mass index was 136.4 g/m 2 , decreasing to 109.1 g/m 2 at 3 years (p < 0.0001). New York Heart Association functional class improved, with 90.4% in class III or IV at baseline and 14.1% at 3 years (p < 0.0001), and Kansas City Cardiomyopathy Questionnaire overall score increased (43.1 to 73.1; p < 0.0001)., Conclusions: At 3-year follow-up, TAVR for bioprosthetic aortic valve failure was associated with favorable survival, sustained improved hemodynamic status, and excellent functional and quality-of-life outcomes. (The PARTNER II Trial: Placement of Aortic Transcatheter Valves II - PARTNER II - Nested Registry 3/Valve-in-Valve [PII NR3/ViV]; NCT03225001)., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)