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Background: Pharmacological treatments for fibrocalcific aortic valve stenosis (FCAVS) have been elusive for >50 years. Here, we tested the hypothesis that reactivation of oxidized sGC (soluble guanylate cyclase), the primary receptor for nitric oxide, with ataciguat is a safe and efficacious strategy to slow progression of FCAVS., Methods: We used quantitative real-time reverse transcription polymerase chain reaction, Western blotting, and immunohistochemistry to characterize sGC signaling and the biological effects of ataciguat on signaling cascades related to nitric oxide, calcification, and fibrosis in excised human aortic valve tissue, aortic valve interstitial cells, and mouse aortic valves. We then conducted randomized, placebo-controlled phase I (14-day safety/tolerance) and phase II (6-month efficacy) trials in patients with moderate aortic valve stenosis., Results: In excised human tissue, we found robust losses in sGC signaling despite upregulation of sGC subunits. In vitro, ataciguat increased sGC signaling and reduced BMP2 (bone morphogenetic protein 2) signaling in aortic valve interstitial cells. In mice with established FCAVS, treatment with ataciguat attenuated BMP signaling and slowed progression of valve calcification and dysfunction. In a phase I, randomized, placebo-controlled trial, treatment with ataciguat for 2 weeks was safe and well tolerated in patients with moderate FCAVS (https://www.clinicaltrials.gov; Unique identifier: NCT02049203). In a separate phase II, randomized, placebo-controlled trial, treatment with ataciguat for 6 months slowed the progression of aortic valve calcification and tended to slow the progression of valvular and ventricular dysfunction in patients with moderate FCAVS (https://www.clinicaltrials.gov; Unique identifier: NCT02481258)., Conclusions: Collectively, this study highlights the therapeutic potential of the targeted restoration of the diseased/inactive form of sGC for treatment of FCAVS., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02049203. URL: https://www.clinicaltrials.gov; Unique identifier: NCT02481258.

Severe aortic valve regurgitation, if not timely treated, can significantly impact patients' survival both for tricuspid aortic valve and bicuspid aortic valve patients, with the latter being significantly younger. Increased understanding of the root anatomy and its physiology has opened the way to techniques of aortic valve repair surgery. The techniques mainly relate to re-establishing a correct root and annular geometry and eliminating leaflet prolapse. These techniques are applied both in the presence of a dilated and normal root and are equally valid for tricuspid or bicuspid valve. Techniques for repairing a bicuspid valve might vary depending on the different valve phenotypes. Medium and long-term results appear favourable and potentially superior to those of prosthetic replacement in terms of valve-related complications and quality of life. Optimal surgical treatment, especially in younger and selected patients, should aim to avoid aortic valve replacement and its related complications., (© The Author(s) 2025. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Bicuspid aortic valve (BAV) is the most common congenital heart defect in adults, often leading to complications such as thoracic aortic aneurysms and aortic stenosis. While BAV is frequently associated with 22q11.2 deletion syndrome (22q11.2DS), the contribution of rare copy number variants (CNVs) in this region to non-syndromic BAV is less clear. This study is aimed to assess the role of rare 22q11.2 CNVs in patients with early-onset BAV (EBAV) and to determine whether these variants are linked to an increased risk of complications., Methods: Whole genome microarray genotyping was conducted on 272 patients with BAV with early onset valve or aortic disease (EBAV) and 272 biological relatives. CNVs were detected using three independent algorithms, focusing on the 22q11.2 region (18-24 Mb). CNV burden in the EBAV cohort was compared with unselected European ancestry controls., Results: Rare duplications and deletions within the 22q11.2 region, particularly involving genes associated with cardiac development, were identified in 7.4% of EBAV probands. These CNVs were significantly enriched compared with the general population and segregated with BAV in families. Individuals carrying rare 22q11.2 CNVs had a higher prevalence of psychiatric diagnoses and learning difficulties, although they did not exhibit the typical features of 22q11.2DS. Importantly, these CNVs were associated with early onset or complex BAV cases, underscoring their potential clinical relevance., Conclusions: Rare 22q11.2 CNVs play a role in non-syndromic BAV, particularly in cases with early onset or complex presentations. CNV screening could be considered as part of risk stratification for patients with BAV, helping to predict complications and guide management., Trial Registration Number: NCT01823432., Competing Interests: Competing interests: The authors declare that they have no known competing financial interests or relationships that could have appeared to influence the work reported in this paper., (© Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Background: Echocardiographic evaluation of vegetations is crucial in infective endocarditis (IE). Although several studies have noted a link between larger vegetations and an increased risk of embolization, a more comprehensive evaluation of vegetation characteristics in a contemporary cohort has not been conducted. Our study aimed to define the short-term risk of symptomatic embolization in patients with IE., Methods and Results: The Mayo Clinic IE registry was screened to identify patients from 2015 to 2021 who had undergone transesophageal echocardiography. Multivariable subdistribution hazards regression analysis was used to identify factors associated with the cumulative incidence of symptomatic embolism over 30 days accounting for the competing risk of death. Overall, 779 patients with IE were included, of whom 517 (66.4%) were men, median age was 65.0 (interquartile range, 52.9-74.8) years, and 89.3% were White. In total, 234 patients had a symptomatic embolic event, a 30-day cumulative incidence of 30.2%. In multivariable analysis, a highly mobile vegetation was the strongest predictor of embolism ( P <0.001). Vegetation length with interaction of IE type was also associated with embolic risk ( P <0.001), with a stronger effect in native valve IE ( P interaction=0.001). Other associated factors included multiple vegetations, younger age, and Staphylococcus aureus . A nomogram that incorporated these factors was constructed to facilitate the prediction of embolic risk., Conclusions: Highly mobile, larger vegetations are associated with embolic events. Embolic risk could be assessed by evaluating length as a continuous variable, alongside other echocardiographic findings, using a newly developed scoring tool; external validation is warranted.

Background: Clinical features and outcomes in severe aortic stenosis (AS) have been described according to the hemodynamic phenotypes., Objectives: The aim of this study was to investigate the clinical features and prognosis of patients with high-gradient (HG) AS with aortic valve area (AVA) >1.0 cm 2 ., Methods: A total of 3,209 patients were identified according to AVA (cm 2 ), peak velocity (m/s), systolic mean pressure gradient (MG) (mm Hg): HG-AVA >1 = >1.0, ≥4, and ≥40, HG-AVA ≤1 = ≤1.0, ≥4, and ≥40; LG-AVA ≤1 (low-gradient) = ≤1.0, <4, and <40; moderate AS = 1.0 1 accounted for 230 individuals (7.2%). Compared with others, patients with HG-AVA >1 were younger (70.2 ± 12.0 years), more frequently male (85.7%), had fewer comorbidities, larger body surface area and stroke volume (115 ± 19.3 mL), and had higher prevalence of bicuspid valve (39.6%). After a follow-up of 944 days (Q1-Q3: 27-2,212 days), 1,523 deaths occurred. Compared with the HG-AVA >1 group, all-cause mortality was higher in HG-AVA ≤1 (HR: 1.4; 95% CI: 1.1-1.7), LG-AVA ≤1 (HR: 2.8; 95% CI: 2.2-3.6), and moderate AS (HR: 1.4; 95% CI: 1.1-1.7). These differences were no longer significant after adjustment for age, comorbidities, bicuspid valve, and cardiac function. In the HG-AVA >1 group, patients with aortic valve replacement had better survival outcomes than those without aortic valve replacement (P < 0.001) after balancing the 2 groups., Conclusions: The underlying relative high-flow status is responsible for HG in patients with HG-AVA >1. This profile has better prognosis than others, being related to underlying younger age and better general and cardiac conditions, but aortic valve replacement may still benefit these patients., Competing Interests: Funding Support and Author Disclosures Dr Oh is the director of the echocardiographic core laboratory for Medtronic trials and a consultant for Medtronic; and he has received a research grant from REDNVIA for the EVOID AS trial. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2025 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Importance: Secondary tricuspid regurgitation (STR) is observed in multiple cardiac and pulmonary diseases. Heart failure with preserved ejection fraction (HFpEF) is a common cause of STR that may be overlooked, along with precapillary etiologies of pulmonary hypertension (PH)., Objectives: To investigate the prevalence of HFpEF and precapillary PH in patients with severe STR of undefined etiology (isolated STR) referred for exercise right heart catheterization (RHC), and to evaluate the performance of noninvasive measures to identify HFpEF., Design, Setting, and Participants: This retrospective cross-sectional study included consecutive adults with severe STR in the absence of EF less than 50%, hemodynamically significant left-sided valve disease, congenital heart disease, infiltrative or hypertrophic cardiomyopathy, pericardial disease, or prior cardiac procedures who underwent rest-and-exercise RHC between February 2006 and June 2023 at Mayo Clinic and transthoracic echocardiography less than 90 days prior. Diastolic dysfunction (DD) was defined by at least 3 of 4 or 2 of 3 abnormal diastolic parameters (medial e', medial E/e', tricuspid regurgitation [TR] velocity, left atrial volume index). HFpEF was diagnosed when pulmonary arterial wedge pressure was at least 15 mm Hg at rest, at least 19 mm Hg with feet up, or at least 25 mm Hg during exercise. Data analysis was performed from November 2023 to March 2024., Main Outcomes and Measures: The prevalence of HFpEF and precapillary PH in severe isolated STR was determined, and performance of noninvasive measures to identify HFpEF was evaluated., Results: Overall, 54 patients with severe isolated STR (mean [SD] age, 70.8 [12.5] years; 34 [63%] female) were identified. The primary indication for RHC was evaluation of TR prior to potential intervention in 36 patients (67%), evaluation of PH in 13 (24%), and confirmation of HFpEF in 5 (9%). HFpEF was identified in 40 patients (74%) but was recognized prior to RHC in only 19 patients (35%). Of the 14 remaining patients without HFpEF, precapillary PH was diagnosed in 10 (71%). Guideline-defined DD was absent in 24 patients (60%) who were subsequently diagnosed with HFpEF. Left atrial emptying fraction (area under the receiver operating characteristic curve [AUC] = 0.90; 95% CI, 0.82-0.98) and strain (AUC = 0.91; 95% CI, 0.83-0.99) had robust discrimination for HFpEF., Conclusions and Relevance: The findings suggest that HFpEF is underdiagnosed and should be rigorously evaluated for in patients with severe isolated STR, along with precapillary PH, as both have distinct requirements for management. Resting DD based on current guidelines is insufficiently sensitive in these patients, indicating a pressing need for other noninvasive diagnostic tools, such as left atrial function assessment.

Background: The prevalence and impact of right ventricular dysfunction (RVD) in degenerative mitral regurgitation (DMR) is unknown. We aimed to determine whether RVD assessed by echocardiography in routine clinical practice is independently associated with mortality in patients with DMR., Methods and Results: We used data from the MIDA-Q (Mitral Regurgitation International DAtabase-Quantitative) registry, which included patients with isolated DMR due to mitral valve prolapse from January 2003 to January 2020 from 5 tertiary centers across North America, Europe, and the Middle East. A cohort of 2917 (mean age: 66 years, 70.8% male patients, follow-up: 5.2 [3.3-8.3] years) consecutive patients with severe DMR was included and long-term mortality was analyzed. RVD, identified in 426 (14.6%) patients, was associated with reduced 8-year survival (55%±3% versus 77%±1%; P <0.001), overall and in all subgroups of patients, even after comprehensive adjustment including left ventricular dilatation and dysfunction, DMR severity, pulmonary pressures, and surgery (adjusted hazard ratio, 1.44 [95% CI, 1.17-1.77]; P <0.001). This excess mortality was observed under medical management (adjusted hazard ratio, 1.57 [95% CI, 1.20-2.05]; P =0.001) and after surgical correction of mitral regurgitation (adjusted hazard ratio, 1.45 [95% CI, 1.02-2.05]; P =0.039). Patients with RVD undergoing surgery within 3 months of diagnosis experienced a better 8-year survival (73%±4% versus 43%±4%; P <0.001), even after adjustment (adjusted hazard ratio, 0.44 [95% CI, 0.29-0.67]; P <0.001) despite an increase of 1-month postoperative mortality (7.1% versus 0.5% for patients without RVD; P <0.001)., Conclusions: RVD is observed in 14.6% of severe DMR and exhibits a powerful and independent association with excess mortality partially attenuated by mitral surgery. Therefore, assessment of right ventricular systolic function should be included in routine DMR evaluation and in the clinical decision-making process.

Aims: Degenerative mitral stenosis (DMS) is due to degenerative mitral annular calcification (MAC) and valvular calcification. However, DMS impacts on the outcome, and therefore, potential treatment needs are poorly known. We aimed at evaluating survival after DMS diagnosis by Doppler echocardiography in routine practice., Methods and Results: A cohort of 2937 (75 ± 12 years, 67% women) consecutive patients were diagnosed between 2003 and 2014 with DMS (diastolic mean gradient ≥ 5 mmHg), with analysis of short- and long-term survival. All patients had overt mitral annular/valvular degenerative calcification without rheumatic involvement. Mean gradient was 6.5 ± 2.4 mmHg, and DMS was considered mild in 50%, moderate in 44%, and severe in 6%. DMS was associated with left atrial enlargement (52 ± 23 mL/m2) and elevated pulmonary pressure (49 ± 16 mmHg) despite generally normal ejection fraction (61 ± 13%). DMS was associated with frequent comorbid conditions (74% hypertension, 58% coronary disease, and 52% heart failure) and humoural alterations (haemoglobin 11.3 ± 1.8 g/dL and creatinine 1.5 ± 1.4 mg/dL). One-year mortality was 22%, most strongly related to older age, higher comorbidity, and abnormal haemoglobin/creatinine but only weakly to DMS severity (with anaemia 42% irrespective of DMS severity, P = 0.99; without anaemia 18, 23, and 28% with mild, moderate, and severe DMS, respectively, P < 0.0004). Long-term mortality was high (56% at 5 years) also mostly linked to aging and weakly to DMS severity [with anaemia P = 0.90; without anaemia: adjusted-hazard ratio: 1.30 (1.19-1.42), P < 0.0001, for moderate vs. mild DMS and 1.63 (1.34-1.98), P < 0.0001, for severe vs. mild DMS]., Conclusion: DMS is a condition of the elderly potentially resulting in severe mitral obstruction and haemodynamic alterations. However, DMS is frequently associated with severe comorbidities imparting considerable mortality following diagnosis, whereas DMS severity is a weak (albeit independent) determinant of mortality. Hence, patients with DMS should be carefully evaluated and interventional/surgical treatment prudently considered in those with limited comorbidity burden, particularly without anaemia. Keywords: Degenerative Mitral Stenosis; Outcome; Natural history; Ecocardiography; Mitral Stenosis., Competing Interests: Conflict of interest: M.E.-S. received consulting fees from Edwards LLC, Mardil Inc., and Cryolife Inc. The other authors have no conflict of interest to declare., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Competing Interests: Conflicts of Interest None.

Objectives: The Ross procedure is currently receiving renewed interest. Its function and durability depend on preservation of pulmonary valve anatomy; limited data exist on normal pulmonary valve geometry. The objective was to compare aortic and pulmonary root and cusp dimensions in adults with normal tricuspid aortic and pulmonary valves., Methods: We reviewed 507 coronary computed tomography studies, selecting those with adequate visibility of both pulmonary and aortic roots for further analysis. Diastolic aortic and pulmonary root and cusp dimensions were measured. Root dimensions at different phases of the cardiac cycle were measured in 3 patients., Results: We analysed studies of 50 patients with the mean age of 54 years [standard deviation (SD): 16]. In end-diastole, pulmonary root had a smaller sinutubular to basal ring ratio than the aortic root [0.82 (SD: 0.09) vs 1.14 (SD: 0.12), P < 0.001]. Aortic and pulmonary cusps had similar dimensions; however, pulmonary cusp effective height was lower [5.9 mm (SD: 1.6) vs 8.4 mm (SD: 1.2), P < 0.001]. Pulmonary basal ring perimeter was largest at end-diastole and smallest at end-systole, with the relative difference of 23.5% (SD: 2.7)., Conclusions: The pulmonary root has a similar cusp size compared to the aortic root, but a different shape, resulting in a lower pulmonary cusp effective height. The perimeter of the pulmonary basal ring changes during the cardiac cycle. These findings suggest that stabilizing the autograft to normal aortic, rather than pulmonary, root dimensions should result in normal autograft cusp configuration. Computed tomography angiography could become a tool for personalized planning of the Ross procedure., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Aortic regurgitation (AR) is associated with left ventricular (LV) volume and pressure overload, resulting in eccentric LV remodeling and enlargement. This condition may be well tolerated for years before the onset of myocardial dysfunction and symptoms. Echocardiography plays a crucial role in the diagnosis of AR, assessing its mechanism and severity, and detecting LV remodeling. The assessment of AR severity is challenging and frequently requires the integration of information from multiple different measurements to assess the severity. Recent data suggest that echocardiographically derived LV volumes (end-systolic volume index > 45 mL/m 2 ), an ejection fraction threshold of <60%, and abnormal global longitudinal strain may help identify early dysfunction and may be used to improve clinical outcomes. Consequently, these parameters can identify candidates for surgery. Cardiac magnetic resonance imaging is emerging as a valuable tool for assessing severity when it remains unclear after an echocardiographic evaluation. This review emphasizes the importance of imaging, particularly echocardiography, in the evaluation of AR. It focuses on various echocardiographic parameters, including technical details, and how to integrate them for assessing the mechanism and severity of AR as well as LV remodeling., Competing Interests: Conflicts of Interest None., (Copyright © 2024 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Background: Aortic regurgitation (AR) is a prevalent valve disease with a long latent period before symptoms appear. Recent data has suggested the role of novel markers of myocardial overload in assessing onset of decompensation., Methods: The aim of this study was to evaluate the role of unsupervised cluster analyses in identifying different clinical clusters, including clinical status, and a large number of echocardiographic variables including left ventricular volumes, and their associations with mortality. Patients with moderate to severe or greater chronic AR identified using echocardiography at the Mayo Clinic in Rochester, Minnesota, were retrospectively analyzed. The primary outcome was all-cause mortality censored at aortic valve surgery. Uniform manifold approximation and projection with the k-means algorithm was used to cluster patients using clinical and echocardiographic variables at the time of presentation. Missing data were imputed using the multiple imputation by chained equations method. A supervised approach trained on the training set was used to find cluster membership in a hold-out validation set. Log-rank tests were used to assess differences in mortality rates among the clusters in both the training and validation sets., Results: Three distinct clusters were identified among 1,100 patients (log-rank P for survival < .001). Cluster 1 (n = 337), which included younger males with severe AR but fewer symptoms, showed the best survival at 75.6% (95% CI, 69.5%-82.3%). Cluster 2 (n = 235), including older patients and more females with elevated filling pressures, showed intermediate survival of 64.2% (95% CI, 56.8%-72.5%). Cluster 3 (n = 253), characterized by severe symptomatic AR, demonstrated the lowest survival of 45.3% (95% CI, 34.4%-59.8%) at 5 years. Similar clusters were identified in the internal validation cohort., Conclusions: Distinct clusters with variable echocardiographic features and mortality differences exist within patients with chronic moderate to severe or greater AR. Recognizing these clusters can refine individual risk stratification and clinical decision-making after verification in future prospective studies., Competing Interests: Conflicts of Interest None., (Copyright © 2024 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Background: The ideal timing for surgery in asymptomatic chronic aortic regurgitation (AR) remains unclear. New thresholds for left ventricular ejection fraction (LVEF), left ventricular (LV) indexed end-systolic volume (iESV), and global longitudinal strain (GLS) have been associated with mortality in these patients. These represent markers of early LV dysfunction., Objectives: The authors sought to assess the relationship between these markers (LVEF <60%, iESV ≥45 mL/m 2 , and GLS worse than -15%) and mortality, comparing them to Class I/IIa American College of Cardiology/American Heart Association guideline recommendations and absence of any of these., Methods: A total of 673 asymptomatic patients with chronic clinically significant (≥ moderate-severe) AR between 2004 and 2019 at a single referral center were retrospectively analyzed. The primary study outcome was all-cause mortality., Results: Mean age was 57 ± 17 years, 97 (14%) were female, 293 (45%) had hypertension, and 273 (41%) had an abnormal number of valve cusps. Aortic valve replacement was performed in 281 (48%) patients, and 69 (10%) died while under surveillance (without aortic valve replacement). LVEF <60% was present in 296 (44%) patients, 122 (25%) of 482 had GLS worse than -15%, and 261 (39%) had iESV ≥45 mL/m 2 . Mortality under surveillance was highest when Class I/IIa recommendations were present (HR: 4.22; 95% CI: 2.15-8.29), followed by the presence of 1 or more markers of early LV dysfunction (HR: 2.18; 95% CI: 1.21-3.92); no markers was used as the reference (all, P < 0.05). LVEF showed the strongest association with mortality, statistically slightly better than GLS and iESV. In the absence of Class I/IIa recommendations, 1 marker of early LV dysfunction was associated with higher, although not statistically significant, mortality compared with no markers (P = 0.063), followed by 2 markers; highest mortality was when all 3 markers were present (HR: 5.46; 95% CI: 2.51-11.90; P < 0.001)., Conclusions: Patients with asymptomatic clinically significant chronic AR incur a survival penalty when Class I/IIa guideline recommendations are attained. In patients without these recommendations, at least 2 markers of early LV dysfunction identify those with higher mortality risk who may benefit from early surgery., Competing Interests: Funding Support and Author Disclosures This research was funded by a grant from the Department of Cardiovascular Medicine, Mayo Clinic. The 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: Aortic-valve-stenosis (AS) is a frequent degenerative valvular-disease and carries dismal outcome under-medical-treatment. Transvalvular pressure gradient reflects severity of the valve-disease but is highly dependent on flow-conditions and on other valvular/aortic characteristics. Alternatively, aortic-valve-area (AVA) represents a measure of aortic-valve lesion severity conceptually essential and practically widely-recognized but exhibits multiple-limitations., Methods: We analyzed the 4D multi-detector computed tomography(MDCT) of 20 randomly selected patients with severe AS. For each-patient, we generated the 3D-model of the valve and of its calcifications, and we computed the anatomical AVA accounting for the 3D-morphology of the leaflets in three-different-ways. Finally, we compared our results vs. Doppler-based AVA E measurements and vs. 2D-planimetric AVA-measurements., Results: 3D-reconstruction and identification of the cusps were successful in 90% of the cases. The calcification patterns where highly-variable over patients, ranging from multiple small deposits to wide and c-shaped deposits running from commissure-to-commissure. AVA E was 82 ± 15 mm 2 . When segmenting 18 image planes, AVA Tight , AVA Proj-Ann , AVA Proj-Tip and their average AVA Ave were equal to 80 ± 16, 88 ± 20, 93 ± 21 and 87 ± 19 mm 2 , respectively, while AVA Plan was equal to 143 ± 50 mm 2 . Linear-regression of the three measurements vs. AVA E yielded regression slopes equal to 1.26, 1.13 and 0.93 for AVA Proj-Ann , AVA Proj-Tip and AVA Tight , respectively. The respective Pearson-coefficients were 0.85,0.86 and 0.90. Conversely, when comparing AVA Plan vs. AVA E , linear regression yielded a slope of 1.73 and a Pearson coefficient of 0.53., Conclusions: We described a new-method to obtain a set of flow-independent quantifications that complement pressure gradient measurements and combine the advantages of previously proposed methods, while bypassing the corresponding-limitations., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)

Bicuspid aortic valve (BAV) is the most common congenital heart lesion with an estimated population prevalence of 1%. We hypothesize that specific gene variants predispose to early-onset complications of BAV (EBAV). We analyzed whole-exome sequences (WESs) to identify rare coding variants that contribute to BAV disease in 215 EBAV-affected families. Predicted damaging variants in candidate genes with moderate or strong supportive evidence to cause developmental cardiac phenotypes were present in 107 EBAV-affected families (50% of total), including genes that cause BAV (9%) or heritable thoracic aortic disease (HTAD, 19%). After appropriate filtration, we also identified 129 variants in 54 candidate genes that are associated with autosomal-dominant congenital heart phenotypes, including recurrent deleterious variation of FBN2, MYH6, channelopathy genes, and type 1 and 5 collagen genes. These findings confirm our hypothesis that unique rare genetic variants drive early-onset presentations of BAV disease., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Objective: Patients with bicuspid aortic valves (BAV) are at increased risk of infective endocarditis (IE). Information of the clinical presentation and the microbiology of BAV-associated IE, however, is limited. Therefore, our study aimed to characterise the clinical features native valve endocarditis (NVE) in the setting of BAV and compared them to patients with prosthetic valve endocarditis (PVE) following BAV replacement., Methods: Adult patients with BAV or history of BAV with aortic valve replacement (AVR) and a definite or possible IE diagnosis within the Mayo Clinic Enterprise (USA) from January 2008 to December 2021, were included. BAV was confirmed by trans-oesophageal echocardiography. IE was defined according to the modified Duke criteria and only an initial episode was included. Statistical analyses were performed to compare clinical characteristics, microbiology, and IE complications., Results: Overall, 161 patients with BAV and IE (NVE [n=60], 37.3%) and PVE [n=101, 62.7%) were included. Mean age±SD was 56.5±16.1 years, and 139 (86.3%) patients were males. PVE patients were older (p<0.01) and had a higher rate of hypertension (p<0.01), chronic heart failure (p<0.01), chronic kidney disease (p<0.01), and perivalvular abscess (p<0.01). BAV patients with NVE had a higher prevalence of isolated mitral valve IE (p<0.01), moderate to severe aortic valve regurgitation (p<0.01) and combined aortic with mitral valve IE (p<0.01). Streptococcus mitis was the most common pathogen in NVE (30.0%) while Staphylococcus aureus was the most common in PVE (15.8%)., Conclusions: Patients with BAV are at risk of both NVE and PVE. Each syndrome has unique clinical features, including microbiologic findings, that should be appreciated in IE diagnosis and management., Competing Interests: Disclosures L.M.B. reports UpToDate, royalty payments (authorship duties); Boston Scientific, consultant duties; and philanthropic funding from Eva and Gene Lane. The other authors had no disclosures or conflicts of interest., (Copyright © 2024 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Background: European and U.S. clinical guidelines diverge regarding pulmonary hypertension (PHTN) in degenerative mitral regurgitation (DMR). Gaps in knowledge underpinning these divergences affect risk assessment and management recommendations attached to systolic pulmonary pressure (SPAP) in DMR., Objectives: This study sought to define PHTN links to DMR severity, prognostic thresholds, and independent outcome impact in a large quantitative DMR registry., Methods: This study gathered a large multicentric registry of consecutive patients with isolated moderate-to-severe DMR, with DMR and SPAP quantified prospectively at diagnosis., Results: In 3,712 patients (age 67 ± 15 years, 36% women) with ≥ moderate-to-severe DMR, effective regurgitant orifice (ERO) was 0.42 ± 0.19 cm 2 , regurgitant volume 66 ± 327 mL/beat and SPAP 41 ± 16 mm Hg. Spline-curve analysis showed excess mortality under medical management emerging around SPAP 35 mm Hg and doubling around SPAP 50 mm Hg. Accordingly, severe pulmonary hypertension (sPHTN) (SPAP ≥50 mm Hg) was detected in 916 patients, moderate pulmonary hypertension (mPHTN) (SPAP 35-49 mm Hg) in 1,128, and no-PHTN (SPAP <35 mm Hg) in 1,668. Whereas SPAP was strongly associated with DMR-ERO, nevertheless excess mortality with sPHTN (adjusted HR: 1.65; 95% CI: 1.24-2.20) and mPHTN (adjusted HR: 1.44; 95% CI: 1.11-1.85; both P ≤ 0.005) was observed independently of ERO and all baseline characteristics and in all patient subsets. Nested models demonstrated incremental prognostic value of mPHTN and sPHTN (all P < 0.0001). Despite higher operative risk with mPHTN and sPHTN, DMR surgical correction was followed by higher survival in all PHTN ranges with strong survival benefit of early surgery (<3 months). Postoperatively, excess mortality was abolished (P ≥ 0.30) in mPHTN, but only abated in sPHTN., Conclusions: This large international registry, with prospectively quantified DMR and SPAP, demonstrates a Doppler-defined PHTN impact on mortality, independent of DMR severity. Crucially, it defines objectively the new and frequent mPHTN range, independently linked to excess mortality under medical management, which is abolished by DMR correction. Thus, at DMR diagnosis, Doppler-SPAP measurement defining these new PHTN ranges, is crucial to guiding DMR management., Competing Interests: Funding Support and Author Disclosures This study was supported by the Mayo Foundation, French Ministry of Health “PHRC-I 2012” (Dr Le Tourneau, API12/N/019), Fédération Française de Cardiologie (Dr Le Tourneau, 2015), and Fondation Cœur et Recherche (Dr Le Tourneau, 2015). The Department of Cardiology of the Leiden University Medical Center received research grants from Abbott Vascular, Bioventrix, Medtronic, Biotronik, Boston Scientific, GE Healthcare, and Edwards Lifesciences. Drs Bax and Ajmone Marsan have received speaker fees from Abbott Vascular. Dr Enriquez-Sarano has received consulting fees from Edwards LLC, Cryolife Inc, ChemImage, and HighLife Inc. 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.)

Aims: Aortic valve calcification (AVC) is prognostic in patients with aortic stenosis (AS). We assessed the AVC prognostic value in non-severe AS patients., Methods and Results: We conducted a retrospective study of 395 patients with non-severe AS, LVEF ≥ 50%. The Agatston method was used for CT AVC assessment. The log-rank test determined the best AVC cut-offs for survival under medical surveillance: 1185  arbitrary unit (AU) in men and 850 AU in women, lower than the established cut-offs for severe AS (2064 AU in men and 1274 AU in women). Patients were divided into 3 AVC groups based on these cut-offs: low (<1185 AU in men and <850 AU in women), sub-severe (1185-2064 AU in men and 850-1274 AU in women), and severe (>2064 AU in men and >1274 AU in women). Of 395 patients (mean age 73 ± 12 years, 60.5% men, aortic valve area 1.23 ± 0.30 cm2, mean pressure gradient 28 ± 8 mmHg), 218 underwent aortic valve intervention (AVI) and 158 deaths occurred during follow-up, 82 before AVI. Median survival time under medical surveillance was 2.1 (0.7-4.9) years. Compared with the low AVC group, both sub-severe and severe AVC groups had higher risk for all-cause death under medical surveillance after comprehensive adjustment including echocardiographic AS severity and coronary artery calcium score (all P ≤ 0.006); while mortality risk was similar between sub-severe and severe AVC groups (all P ≥ 0.2). This mortality risk pattern persisted in the overall survival analysis after adjustment for AVI. AVI was protective of all-cause death in the sub-severe and severe AVC (all P ≤ 0.01), but not in the low AVC groups., Conclusion: Sub-severe AVC is a robust risk stratification parameter in patients with non-severe AS and may inform AVI timing., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Bicuspid aortic valve (BAV), the most common congenital heart defect, is a major cause of aortic valve disease requiring valve interventions and thoracic aortic aneurysms predisposing to acute aortic dissections. The spectrum of BAV ranges from early onset valve and aortic complications (EBAV) to sporadic late onset disease. Rare genomic copy number variants (CNVs) have previously been implicated in the development of BAV and thoracic aortic aneurysms. We determined the frequency and gene content of rare CNVs in EBAV probands (n = 272) using genome-wide SNP microarray analysis and three complementary CNV detection algorithms (cnvPartition, PennCNV, and QuantiSNP). Unselected control genotypes from the Database of Genotypes and Phenotypes were analyzed using identical methods. We filtered the data to select large genic CNVs that were detected by multiple algorithms. Findings were replicated in a BAV cohort with late onset sporadic disease (n = 5040). We identified 3 large and rare (< 1,1000 in controls) CNVs in EBAV probands. The burden of CNVs intersecting with genes known to cause BAV when mutated was increased in case-control analysis. CNVs intersecting with GATA4 and DSCAM were enriched in cases, recurrent in other datasets, and segregated with disease in families. In total, we identified potentially pathogenic CNVs in 9% of EBAV cases, implicating alterations of candidate genes at these loci in the pathogenesis of BAV., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Carlisle et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background and Aims: Incidence and types of secondary tricuspid regurgitation (TR) are not well defined in atrial fibrillation (AFib) and sinus rhythm (SR). Atrial secondary TR (A-STR) is associated with pre-existing AFib; however, close to 50% of patients with A-STR do not have AFib. The aim of this study was to assess incidence, types, and outcomes of ≥ moderate TR in AFib vs. SR., Methods: Adults with and without new-onset AFib without structural heart disease or ≥ moderate TR at baseline were followed for the development of ≥ moderate TR. Tricuspid regurgitation types were pacemaker, left-sided valve disease, left ventricular (LV) dysfunction, pulmonary hypertension (PH), isolated ventricular, and A-STR., Results: Among 1359 patients with AFib and 20 438 in SR, 109 and 378 patients developed ≥ moderate TR, respectively. The individual types of TR occurred more frequently in AFib related to the higher pacemaker implantation rates (1.12 vs. 0.19 per 100 person-years, P < .001), larger right atrial size (median 78 vs. 53 mL, P < .001), and higher pulmonary pressures (median 30 vs. 28 mmHg, P < .001). The most common TR types irrespective of rhythm were LV dysfunction-TR and A-STR. Among patients in SR, those with A-STR were older, predominantly women with more diastolic abnormalities and higher pulmonary pressures. All types of secondary TR were associated with all-cause mortality, highest in PH-TR and LV dysfunction-TR., Conclusions: New-onset AFib vs. SR conferred a higher risk of the individual TR types related to sequelae of AFib and higher pacemaker implantation rates, although the distribution of TR types was similar. Secondary TR was universally associated with increased mortality., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Whipple disease is a rare systemic illness associated with weight loss, diarrhea, and arthralgia. Asymptomatic carriage is common, but the disease can be complicated by cardiac involvement and may result in culture-negative endocarditis. Cardiac manifestations of the disease can lead to death. This report presents the case of a 66-year-old man with Whipple disease and biventricular heart failure with cardiogenic shock. Medical therapy followed by successful replacement of the aortic and mitral valves resulted in substantial improvement., (© 2024 The Authors. Published by The Texas Heart Institute®.)

Objectives: The objective of the study was to quantify the differences in cusp size and shape in patients with normal and dilated trileaflet aortic roots and in dilated roots with or without aortic regurgitation., Methods: A retrospective analysis of computed tomography studies in patients with normal and dilated trileaflet aortic roots was performed measuring root and cusp dimensions. Normal root size was defined as sinuses of Valsalva diameter less than 40 mm, dilated as 45 mm or greater. Root measurements normalized to basal ring diameter and cusp measurements normalized to geometric height were analyzed to assess the shape. Additionally, comparison of dilated roots with or without aortic regurgitation was made., Results: We analyzed 146 normal and 104 dilated aortic roots and 73 propensity-matched pairs. Dilated roots were larger in all dimensions and had increased ratio between commissural and basal ring diameter (1.58 ± 0.23 vs 1.11 ± 0.10, P < .001). Cusps in dilated roots were larger in all measured dimensions and were elongated with increased normalized cusp insertion length (3.64 ± 0.39 vs 3.26 ± 0.20, P < .001) and normalized free margin length (2.53 ± 0.30 vs 2.16 ± 0.19, P < .001). In patients with dilated root and no cusp prolapse (n = 83), those with moderate or severe aortic regurgitation had larger commissural diameter but similar cusp dimensions compared with those with no or mild aortic regurgitation., Conclusions: The cusps in dilated roots elongate transversely and to a lesser degree radially. Functional aortic regurgitation is caused by extensive commissural dilatation and not by inadequate cusp adaptation., Competing Interests: Conflict of Interest Statement The authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2024 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Severe aortic stenosis (AS) is the guideline-based indication for aortic valve replacement (AVR), which has markedly increased with transcatheter approaches, suggesting possible increasing AS incidence. However, reported secular trends of AS incidence remain contradictory and lack quantitative Doppler echocardiographic ascertainment., Methods: All adults residents in Olmsted County (MN, USA) diagnosed over 20 years (1997-2016) with incident severe AS (first diagnosis) based on quantitatively defined measures (aortic valve area ≤ 1 cm2, aortic valve area index ≤ 0.6 cm2/m2, mean gradient ≥ 40 mmHg, peak velocity ≥ 4 m/s, Doppler velocity index ≤ 0.25) were counted to define trends in incidence, presentation, treatment, and outcome., Results: Incident severe AS was diagnosed in 1069 community residents. The incidence rate was 52.5 [49.4-55.8] per 100 000 patient-year, slightly higher in males vs. females and was almost unchanged after age and sex adjustment for the US population 53.8 [50.6-57.0] per 100 000 residents/year. Over 20 years, severe AS incidence remained stable (P = .2) but absolute burden of incident cases markedly increased (P = .0004) due to population growth. Incidence trend differed by sex, stable in men (incidence rate ratio 0.99, P = .7) but declining in women (incidence rate ratio 0.93, P = .02). Over the study, AS clinical characteristics remained remarkably stable and AVR performance grew and was more prompt (from 1.3 [0.1-3.3] years in 1997-2000 to 0.5 [0.2-2.1] years in 2013-16, P = .001) but undertreatment remained prominent (>40%). Early AVR was associated with survival benefit (adjusted hazard ratio 0.55 [0.42-0.71], P < .0001). Despite these improvements, overall mortality (3-month 8% and 3-year 36%), was swift, considerable and unabated (all P ≥ .4) throughout the study., Conclusions: Over 20 years, the population incidence of severe AS remained stable with increased absolute case burden related to population growth. Despite stable severe AS presentation, AVR performance grew notably, but while declining, undertreatment remained substantial and disease lethality did not yet decline. These population-based findings have important implications for improving AS management pathways., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Clinical outcome and interventional thresholds for degenerative mitral regurgitation (DMR) were developed in studies of patients at European and American institutions (EAIs), but little is known about patients at Asian institutions (AsIs)., Objectives: This study sought to contrast DMR presentation/management/outcomes of AsI patients vs EAI patients., Methods: Patients with DMR due to flail leaflet from Hong Kong and Singapore (AsI cohort, n = 737) were compared with EAI patients (n = 682) enrolled in the MIDA (Mitral regurgitation International Database) registry with similar eligibility criteria., Results: AsI patients presented similar DMR lesion/consequences vs EAI patients, but they were younger, with fewer symptoms (74% vs 44% Class I), more sinus rhythm (83% vs 69%), and lower EuroSCORE II (European System for Cardiac Operative Risk Evaluation II) (0.9 ± 0.5 vs 1.4 ± 1.5; all P  < 0.0001). Imaging showed smaller absolute left atrial/ventricular dimensions in AsI patients, belying cardiac dilatation with larger body surface area-indexed diameters (all P  < 0.01). Surgical/interventional mitral repair was similarly predominant (90% vs 91%; P  = 0.47), and early repair was similarly beneficial (for AsI patients, adjusted HR: 0.28; 95% CI: 0.16-0.49; for EAI patients, HR: 0.32; 95% CI: 0.20-0.49; both P  < 0.0001). However, AsI patients underwent fewer interventions (55% ± 2% vs 77% ± 2% at 1 year; P  < 0.0001) and incurred excess mortality (adjusted HR: 1.60 [95% CI: 1.13-2.27] vs EAI patients; P  = 0.008) at long-term postdiagnosis. Propensity score matching (434 patient pairs), which balanced all clinical characteristics, confirmed that there was undertreatment and excess mortality in the long term in AsI patients with DMR ( P  < 0.0001)., Conclusions: Imaging may underestimate volume overload in AsI patients due to smaller cardiac cavities related to smaller body size compared with EAI patients with similar mitral lesions and DMR severity. AsI patients enjoy similar mitral repair predominance and early intervention benefits but undergo fewer mitral interventions than EAI patients and incur subsequent excess mortality, suggesting the need to account for imaging and cultural specificity to improve DMR outcomes worldwide., Competing Interests: Dr Enriquez-Sarano has received personal fees from Edwards LLC, ChemImage Inc, and CryoLife Inc, outside the submitted work. Dr Ding has received personal fees from GE Healthcare; and nonfinancial support from Phillips Healthcare, outside the submitted work. Dr Lee has received grant support from Abbott, outside the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Background: The natural history of moderate/severe atrial functional mitral regurgitation (AFMR) is unknown., Objectives: The authors sought to study the incidence of left ventricular (LV) systolic dysfunction (LVSD), progression or regression of ≥mild-moderate AFMR, and impact on mortality., Methods: Adults with left atrial (LA) volume index ≥40 mL/m 2 , ≥mild-moderate AFMR, and follow-up echocardiogram were followed for incident LVSD (ejection fraction <50% and ≥10% lower than baseline), progression of mild-moderate/moderate AFMR to severe, and persistent regression of AFMR to no/trivial. Relation of AFMR progression or regression as time-dependent covariates with all-cause mortality was studied. Incidence of LVSD was compared with patients with no/mild AFMR matched on age, sex, comorbidities and ejection fraction. Patients were followed until mitral intervention, myocardial infarction, or last follow-up., Results: A total of 635 patients (median age 75 years, 51% female, 96% mild-moderate/moderate AFMR, 4% severe AFMR) were included. Over a median 2.2 years (Q1-Q3: 1.0-4.3 years), incidence rates per 100 person-years were 3.2 for LVSD (P = 0.52 vs patients with no/mild AFMR), 1.9 for progression of AFMR, and 3.9 for regression. Female sex and larger LA volume index were independently associated with progression, whereas younger age, male sex, absent atrial fibrillation, and higher LA emptying fraction were independently associated with regression. Neither AFMR progression nor regression was independently associated with mortality. Instead, independent risk factors for mortality included older age, concentric LV geometry, and higher estimated LV filling and pulmonary pressures., Conclusions: In patients with predominantly mild-moderate/moderate AFMR, regression of MR was more common than progression, but neither was associated with mortality. Instead, diastolic function abnormalities were more important. Over a median 2-year follow-up, LVSD risk was not increased., Competing Interests: Funding Support and Author Disclosures The 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.)

Objective: CT aortic valve calcium score (AVC score ) and density (AVC density ) thresholds have been recommended for aortic stenosis (AS) severity assessment in tricuspid aortic valve (TAV). We aimed to compare AVC score and AVC density in bicuspid aortic valve (BAV) versus TAV., Methods: Retrospective single-centre study of patients with echocardiographic AS-severity and CT-AVC assessments within 6 months, and left ventricular ejection fraction ≥50%, all referred for clinical AS evaluation.Severe AS was defined as aortic valve area (AVA) ≤1 cm 2 or indexed AVA ≤0.6cm 2 /m 2 plus mean gradient ≥40 mm Hg or peak velocity ≥4 m/s. AVC was assessed by Agatston method., Results: Of the 1957 patients, 328 had BAV and 1629 had TAV, age 65±11 vs 80±9 years (p<0.001), men 65% vs 56% (p=0.006), respectively. BAV morphology was associated with higher AVC score and AVC density independent of age, comorbidities and AS severity (p<0.001) in men only (sex and BAV interaction p<0.001). In patients with severe AS, mean AVC score and AVC density were higher in BAV-men than that in TAV-men (both p<0.001), but similar in BAV-women and TAV-women (both p≥0.4). Such patterns remained the same after adjustment for clinical covariates and AS severity. Best thresholds for severe AS diagnosis in BAV-men were 2916 AU by AVC score and 600 AU/cm 2 by AVC density which were higher than the guideline-recommended thresholds, while thresholds in BAV-women (1036 AU and 282 AU/cm 2 ) were similar to guideline-recommended ones., Conclusion: Valve calcification in AS differs according to valve morphology and sex. BAV-men with severe AS exhibit greater AVC score and AVC density than TAV-men. This presents a diagnostic challenge to the current guidelines, which needs confirmation in larger studies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: In patients with aortic root aneurysm, the aortic basal ring is frequently dilated. It has been speculated that the muscular part of the basal ring dilates most. The purpose of this study was to analyse the segmental dilatation of the basal ring, comparing normal and dilated roots in patients with tricuspid aortic valves., Methods: Retrospective analysis of computed tomography studies in patients with normal and dilated aortic roots was performed. Lengths of segments of the basal ring corresponding to each of the 3 sinuses, and to the muscular and fibrous parts were measured. Fractions of these segments relative to the total basal ring perimeter were calculated., Results: We analysed 152 normal and 126 dilated aortic roots and 86 propensity-matched pairs. Basal ring dilatation was present in all segments of dilated aortic roots with subtle differences between the segments corresponding to the 3 sinuses. The muscular part of the basal ring dilated proportionately to its fibrous part, with no difference in fractions of measured muscular part in normal and dilated roots [42.2% (interquartile range 4.3%) vs 42.1% (interquartile range 6.3%)]., Conclusions: Basal ring dilatation was present in all segments corresponding to the 3 sinuses in dilated aortic roots. Both muscular and fibrous parts dilated equally, supporting the need to stabilize the entire basal ring when performing aortic valve repair surgery., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Objectives: Prior data indicate a very rare risk of serious adverse drug reaction (ADR) to ultrasound enhancement agents (UEAs). We sought to evaluate the frequency of ADR to UEA administration in contemporary practice., Methods: We retrospectively reviewed 4 US health systems to characterize the frequency and severity of ADR to UEA. Adverse drug reactions were considered severe when cardiopulmonary involvement was present and critical when there was loss of consciousness, loss of pulse, or ST-segment elevation. Rates of isolated back pain and headache were derived from the Mayo Clinic Rochester stress echocardiography database where systematic prospective reporting of ADR was performed., Results: Among 26,539 Definity and 11,579 Lumason administrations in the Mayo Clinic Rochester stress echocardiography database, isolated back pain or headache was more frequent with Definity (0.49% vs 0.04%, P < .0001) but less common with Definity infusion versus bolus (0.08% vs 0.53%, P = .007). Among all sites there were 201,834 Definity and 84,943 Lumason administrations. Severe and critical ADR were more frequent with Lumason than with Definity (0.0848% vs 0.0114% and 0.0330% vs 0.0010%, respectively; P < .001 for each). Among the 3 health systems with >2,000 Lumason administrations, the frequency of severe ADR with Lumason ranged from 0.0755% to 0.1093% and the frequency of critical ADR ranged from 0.0293% to 0.0525%. Severe ADR rates with Definity were stable over time but increased in more recent years with Lumason (P = .02). Patients with an ADR to Lumason since the beginning of 2021 were more likely to have received a COVID-19 vaccination compared with matched controls (88% vs 75%; P = .05) and more likely to have received Moderna than Pfizer-Biotech (71% vs 26%, P < .001)., Conclusion: Severe and critical ADR, while rare, were more frequent with Lumason, and the frequency has increased in more recent years. Additional work is needed to better understand factors, including associations with recently developed mRNA vaccines, which may be contributing to the increased rates of ADR to UEA since 2021., Competing Interests: Conflicts of Interest None., (Copyright © 2023 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

This consensus of nomenclature and classification for congenital bicuspid aortic valve and its aortopathy is evidence-based and intended for universal use by physicians (both pediatricians and adults), echocardiographers, advanced cardiovascular imaging specialists, interventional cardiologists, cardiovascular surgeons, pathologists, geneticists, and researchers spanning these areas of clinical and basic research. In addition, as long as new key and reference research is available, this international consensus may be subject to change based on evidence-based data1.