Ali, Mays T.

Abstract Background Guidelines acknowledge that discordant low-gradient (LG) aortic stenosis (AS) may be severe, but verifying this can be challenging. Right heart catheterization during exercise is considered the gold standard evaluating ventricular hemodynamics. No invasive studies have compared the hemodynamic response of discordant LG and severe AS during exercise. Purpose To describe exercise hemodynamics in patients with asymptomatic discordant AS and left ventricular ejection fraction ≥50%, and to identify the variables associated with the steepness of the pulmonary capillary wedge pressure (PCWP)/cardiac output (CO) slope defined as (peak exercise PCWP-rest PCWP)/(peak exercise CO-rest CO). Methods Patients with aortic valve area (AVA) ≤1.5 cm² underwent right heart catheterization at rest and during maximal exercise measuring pulmonary artery pressures, PCWP, CO and PCWP/CO slope. Patients were stratified in three groups: 1) discordant LG AS (AVA ≤1.0 cm² and mean gradient <40 mmHg); 2) moderate AS (AVA >1.0 cm²) and 3) high-gradient severe AS (AVA ≤1.0 cm² and mean gradient ≥40 mmHg). Results Among 86 patients, 17 (20%) had discordant LG, 49 (57%) moderate, and 20 (23%) high-gradient severe AS. The PCWP/CO slope was significantly steeper in discordant LG: median 3.3 mmHg/L/min (interquartile range: 2.2 mmHg/L/min) and high-gradient severe AS: 2.7 mmHg/L/min (1.5 mmHg/L/min) compared to moderate AS: 1.9 mmHg/L/min (2.0 mmHg/L/min), p=0.004. In a linear regression model adjusted for age, sex and rest PCWP, systemic arterial compliance and AS severity were significantly associated with the PCWP/CO slope. Furthermore, patients with discordant LG AS had a leftward and upward shift in the PCWP/CO slope. Conclusions Discordant LG and high-gradient severe AS had similar hemodynamic response to exercise with steeper PCWP/CO slope than in moderate AS, suggesting that discordant LG AS is a severe form of AS. In addition, the left-upward shift in PCWP/CO slope for discordant LG compared to high-gradient severe AS indicates that, this group also has latent heart failure with preserved ejection fraction physiology.

Abstract Background Dobutamine stress echocardiography (DSE) is recommended to distinguish between true-severe and pseudo-severe aortic stenosis (AS) in patients with low flow low-gradients and left ventricular ejection fraction (LVEF) <50%. However, DSE has mostly been tested in the setting of LVEF<35%. Purpose The purpose of this study was to examine the diagnostic accuracy of DSE according to aortic valve calcification (AVC) score, in patents with low-flow, low-gradient AS across a wide range of LVEF. Methods Patients with aortic mean gradient <40 mmHg, aortic valve area (AVA) <1.0 cm2, and stroke volume index (SVi) ≤35 mL/m2 undergoing DSE were identified from three prospectively collected patient cohorts, and stratified according to LVEF; <35%, 35-50% and >50%. Severe AS was defined as AVC score ≥2000 AU among men, and ≥1200 AU for women. Recommendation for severe AS according to DSE, are an AVA <1.0 cm2 combined with an aortic mean gradient ≥40 mmHg or peak velocity ≥4 m/s. Receiver operating characteristic curves for DSE-derived AVA, mean gradient and Vmax were used to identify optimal cut-off points for each LVEF subgroup. Results Of the 221 patients included in the study, 78 (35%) presented with LVEF <35%, 67 (30%) with LVEF 35-50%, and 76 (34%) with LVEF >50%. Baseline characteristics are presented in the table. Based on AVC, severe AS was present in 102 (46%) of patients. Using recommended thresholds for severe AS for AVC and DSE, led to a sensitivity of 49%, a specificity of 84% and an accuracy of 67% for DSE for all patients with LVEF <50%, but with significant heterogeneity between groups figure. AVA performed rather uniformly across LVEF subgroups; (AUC =0.68 vs 0.62 vs 0.54, p=0.36) LVEF<35%, LVEF 35-50%, LVEF>50% respectively and displayed a rather uniform optimal cut-off (1.0 cm2 vs 0.9 cm2 vs 0.8 cm2). However, mean gradient and Vmax during DSE, both showed significantly diagnostic heterogeneity across LVEF groups (AUC= 0.90 vs 0.67 vs 0.65, p=<0.001 and AUC= 0.90 vs 0.66 vs 0.60, p=<0.001) with different optimal thresholds (30 mmHg & 3.8 m/s, 45 mmHg & 4.3 m/s and 37mmHg & 4 m/s, LVEF<35%, LVEF 35-50%, LVEF>50%, respectively). Conclusion Our study shows, that the association between DSE gradients and AS severity assessed by AVC demonstrates important heterogeneity depending on LVEF. While DSE had the highest accuracy in patients with LVEF<35% both patients with LVEF 35-50%, and patients with LVEF>50% showed significantly less concordance between DSE and AVC.

Abstract Introduction/Objective High-grade endometrial cancer (EC) recurs in 50% of patients following surgery and first-line chemotherapy. There are no established blood-based biomarkers with sufficient specificity and sensitivity to monitor EC patients for residual disease and recurrence. The ability to detect and monitor EC currently relies on serial imaging based approaches. Liquid biopsies via blood-based tests for cell-free circulating tumor DNA (ctDNA) are becoming increasingly popular, but none have been FDA approved for EC and current approaches have not been validated in patients with uncommon tumor mutations. We hypothesized that personalized testing panels based on tumor-specific chromosomal rearrangements would allow ctDNA to be monitored and that ctDNA presence correlates with other clinical indicators of recurrence. Methods/Case Report Twelve patients with FIGO Stage I-IV and biopsy confirmed high-grade EC were prospectively enrolled and underwent primary tumor resection. DNA was isolated from tumor tissue and sequenced on Illumina NGS platforms [San Diego, CA]. BIMA algorithm and SVAtools identified junctions of somatic chromosomal rearrangements and 4-5 junctions were chosen per patient, based primarily on copy number/amplification level. Blood was collected before surgery, and longitudinally between 1 and 7 timepoints. Total cell-free DNA (cfDNA) was extracted from platelet poor plasma with the Qiagen CNA kit [Germany]. Personalized ctDNA qPCR Taqman [IDT, Coralville, Iowa] probe assays were developed with pooled pre-amplification to maximize sensitivity for the multiple junctions and normalized to input. Results (if a Case Study enter NA) ctDNA was detected in 9/12 and 5/12 cases pre- and post-surgery, respectively. The detection or absence of measurable ctDNA following surgery showed high correlation with cancer recurrence as detected by CT or MRI scans. Conclusion The detection of ctDNA in high-grade EC using personalized junction panels shows promise for a blood-based assay that may help physicians better monitor and treat patients.

Background: Immunocompromised (IC) patients are at greater risk from cardiac surgery. Transcatheter aortic valve replacement (TAVR) may be more preferable for treating severe aortic stenosis (AS), though data regarding outcomes of IC patients are limited. Methods: We reviewed TAVR procedures performed at our institution from 1/2015-12/2019.We defined IC as either active malignancy receiving oncologic treatment or post organ transplant on immunosuppression, HIV, chronic steroid use (>5mg/day), or autoimmune disorder. Survival probability was estimated using the Kaplan-Meier (KM) method. Cox regression was used to evaluate the association of IC with survival. Results: Of 173 patients who underwent TAVR, 56 (32%) were IC: 30 (54%) had active malignancy undergoing active treatment, 19 (34%) were IC without malignancy, and 7 (13%) had both. Among the 19 IC patients without malignancy, 4 were post organ transplant, 3 were taking chronic steroids, 2 had autoimmune disorder, 1 had HIV, and 10 had ≥2 combination of the above. IC patients, as compared to non-IC patients, had similar baseline demographics and STS risk score (median 4.3 vs. 4.4), respectively. There were 37 deaths (16 IC and 21 non-IC) over a median follow up of 1.4 years (IQR 1.0-2.0 years). 1-year survival after TAVR was 84.5% for IC patients and 89.0% for non-IC patients (log rank p = 0.51). After adjusting for age and sex, an association between IC and survival was observed but not found to be statistically significant (adjusted HR, 1.55; 95% CI, 0.80-3.00). Conclusions: IC patients undergoing TAVR have similar baseline characteristics as non-IC patients with a trend towards worse survival. Longer term follow-up may help clarify the impact of IC status on survival after TAVR.

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Danish Heart Association. Background First-phase ejection fraction (EF1), the ejection fraction (EF) until the time of peak systolic flow may be a sensitive marker of subclinical left ventricular (LV) dysfunction. This study investigated the prognostic value of EF1 in asymptomatic and symptomatic severe aortic stenosis (AS). Methods This study included 94 asymptomatic and 108 symptomatic patients with severe AS. The prognostic value of EF1 was compared with other echocardiographic markers and magnetic resonance imaging (MRI) measured end-systolic wall stress and late gadolinium enhancement fibrosis (LGE). Asymptomatic patients were followed up for 3.0 years (primary outcome death or aortic valve replacement). Symptomatic patients were followed up for 4.3 years (primary outcome death). Results In multivariate regression analysis wall stress (p < 0.001) and LGE (p = 0.03) were associated with EF1. In the asymptomatic cohort EF1 was significantly associated with the end-point, especially among the subgroup of patients with a mean gradient < 40 mmHg (HR 0.91, p = 0.005), while global longitudinal strain was not. In the surgical cohort, EF1 was borderline associated with death (p = 0.08) which was significant after correction for LGE (HR 0.90, p = 0.02). Conclusion EF1 is a predictor of death or AVR in asymptomatic AS, especially among discordantly graded patients with low area and low gradient. Univariate β (95% CI) p-value Multivariate β (95% CI) p-value Age (years) .03 (-.09 to .16) 0.58 .03 (-.12 to .18) 0.69 Sex (male) -.12 (-2.26 to 2.03) 0.91 .24 (-2.31 to 2.80) 0.85 Hypertension -.08 (-2.22 to 2.07) 0.95 Aortic valve area (0.01 cm2) .09 (.04 to .14) 0.001 Aortic mean gradient (mmHg) -.02 (-.08 to .04) 0.56 LV end-diastolic volume (ml) -.07 (-.11 to -.03) <0.001 LV end-systolic volume (ml) -.17 (-.22 to -.12) <0.001 -.07 (-.15 to .02) 0.11 LV ejection fraction (%) .28 (.19 to .38) <0.001 LV peak ejection time (ms) -.07 (-.16 to .02) 0.13 LGE fibrosis -3.04 (-5.67 to -.42) 0.02 -2.64 (-4.99 to -.30) 0.03 Wall stress (kdynes/m3) -.10 (-.13 to -.08) <0.001 -.08 (-.12 to -.04) <0.001 Multivariate linear regression analysis for associations with first phase ejection fraction. LV is left ventricular, LGE late gadolinium enhancement Abstract Figure. AVR-free survival according to EF1