Novel echocardiographic pixel intensity quantification method for differentiating transthyretin cardiac amyloidosis from light chain cardiac amyloidosis and other phenocopies.

AIMS: Differentiating cardiac amyloidosis (CA) subtypes is important considering the significantly different therapies for transthyretin (ATTR)-CA and light chain (AL)-CA. Therefore, an echocardiographic method to distinguish ATTR-CA from AL-CA would provide significant value. We assessed a novel echocardiographic pixel intensity method to quantify myocardial calcification to differentiate ATTR-CA from phenocopies of CA and from AL-CA, specifically. METHODS AND RESULTS: 167 patients with ATTR-CA (n=53), AL-CA (n=32), hypertrophic cardiomyopathy (n=37), and advanced chronic kidney disease (n=45) were retrospectively evaluated. The septal reflectivity ratio (SRR) was measured as the average pixel intensity of the visible anterior septal wall divided by the average pixel intensity of the visible posterior lateral wall. SRR and other myocardial strain-based echocardiographic measures were evaluated with receiver operator characteristic analysis to evaluate accuracy in distinguishing ATTR-CA from AL-CA and other forms of left ventricular hypertrophy. Mean septal reflectivity ratio (SRR) was significantly higher in the ATTR-CA cohort compared to the other cohorts (p <0.001). SRR demonstrated the largest AUC (0.91, p<0.0001) for distinguishing ATTR from all other cohorts and specifically for distinguishing ATTR-CA from AL-CA (AUC=0.90, p<0.0001, specificity 96%, sensitivity 63%). There was excellent inter- and intra-operator reproducibility with an ICC of 0.91 (p <0.001) and 0.89 (p <0.001), respectively. CONCLUSION: The SRR is a reproducible and robust parameter for differentiating ATTR-CA from other phenocopies of CA and specifically ATTR-CA from AL-CA.

Cardiac Structural and Functional Remodeling After Transcatheter Mitral Valve in Valve Implantation: Early Changes and Prognostic Significance.

Background: Transcatheter mitral valve-in-valve (MViV) replacement has emerged as an alternative to redo mitral valve (MV) surgery for the management of failed bioprosthetic MVs. The degree of cardiac remodeling assessed by echocardiography has been shown to have prognostic implications in degenerative mitral regurgitation patients undergoing MV surgery. The impact of transcatheter MViV in patients with degenerative bioprosthetic MV failure on cardiac remodeling and its associated prognosis remains undescribed. Objectives: The aim of this study is to describe the early anatomic and functional changes of the left-sided chambers and right ventricle by echocardiography posttranscatheter MViV intervention and their impact on mortality outcomes. Additionally, we sought to analyze the outcome of heart failure in bioprosthetic MV failure patients undergoing transcatheter MViV replacement. Methods: We analyzed consecutive patients undergoing MViV intervention for symptomatic bioprosthetic MV failure. Echocardiograms before intervention and within 100 days postintervention were analyzed. A chart review was performed to obtain baseline characteristics, follow-up visits, 30-day heart failure and 1-year all-cause mortality outcomes. Results: A total of 62 patients (mean age 69 ± 13 years, 61% male) were included in the study. Most patients were undergoing MViV intervention for prosthetic mitral stenosis n = 48 (77.4%) and the rest for mitral regurgitation or mixed disease. Compared with baseline, significant reductions were observed in median left atrial volume (LAV; 103 [81-129] ml vs. 95.2 [74.5-117.5] ml, p < 0.01) and mean (SD) left atrial conduit strain (9.1% ± 5.2% vs. 10.8% ± 4.8%, p = 0.039) within 100 days postintervention. Early reduction in right ventricular free wall global longitudinal strain and fractional area change also occurred postintervention. No significant change in left ventricular chamber dimensions or ejection fraction was observed. During the 1-year follow up period, 5 (8%) patients died. While baseline LAV was not associated with 1-year all-cause mortality (OR 0.98 CI 0.95-1.01; p = 0.27), a change in LAV in the follow up period was associated with all-cause mortality at 1 year (OR 1.06 CI 1.01-1.12; p = 0.023). At 30 days postintervention, 65% of patients had an improvement in their New York Heart Association functional class. Conclusion: In this retrospective study of patients undergoing transcatheter MViV intervention for failed bioprosthetic MVs, early reverse remodeling of the left atrium occurs within 100 days postintervention and reduction in LAV is associated with reduced all-cause mortality at 1 year. In addition, there is significant improvement in heart failure symptoms at 30 days following intervention but further investigation into the longitudinal remodeling changes and long-term outcomes is needed.

Closing the Last Mile Gap in Access to Multimodality Imaging in Rural Settings: Design of the Imaging Core of the Risk Underlying Rural Areas Longitudinal Study.

Achieving optimal cardiovascular health in rural populations can be challenging for several reasons including decreased access to care with limited availability of imaging modalities, specialist physicians, and other important health care team members. Therefore, innovative solutions are needed to optimize health care and address cardiovascular health disparities in rural areas. Mobile examination units can bring imaging technology to underserved or remote communities with limited access to health care services. Mobile examination units can be equipped with a wide array of assessment tools and multiple imaging modalities such as computed tomography scanning and echocardiography. The detailed structural assessment of cardiovascular and lung pathology, as well as the detection of extracardiac pathology afforded by computed tomography imaging combined with the functional and hemodynamic assessments acquired by echocardiography, yield deep phenotyping of heart and lung disease for populations historically underrepresented in epidemiological studies. Moreover, by bringing the mobile examination unit to local communities, innovative approaches are now possible including engagement with local professionals to perform these imaging assessments, thereby augmenting local expertise and experience. However, several challenges exist before mobile examination unit-based examinations can be effectively integrated into the rural health care setting including standardizing acquisition protocols, maintaining consistent image quality, and addressing ethical and privacy considerations. Herein, we discuss the potential importance of cardiac multimodality imaging to improve cardiovascular health in rural regions, outline the emerging experience in this field, highlight important current challenges, and offer solutions based on our experience in the RURAL (Risk Underlying Rural Areas Longitudinal) cohort study.

Multiplexed screening reveals how cancer-specific alternative polyadenylation shapes tumor growth in vivo.

Alternative polyadenylation (APA) is strikingly dysregulated in many cancers. Although global APA dysregulation is frequently associated with poor prognosis, the importance of most individual APA events is controversial simply because few have been functionally studied. Here, we address this gap by developing a CRISPR-Cas9-based screen to manipulate endogenous polyadenylation and systematically quantify how APA events contribute to tumor growth in vivo. Our screen reveals individual APA events that control mouse melanoma growth in an immunocompetent host, with concordant associations in clinical human cancer. For example, forced Atg7 3' UTR lengthening in mouse melanoma suppresses ATG7 protein levels, slows tumor growth, and improves host survival; similarly, in clinical human melanoma, a long ATG7 3' UTR is associated with significantly prolonged patient survival. Overall, our study provides an easily adaptable means to functionally dissect APA in physiological systems and directly quantifies the contributions of recurrent APA events to tumorigenic phenotypes.

Age-Stratified Surgical Aortic Valve Replacement for Aortic Stenosis.

BACKGROUND: The management of aortic stenosis has evolved to stratification by age as reflected in recent societal guidelines. We evaluated age-stratified surgical aortic valve replacement (SAVR) trends and outcomes in patients with bicuspid aortic valve (BAV) or tricuspid aortic valve (TAV) from The Society of Thoracic Surgeons Adult Cardiac Surgery Database. METHODS: This cohort included adults (≥18 years) undergoing SAVR for severe aortic stenosis between July 2011 and December 2022. Comparisons were stratified by age (<65 years, 65-79 years, ≥80 years) and BAV or TAV status. Primary end points included operative mortality, composite morbidity and mortality, and permanent stroke. Observed to expected ratios by The Society of Thoracic Surgeons predicted risk of mortality were calculated. RESULTS: In total, 200,849 SAVR patients (55,326 BAV [27.5%], 145,526 TAV [72.5%]) from 1238 participating hospitals met study criteria. Annual SAVR volumes decreased by 45% (19,560 to 10,851) during the study period. The decrease was greatest (96%) for patients ≥80 years of age (4914 to 207). The relative prevalence of BAV was greater in younger patients (<65 years, 69,068 [49.5% BAV]; 65-79 years, 104,382 [19.1% BAV]; ≥80 years, 27,399 [4.5% BAV]). The observed mortality in <80-year-old BAV patients (<65 years, 1.08; 65-79 years, 1.21; ≥80 years, 3.68) was better than the expected mortality rate (<65 years, 1.22; 65-79 years, 1.54; ≥80 years, 3.14). CONCLUSIONS: SAVR volume in the transcatheter era has decreased substantially, particularly for patients ≥80 years old and for those with TAV. Younger patients with BAV have better than expected outcomes, which should be carefully considered during shared decision-making in the treatment of aortic stenosis. SAVR should remain the preferred therapy in this population.

Echocardiographic parameters associated with less reverse left ventricular remodeling after transcatheter aortic valve implant in subjects with prosthesis patient mismatch.

BACKGROUND: Transaortic valve implant (TAVI) is the treatment of choice for severe aortic stenosis (AS). Some patients develop prosthesis patient mismatch (PPM) after TAVI. It is challenging to determine which patients are at risk for clinical deterioration. METHODS: We retrospectively measured echocardiographic parameters of left ventricular (LV) morphology and function, prosthetic aortic valve effective orifice area (iEOA) and hemodynamics in 313 patients before and 1 year after TAVI. Our objective was to compare the change in echocardiographic parameters associated with left ventricular reverse modeling in subjects with and without PPM. Our secondary objective was to evaluate echo parameters associated with PPM and the relationship to patient functional status and survival post-TAVI. RESULTS: We found that 82 (26.2%) of subjects had moderate and 37 (11.8%) had severe PPM post-TAVI. There was less relative improvement in LVEF with PPM (1.9 ± 21.3% vs. 8.2 + 30.1%, p = .045). LV GLS also exhibited less relative improvement in those with PPM (13.4 + 34.1% vs. 30.9 + 73.3%, p = .012). NYHA functional class improved in 84.3% of subjects by one grade or more. Echocardiographic markers of PPM were worse in those without improvement in NYHA class (mean AT/ET was .29 vs. .27, p = .05; DVI was .46 vs. .51, p = .021; and iEOA was .8 cm/m2 vs. .9 cm/m2 , p = .025). There was no association with PPM and survival. CONCLUSIONS: There was no improvement in LVEF and less improvement in LV GLS in those with PPM post-TAVI. Echocardiographic markers of PPM were present in those with lack of improvement in NYHA functional class.

Valvular and ascending aortic hemodynamics of the On-X aortic valved conduit by same-day echocardiography and 4D flow MRI.

This study aims to assess whether the On-X aortic valved conduit better restores normal valvular and ascending aortic hemodynamics than other commonly used bileaflet mechanical valved conduit prostheses from St. Jude Medical and Carbomedics by using same-day transthoracic echocardiography (TTE) and 4D flow magnetic resonance imaging (MRI) examinations. TTE and 4D flow MRI were performed back-to-back in 10 patients with On-X, six patients with St. Jude (two) and Carbomedics (four) prostheses, and 36 healthy volunteers. TTE evaluated valvular hemodynamic parameters: transvalvular peak velocity (TPV), mean and peak transvalvular pressure gradient (TPG), and effective orifice area (EOA). 4D flow MRI evaluated the peak systolic 3D viscous energy loss rate (VELR) density and mean vorticity magnitude in the ascending aorta (AAo). While higher TPV and mean and peak TPG were recorded in all patients compared to healthy subjects, the values in On-X patients were closer to those in healthy subjects (TPV 1.9 ± 0.3 vs. 2.2 ± 0.3 vs. 1.2 ± 0.2 m/s, mean TPG 7.4 ± 1.9 vs. 9.2 ± 2.3 vs. 3.1 ± 0.9 mmHg, peak TPG 15.3 ± 5.2 vs. 18.9 ± 5.2 vs. 6.1 ± 1.8 mmHg, p < 0.001). Likewise, while higher VELR density and mean vorticity magnitude were recorded in all patients than in healthy subjects, the values in On-X patients were closer to those in healthy subjects (VELR: 50.6 ± 20.1 vs. 89.8 ± 35.2 vs. 21.4 ± 9.2 W/m3, p < 0.001) and vorticity (147.6 ± 30.0 vs. 191.2 ± 26.0 vs. 84.6 ± 20.5 s-1, p < 0.001). This study demonstrates that the On-X aortic valved conduit may produce less aberrant hemodynamics in the AAo while maintaining similar valvular hemodynamics to St. Jude Medical and Carbomedics alternatives.

Deep Learning for Cardiovascular Imaging: A Review.

Importance: Artificial intelligence (AI), driven by advances in deep learning (DL), has the potential to reshape the field of cardiovascular imaging (CVI). While DL for CVI is still in its infancy, research is accelerating to aid in the acquisition, processing, and/or interpretation of CVI across various modalities, with several commercial products already in clinical use. It is imperative that cardiovascular imagers are familiar with DL systems, including a basic understanding of how they work, their relative strengths compared with other automated systems, and possible pitfalls in their implementation. The goal of this article is to review the methodology and application of DL to CVI in a simple, digestible fashion toward demystifying this emerging technology. Observations: At its core, DL is simply the application of a series of tunable mathematical operations that translate input data into a desired output. Based on artificial neural networks that are inspired by the human nervous system, there are several types of DL architectures suited to different tasks; convolutional neural networks are particularly adept at extracting valuable information from CVI data. We survey some of the notable applications of DL to tasks across the spectrum of CVI modalities. We also discuss challenges in the development and implementation of DL systems, including avoiding overfitting, preventing systematic bias, improving explainability, and fostering a human-machine partnership. Finally, we conclude with a vision of the future of DL for CVI. Conclusions and Relevance: Deep learning has the potential to meaningfully affect the field of CVI. Rather than a threat, DL could be seen as a partner to cardiovascular imagers in reducing technical burden and improving efficiency and quality of care. High-quality prospective evidence is still needed to demonstrate how the benefits of DL CVI systems may outweigh the risks.

Cardiac Effects of Long-Duration Space Flight.

BACKGROUND: Ventricular mass responds to changes in physical activity and loading, with cardiac hypertrophy after exercise training, and cardiac atrophy after sustained inactivity. Ventricular wall stress (ie, loading) decreases during microgravity. Cardiac atrophy does not plateau during 12 weeks of simulated microgravity but is mitigated by concurrent exercise training. OBJECTIVES: The goal of this study was to determine whether the current exercise countermeasures on the International Space Station (ISS) offset cardiac atrophy during prolonged space flight. METHODS: We measured left ventricular (LV) and right ventricular (RV) mass and volumes (via magnetic resonance imaging) in 13 astronauts (4 females; age 49 ± 4 years), between 75 and 60 days before and 3 days after 155 ± 31 days aboard the ISS. Furthermore, we assessed total cardiac work between 21 and 7 days before space flight and 15 days before the end of the mission. Data were compared via paired-samples t-tests. RESULTS: Total cardiac work was lower during space flight (P = 0.008); however, we observed no meaningful difference in LV mass postflight (pre: 115 ± 30 g vs post: 118 ± 29 g; P = 0.053), with marginally higher LV stroke volume (P = 0.074) and ejection fraction postflight (P = 0.075). RV mass (P = 0.999), RV ejection fraction (P = 0.147), and ventricular end-diastolic (P = 0.934) and end-systolic volumes (P = 0.145) were not different postflight. There were strong positive correlations between the relative change in LV mass with the relative changes in total cardiac output (r = 0.73; P = 0.015) and total cardiac work (r = 0.53; P = 0.112). CONCLUSIONS: The current exercise countermeasures used on the ISS appear effective in offsetting reductions in cardiac mass and volume, despite overall reductions in total cardiac work, during prolonged space flight.

pgMAP: a pipeline to enable guide RNA read mapping from dual-targeting CRISPR screens.

We developed pgMAP, an analysis pipeline to map gRNA sequencing reads from dual-targeting CRISPR screens. pgMAP output includes a dual gRNA read counts table and quality control metrics including the proportion of correctly-paired reads and CRISPR library sequencing coverage across all time points and samples. pgMAP is implemented using Snakemake and is available open-source under the MIT license at https://github.com/fredhutch/pgmap_pipeline.

Late results of chord transfer and other techniques for anterior leaflet repair without neochords.

OBJECTIVE: Anterior and bileaflet degenerative mitral regurgitation repairs are challenging. We examined our early and late outcomes for repair using 4 techniques, without neochord repair. METHODS: Between February 1, 2006, and June 30, 2021, a total of 2368 patients received mitral valve ± other surgery by 1 surgeon, including 1160 with degenerative mitral regurgitation. Clinical follow-up was conducted annually (mean 6.8 ± 4.4 years). RESULTS: Repair was performed in 1137 patients (98%) (mean age, 60.5 ± 11.9 years). Repair rate varied between groups: 99% for isolated posterior leaflet (794/799), 91% for isolated anterior leaflet (83/91), and 96% for bileaflet prolapse (260/270; P < .001). Thirty-day mortality was 0.2%. On a scale of 0 to 4+ mitral regurgitation, mean mitral regurgitation grade decreased from 3.8 ± 0.6 preoperatively to 0.07 ± 0.3 at discharge, including moderate (2+) in 0.6% (7/1137) overall and 0.9% (3/343) with anterior prolapse. None were more than 2+ at discharge. Among the 3 groups of leaflet prolapse, there was no significant difference in long-term survival (P = .26), freedom from mitral valve reintervention (P = .12; 99.4% overall), and freedom from more than moderate (2+) mitral regurgitation (P = .16; 98.3% overall). The 4 most common anterior leaflet repair techniques (chord transfer 17%; commissuroplasty 10%; Alfieri [edge-to-edge] 6%); ring with posterior resection (4.3%) had similar freedom from 10-year reintervention (99.4%, 94%, 100%, and 100%, respectively; P = .29). CONCLUSIONS: Complex anterior leaflet prolapse repairs are successful using a variety of techniques without neochord implantation. Although neochords are popular, there are other ways to repair complex valves that do not require as much judgment and experience.

Characterization of Screen Failures Among Patients Evaluated for Transcatheter Tricuspid Valve Repair (TriSelect-Study).

BACKGROUND: Transcatheter tricuspid valve repair (TTVr) has significantly expanded treatment options for tricuspid regurgitation (TR). However, a sizeable proportion of patients are still declined for TTVr and little is known about their clinical characteristics and cardiac morphology. OBJECTIVES: This study sought to characterize patients who screen fail for TTVr with respect to their clinical characteristics and cardiac morphology. METHODS: A total of 547 patients were evaluated for TTVr between January 2016 to December 2021 from 3 centers in the United States and Germany. Clinical records and echocardiographic studies were used to assess medical history and right ventricular (RV) and tricuspid valve (TV) characteristics. RESULTS: Median age was 80 (IQR: 74-83) years and 60.0% were female. Over half (58.1%) were accepted for TTVr. Of those who were deemed unsuitable for TTVr (41.9%), the most common exclusion reasons were anatomical criteria (56.8%). In the regression analysis, RV and right atrial size, TV coaptation gap, and tethering area were identified as independent screen failure predictors. Other rejection reasons included clinical futility (17.9%), low symptom burden (12.7%), and technical limitations (12.7%). Most of the excluded patients (71.6%) were managed conservatively with medical therapy, while a small number either proceeded to TV surgery (22.3%) or subsequently became eligible for transcatheter tricuspid valve replacement in later available clinical trials in the United States (6.1%). CONCLUSIONS: The majority of TTVr screen failure patients are excluded due to TV, right atrial, and RV enlargement. However, a significant proportion is excluded due to clinical futility. These identifiable anatomical and clinical characteristics emphasize the importance of earlier referral and intervention of TR and the need for continued innovation of Transcatheter tricuspid valve interventions.

Relationship between left atrial reservoir strain, volumes, and geometry: Insights from simple theoretical model.

BACKGROUND: Left atrial (LA) volume is related to LA reservoir strain (LASR ), but the relationship is not fully resolved. We sought to model the relationship between LA end-diastolic and end-systolic volumes (LAEDV and LAESV) and LASR based on a geometrical approach to exploit the relationship between LASR and volume. METHODS: Modeling the LA as a hemisphere with radius r, LASR was recognized to vary linearly with r and LA volume with r3 . Expanding this cubic relation as a Taylor series resulted in a simple linear equation: LAESV/LAEDV = 1 + 3 × LASR . To validate this, 52 transthoracic echocardiograms were analyzed from 18 patients who underwent transcatheter edge-to-edge repair (TEER) with MitraClip with serial assessment pre-procedure, 1 month post-clip, and 12 months post-TEER. Linear regression was performed to compare the geometric equation to a statistical model created by a line of best fit to relate LAESV/LAEDV to LASR . RESULTS: The statistical and geometric model both resulted in a strong correlation (r = .8, p < .001, respectively). The slope of the line in the statistical model was 3.3, which was statistically indistinguishable from the expected slope of 3 based on the geometric model (Figure 2A). Using the geometric model to compare the measured versus calculated LAESV/LAEDV also resulted in a strong correlation (r = .8, p < .001)(Figure 2B). CONCLUSION: We describe the relationship between LA volume and strain mathematically by considering the geometry of the LA. This model enhances our understanding of the interaction between atrial strain and volume. Further research is necessary to validate this using 3D atrial volumes in a broader cohort of subjects.

The Emerging Role of Artificial Intelligence in Valvular Heart Disease.

Valvular heart disease (VHD) is a morbid condition in which timely identification and evidence-based treatments can lead to improved outcomes. Artificial intelligence broadly refers to the ability for computers to perform tasks and problem solve like the human mind. Studies applying AI to VHD have used a variety of structured (eg, sociodemographic, clinical) and unstructured (eg, electrocardiogram, phonocardiogram, and echocardiograms) and machine learning modeling approaches. Additional researches in diverse populations, including prospective clinical trials, are needed to evaluate the effectiveness and value of AI-enabled medical technologies in clinical care for patients with VHD.

Percutaneous MitraClip Device or Surgical Mitral Valve Repair in Patients With Primary Mitral Regurgitation Who Are Candidates for Surgery: Design and Rationale of the REPAIR MR Trial.

Background The current standard of care for the treatment of patients with primary mitral regurgitation (MR) is surgical mitral valve repair. Transcatheter edge-to-edge repair with the MitraClip device provides a less invasive treatment option for patients with both primary and secondary MR. Worldwide, >150 000 patients have been treated with the MitraClip device. However, in the United States, MitraClip is approved for use only in primary patients with MR who are at high or prohibitive risk for mitral valve surgery. The REPAIR MR (Percutaneous MitraClip Device or Surgical Mitral Valve Repair in Patients With Primary Mitral Regurgitation Who Are Candidates for Surgery) trial is designed to compare early and late outcomes associated with transcatheter edge-to-edge repair with the MitraClip and surgical repair of primary MR in older or moderate surgical risk patients. Methods and Results The REPAIR MR trial is a prospective, randomized, parallel-controlled, open-label multicenter, noninferiority trial for the treatment of severe primary MR (verified by an independent echocardiographic core laboratory). Patients with severe MR and indications for surgery because of symptoms (New York Heart Association class II-IV), or without symptoms with left ventricular ejection fraction ≤60%, pulmonary artery systolic pressure >50 mm Hg, or left ventricular end-systolic diameter ≥40 mm are eligible for the trial provided they meet the moderate surgical risk criteria as follows: (1) ≥75 years of age, or (2) if <75 years of age, then the subject has a Society of Thoracic Surgeons Predicted Risk Of Mortality score of ≥2% for mitral repair (or Society of Thoracic Surgeons replacement score of ≥4%), or the presence of a comorbidity that may introduce a surgery-specific risk. The local surgeon must determine that the mitral valve can be surgically repaired. Additionally, an independent eligibility committee will confirm that the MR can be reduced to mild or less with both the MitraClip and surgical mitral valve repair with a high degree of certainty. A total of 500 eligible subjects will be randomized in a 1:1 ratio to receive the MitraClip device or to undergo surgical mitral valve repair (control group). There are 2 co-primary end points for the trial, both of which will be evaluated at 2 years. Each subject will be followed for 10 years after enrollment. The study has received approval from both the Food and Drug Administration and the Centers for Medicare and Medicaid Services, and enrolled its first subject in July 2020. Conclusions The REPAIR MR trial will determine the safety and effectiveness of transcatheter edge-to-edge repair with the MitraClip in patients with primary MR who are at moderate surgical risk and are candidates for surgical MV repair. The trial will generate contemporary comparative clinical evidence for the MitraClip device and surgical MV repair. Registration https://clinicaltrials.gov/ct2/show/NCT04198870; NCT04198870.

Impact of assuming a circular orifice on flow error through elliptical regurgitant orifices: computational fluid dynamics and in vitro analysis of proximal flow convergence.

Grounded in hydrodynamic theory, proximal isovelocity surface area (PISA) is a simplistic and practical technique widely used to quantify valvular regurgitation flow. PISA provides a relatively reasonable, though slightly underestimated flow rate for circular orifices. However, for elliptical orifices frequently seen in functional mitral regurgitation, PISA underestimates the flow rate. Based on data obtained with computational fluid dynamics (CFD) and in vitro experiments using systematically varied orifice parameters, we hypothesized that flow rate underestimation for elliptical orifices by PISA is predictable and within a clinically acceptable range. We performed 45 CFD simulations with varying orifice areas 0.1, 0.3 and 0.5 cm2, orifice aspect ratios 1:1, 2:1, 3:1, 5:1, and 10:1, and peak velocities (Vmax) 400, 500 and 600 cm/s. The ratio of computed effective regurgitant orifice area to true effective area (EROAC/EROA) against the ratio of aliasing velocity to peak velocity (VA/Vmax) was analyzed for orifice shape impact. Validation was conducted with in vitro imaging in round and 3:1 elliptical orifices. Plotting EROAC/EROA against VA/Vmax revealed marginal flow underestimation with 2:1 and 3:1 elliptical axis ratios against a circular orifice (< 10% for 8% VA/Vmax), rising to ≤ 35% for 10:1 ratio. In vitro modeling confirmed CFD findings; there was a 8.3% elliptical EROA underestimation compared to the circular orifice estimate. PISA quantification for regurgitant flow through elliptical orifices produces predictable, but generally small, underestimation deemed clinically acceptable for most regurgitant orifices.