Michelena, Héctor I.

Introduction: Left ventricular longitudinal strain (LV-LS) 1) predicts mortality in patients with aortic stenosis (AS) and 2) is highly correlated to type-B natriuretic peptide (BNP) values. The BNP ratio (measured BNP/maximal expected BNP value specific for age and sex) is a powerful independent predictor of death in patients with AS. Hypothesis: we hypothesize that BNP activation (i.e. BNP ratio >1) affects the association between LV-LS and mortality in patients with asymptomatic AS and preserved LV ejection fraction (EF ≥50%). Methods: 315 patients (age 74±12 years, 56% men and mean aortic valve area = 1.02±0.15cm2) underwent simultaneous Doppler echocardiographic and BNP measurements. LV-LS was calculated as the average of 12 LV segments from apical 2- and 4-chamber views using Velocity Vector Imaging. Results: Mean LV-LS was -16.8±3.2%, LV EF 66±7%, median BNP level 121 (interquartile 48-320) pg/ml. 58% of patients had BNP activation. Better LV-LS was associated with lower log BNPratio (regression coefficient 0.10, p<0.001). After a median follow-up of 6.5 yrs (interquartile: 3.6-8.2), 119 deaths occurred. After adjustment for age, sex, Charlson score index, hemoglobin level, aortic valve replacement (as a time dependent variable), LV-LS and log BNPratio were separately associated with increased risk for death (all p<0.01). Further adjustment for predictors of mortality, LV-LS and log-BNP ratio remained associated with increased risk for death (hazard ratio HR [95%CI]: 1.09 [1.03-1.15]; p=0.003 and 1.82 [1.52-2.19]; p<0.0001 respectively). In patients without BNP activation (i.e. normal BNP), LV-LS was associated with mortality (HR: 1.22 [1.04-1.43]; p=0.01) while it was not in patients with BNP activation (p=0.22). Conclusions: In patients with asymptomatic AS, without clinically obvious myocardial impairment (i.e. normal LVEF), a notable proportion of patients present with myocardial alterations detected by an elevated BNPratio or reduced LV-LS. These signs of myocardial alterations were predictive of mortality after diagnosis. Thus both BNP and LV-LS should be assessed in the clinical setting to provide complementary information on prognosis in patients with asymptomatic AS and preserved LV EF.

Introduction: The prevalence of bicuspid aortic valves (BAV) is enriched thirty-fold in women with Turner Syndrome (TS) in comparison with the general population. Hypothesis: Common autosomal variants influence the development of BAV in TS women, who may be uniquely sensitized to these variants by the loss of one X chromosome. We sought to identify autosomal BAV susceptibility genes in a cohort of TS women (average age 30 years, 38% BAV, 18% coarctation). Methods: A total of 106 TS women of European ancestry with BAV and 173 TS women with tricuspid aortic valves were genotyped on Illumina Omni-Express arrays. Valve phenotypes were determined by independent review of echocardiograms from the enrolling sites. Tests of association were performed using logistic regression without adjustment for covariates and were summarized in a meta-analysis. Results: Xp dosage was inversely and quantitatively associated with BAV status (P=0.02). Large, recurrent copy number variants in 1p36.13, 3q29, 8p23.1 and 9p24.3 were significantly enriched in BAV cases. After exclusion of 26 outlier samples in multidimensional scaling analysis, there was no significant genomic inflation (lambda= 1.02). The strongest genome-wide association signals were observed in 1p36.23, 3q23, 12q21.2, 18q21 and 22q13.31, and did not overlap with previously reported loci for BAV. A total of 13 SNPs in 18q21 were positively associated with BAV (OR=2.5-4.3) with a minimum P value of 1x10-7. Replication of these regions in independent groups of cases is ongoing. Conclusion: Our results demonstrate that autosomal variants with large magnitudes of effect contribute to BAV in TS women, confirming our hypothesis, and provide evidence for gene-gene interactions in BAV formation.

Introduction: In asymptomatic patients with severe aortic stenosis (SAS), left ventricular (LV) ejection fraction (EF) <50% is generally considered to be the threshold for referral for aortic valve replacement (AVR). Hypothesis: We investigated the importance of LVEF on long-term outcome after AVR in symptomatic and asymptomatic SAS patients and studied whether LVEF < 50% is the optimal threshold for referral for AVR. Methods and Results: We retrospectively identified 2017 patients with SAS (aortic valve area (AVA)<1cm2, mean aortic valve gradient ≥40 mm Hg, or indexed AVA <0.6 cm2/m2) who underwent surgical AVR from January 1995 to June 2009 at our institution. Patients were divided into 4 groups depending on preoperative LVEF (<50% in 300 (15%) patients, 50-59% in 331 (17%), 60-69% in 908 (45%), and ≥70% in 478 (24%)). The primary end-point was all-cause mortality. During follow-up of 5.3±4.4 years, 1056 (52%) died. Five-year mortality rate increased with decreasing LVEF (41% (n=106), LVEF<50%); 35% (n=98), LVEF 50-59%; 26% (n=192), LVEF 60-69%; 22% (n=90), LVEF≥70%, p<0.0001). Compared to patients with LVEF≥60%, patients with LVEF 50-59% had increased mortality (HR 1.58, p<0.001), with a similar risk increase in both symptomatic (HR=1.56, p<0.001) and asymptomatic patients (HR 1.58, p=0.006, Figure). In a Cox regression analysis corrected for standard risk factors, LV mass index, AVA, and stroke volume index, LVEF was predictive of all-cause mortality (HR=0.89 per 10%, p<0.001). When this multivariable analysis was repeated in the subset of 1333 patients with no history of coronary artery disease, LVEF was still associated with all-cause mortality (HR=0.90 per 10%, p=0.009). Conclusion: In patients with SAS undergoing AVR, patients with LVEF 50-59% have also increased mortality compared to patients with LVEF>60%, suggesting that a different LVEF threshold should be used when referring for AVR.

Introduction: Levels of type-B natriuretic peptide (BNP) adjusted for age and sex are a powerful predictor of mortality after the diagnosis of aortic stenosis (AS). Objective: To assess whether BNP activation (compared to normal values) affects mortality after aortic valve replacement (AVR). Methods: In 494 patients with AS, plasma level of BNP was measured pre-operatively at the time of Doppler-Echocardiography. BNP was normalized as BNPratio (BNP measured/BNP maximum normal value for age and sex) to evaluate the impact of BNP activation on post-operative outcomes. Results: Mean age was73±11 years and 300 (61%) patients were male. Mean aortic valve area was 0.82±0.20cm2, mean gradient 51±16mmHg, and mean Left Ventricular Ejection Fraction 59±15%. Incidence of hypertension was 65%, diabetes 27% and chronic kidney disease 22%. Median of BNP was 211 (interquartile: 87-508) and BNPratio 2.2 (1.0-5.2). After adjustment age, gender, body surface area, Charlson score index, presence of symptoms, creatinine, hemoglobin, systolic blood pressure, indexed aortic valve area and left ventricular ejection fraction, the BNPratio (log transformed) was a predictor of long-term mortality (p<0.0001) with an hazard ratio 1.34 (1.14-1.60). Moreover, stratification by BNPratio showed increasing long-term post-operative mortality with BNPratios>2 (Figure). Conclusions: BNP activation defined using BNPratios (normalized for age and sex) is a powerful independent predictor of long-term mortality after aortic valve replacement for AS. Furthermore, patients with a BNPratio>2 before aortic valve replacement incur excess mortality during follow-up in relation to the increasing BNPratio. These data support the use of the BNPratio to guide the timing of AVR.

Objective To compare the prevalence and patterns of anomalous coronary artery origin from the opposite sinus (ACAOS) in patients with bicuspid aortic valve (BAV) and tricuspid aortic valve (TAV). Methods Retrospective review of consecutive patients with surgically excised BAV and TAV was performed from 1994 to 2015. Clinical notes, echocardiograms, coronary angiograms, CT angiographies, and pathology reports were reviewed. ACAOS included right coronary artery from the left cusp, left circumflex artery from the right cusp and left main or left anterior descending artery from the right cusp. Results 2371 (years 1994–2015) and 1679 (years 2009–2015) consecutive patients with pathology-confirmed BAV and TAV, respectively, and defined preoperative coronary anatomy were identified. A left dominant coronary circulation was present in 386 (18%) patients with BAV and 179 (11%) patients with TAV (p<0.001). ACAOS was identified in 43 (1.8%) patients with BAV and 15 (0.9%) patients with TAV, p=0.02. Among patients with BAV and ACAOS, the most common phenotype was right-left fusion (n=34, 79%) with present raphe (n=36, 84%), with no association between BAV phenotype and ACAOS type. On multivariate analysis, BAV status and size of the mid-ascending aorta were independently associated with ACAOS (OR 3.29; CI 1.26 to 8.6; p=0.02; OR 0.93; CI 0.87 to 0.98; p=0.01; respectively). Only two patients with ACAOS, one with BAV and one with TAV, had a perioperative coronary ischaemic event. Conclusions The prevalence of the potentially malignant ACAOS is significantly higher (threefold higher odds) in patients with BAV as compared with TAV, yet remains uncommon in absolute terms. Most patients with BAV and ACAOS had right-left cusp fusion and present raphe. Perioperative coronary events are rare in patients with ACAOS.

Introduction: Bicuspid Aortic Valve (BAV), the most common congenital heart defect, is a major cause of aortic regurgitation or stenosis requiring valve replacement and thoracic aortic aneurysms predisposing to acute aortic dissections (TAD). The spectrum of BAV ranges from severe early onset valve and aortic complications to sporadic late onset disease. Hypothesis: Early onset BAV (EBAV) cases with valve or aortic complications that require intervention prior to age 30 are enriched for rare genetic variants that cause BAV and TAD. Methods: We performed whole exome sequencing of 147 EBAV cases in 141 families who were enrolled in the UTHealth Bicuspid Aortic Valve Research Registry. Candidate variants in the EBAV cohort (26% female, mean age 18, 44% with TAD) were compared to unselected controls from the Genome Aggregation Database (gnoMAD) and the Database of Genotypes and Phenotypes (dbGAP). We considered variants with minor allele frequencies (MAF) < 1%, Combined Annotation Dependent Depletion (CADD) scores > 25, and damaging (Polyphen-2) or deleterious (SIFT) functional prediction scores. Genomic copy number variants (CNVs) were detected using CoNIFER and prioritized when deletions involved genes with probability of loss intolerance (pLI) > 0.9. Variants were validated using quantitative PCR or Sanger sequencing. Results: We identified 6 rare variants of USP10 in 6 EBAV families (4% of cohort): 4 CNVs (2 duplications and 2 deletions) that are rare in dbGAP controls (4 in 15,414) and 2 deleterious rare missense variants (MAF<5x10 -5 in gnoMAD). Two of the 4 CNVs were de novo events in trios. In contrast, rare deleterious variants of the known causal BAV genes NOTCH1 (1), ROBO4 (1), GATA4 (1), GATA5 (1), and SMAD6 (4) were found in 7 total families. USP10 encodes a ubiquitin peptidase that is required for endothelial Notch signaling during vascular development. Conclusions: We identified rare and de novo variants of USP10 that implicate USP10 as a new candidate gene for BAV.

Abstract Aims Early detection of aortic stenosis (AS) is becoming increasingly important with a better outcome after aortic valve replacement in asymptomatic severe AS patients and a poor outcome in moderate AS. We aimed to develop artificial intelligence-enabled electrocardiogram (AI-ECG) using a convolutional neural network to identify patients with moderate to severe AS. Methods and results Between 1989 and 2019, 258 607 adults [mean age 63 ± 16.3 years; women 122 790 (48%)] with an echocardiography and an ECG performed within 180 days were identified from the Mayo Clinic database. Moderate to severe AS by echocardiography was present in 9723 (3.7%) patients. Artificial intelligence training was performed in 129 788 (50%), validation in 25 893 (10%), and testing in 102 926 (40%) randomly selected subjects. In the test group, the AI-ECG labelled 3833 (3.7%) patients as positive with the area under the curve (AUC) of 0.85. The sensitivity, specificity, and accuracy were 78%, 74%, and 74%, respectively. The sensitivity increased and the specificity decreased as age increased. Women had lower sensitivity but higher specificity compared with men at any age groups. The model performance increased when age and sex were added to the model (AUC 0.87), which further increased to 0.90 in patients without hypertension. Patients with false-positive AI-ECGs had twice the risk for developing moderate or severe AS in 15 years compared with true negative AI-ECGs (hazard ratio 2.18, 95% confidence interval 1.90–2.50). Conclusion An AI-ECG can identify patients with moderate or severe AS and may serve as a powerful screening tool for AS in the community.

Abstract Funding Acknowledgements Type of funding sources: None. BACKGROUND Detection of immobile leaflets immediately following bioprosthetic valve implantation is a rare but important intraoperative finding. Restriction of leaflet movement can occur in the closed or open position, leading to abnormal prosthesis function. We sought to determine the clinical implications of immobile leaflets seen on intraoperative echocardiography. METHODS Patients with immobile leaflets identified on intra-operative/procedure echocardiography immediately post implantation between 2009-2020 were identified from an institutional database. All echocardiograms were reviewed de-novo to confirm immobile leaflets in the immediate post-implantation period. Identified cases were matched 1:2 to controls for age; sex; prosthesis position, model and size; and implantation approach (surgical vs. transcatheter). Nominal logistic regression and proportional hazards were used to analyze outcomes. RESULTS Thirty patients with immobile leaflets immediately post-bioprosthesis implantation were included. Clinical characteristics are summarized in the Table. Immobile leaflets were documented in procedural reports in only 18 (60%) patients. Moderate stenosis was present intraoperatively in 1 patient, none demonstrated ≥moderate regurgitation, and none resulted in immediate corrective action. In 3 (10%), valve re-intervention was required within 30 days due to symptomatic prosthesis dysfunction. Presence of restricted leaflet motion was associated with higher need for post-operative extracorporeal membrane oxygenation use (odds-ratio 7.3, p = 0.02) and composite end-point of death, valve re-replacement, prosthesis thrombosis, or cardiac hospitalizations (risk ratio 2.1, p = 0.03, Figure). CONCLUSION Immobile leaflet(s) immediately post-bioprosthetic valve implantation is an uncommon, under-reported, and under-treated phenomenon. Even in the absence of significant prosthetic valve dysfunction, it can be associated with worse post-operative course as well as worse outcomes. Baseline characteristics Age 76 (67-84) Sex, male 10 (33%) Surgical approach 25 (83%) Aortic 5 (17%) Mitral 12 (40%) Tricuspid 12 (40%) Pulmonary 1 (3%) Re-intervention within 10 days 3 (10%) Numbers are presented as median (interquartile range) or number (percentage). Abstract Figure. Clinical outcome of stuck leaflets

Abstract Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): Mayo Clinic Foundation Background Left atrial (LA) volume is linked to outcome in degenerative mitral regurgitation (DMR) but does not encompass LA function assessment. Thus, we ought to determine the prognostic role of left atrial coupling-index (LACI), as left atrial volume-index (LAVI) by Tissue-Doppler-Imaging a’ (TDI-a’), in a large cohort of DMR. Methods All consecutive 4792 patients (61 ± 16 years, 48% women) with isolated degenerative mitral valve disease diagnosed at Mayo Clinic 2003-2011, comprehensively characterized, in whom LAVI and TDI-a’ in sinus rhythm was prospectively measured in routine practice, was enrolled and their long-term survival analyzed. Results LACI (5.8 ± 3.7–T1 &lt; 3.8; T2 3.8-6.3; T3 &gt; 6.3) was significantly higher through different DMR grades (no, mild, moderate, severe DMR: 3.77 ± 2.26, 5.08 ± 2.95, 6.54 ± 3.74 and 7.84 ±4.29 respectively; p &lt; 0.0001). Independent determinants of LA dysfunction assessed by LACI were age, E/e’, left-ventricle (LV) end-systolic-diameter, mitral-regurgitation (MR) grade, and LV ejection-fraction (all P ≤ 0.0001). LACI &gt; 6 was independently associated with dyspnea, edema, more severe functional tricuspid-regurgitation and elevated pulmonary artery pressure, irrespective of age, sex, Charlson-comorbidity-index, ventricular function and MR severity. Total follow-up was 7.03 ± 3.0 years, during which 1146 (24%) underwent mitral-valve surgery (94% repair-6% replacement) and 880 (18%) died, 780 under medical treatment and 100 after surgery. Overall survival throughout follow-up (10-year 76 ± 1%) was strongly associated with LACI (88 ± 1% vs. 78 ± 1% and 62 ± 2% for LACI &lt;3.8, 3.8-6.3 and ≥6.3, P &lt; 0.0001) even adjusting comprehensively, including for DMR severity (adjusted-hazard-ratio 1.23[1.07-1.43] for LACI &gt; 5.79, P = 0.005). Mortality under medical management was profoundly affected by LACI (adjusted-hazard-ratio 1.11[1.05-1.18] per 3 unit increment; 1.35[1.15-1.58] for LACI &gt; 5.79 vs. ≤5.79, both P = 0.0002). Survival improved after mitral surgery (time-dependent adjusted-hazard-ratio 0.40[0.28-0.65], P &lt; 0.0001) but remained humbly linked to LACI (10-year 93 ± 3% vs. 90 ± 2% and 80 ± 3% for LACI tertiles, P = 0.0008). Most importantly, LACI provided incremental prognostic information over LAVI and other conventional determinants of survival (P &lt; 0.0001) with Net-reclassification-improvement vs. LAVI of 0.21 ± 0.02, P &lt; 0.0001. Conclusion LA function assessed by LACI in routine practice, by conventional echocardiographic measurements, displays incremental and independent link to excess-mortality, considerable under medical management and partially alleviated by mitral surgery. Thus, LACI is a simple tool of crucial interest in DMR risk-stratification. Abstract Figure. LACI in DMR

Abstract This International Consensus Classification and Nomenclature for the congenital bicuspid aortic valve condition recognizes 3 types of bicuspid valves: 1. The fused type (right-left cusp fusion, right-non-coronary cusp fusion and left-non-coronary cusp fusion phenotypes); 2. The 2-sinus type (latero-lateral and antero-posterior phenotypes); and 3. The partial-fusion (forme fruste) type. The presence of raphe and the symmetry of the fused type phenotypes are critical aspects to describe. The International Consensus also recognizes 3 types of bicuspid valve-associated aortopathy: 1. The ascending phenotype; 2. The root phenotype; and 3. Extended phenotypes.