Optogenetic closed-loop feedback control of the unfolded protein response optimizes protein production.

In biotechnological protein production processes, the onset of protein unfolding at high gene expression levels leads to diminishing production yields and reduced efficiency. Here we show that in silico closed-loop optogenetic feedback control of the unfolded protein response (UPR) in S. cerevisiae clamps gene expression rates at intermediate near-optimal values, leading to significantly improved product titers. Specifically, in a fully-automated custom-built 1L-photobioreactor, we used a cybergenetic control system to steer the level of UPR in yeast to a desired set-point by optogenetically modulating the expression of α-amylase, a hard-to-fold protein, based on real-time feedback measurements of the UPR, resulting in 60% higher product titers. This proof-of-concept study paves the way for advanced optimal biotechnology production strategies that diverge from and complement current strategies employing constitutive overexpression or genetically hardwired circuits.

Contemporary post-marketing adverse events and modes of failure related to VASCADE Vascular Closure System: The utility of the MAUDE database.

OBJECTIVES: To analyze post-marketing surveillance data from the United States Food and Drug Administration (FDA) Manufacturer and User Facility Device Experience (MAUDE) database for the VASCADE Vascular Closure System (Cardiva Medical Inc., Santa Clara, CA). BACKGROUND: The VASCADE Vascular Closure System is a closure device for femoral arterial and venous access-site closure that was approved by the FDA in 2013. However, post-marketing data and experience on the most commonly reported complications and modes of failure associated with the VASCADE Vascular Closure System are limited. METHODS: Post-marketing surveillance data from the FDA MAUDE database from October 2013 through March 2020 were analyzed, yielding 201 reports. RESULTS: Of the 201 reports of major complications involving VASCADE devices, 156 reports involved either injury (145) or death (11) related to the device. Of the 145 injury reports, bleeding was the most common adverse outcome described (85), followed by pseudoaneurysm (29) and pulselessness of an extremity (21). The device malfunction incidents (41 reports) were reported in three main categories, with deployment failure being the most commonly reported complication. CONCLUSIONS: Our analysis of the MAUDE database demonstrates that in contemporary post-marketing practice, physicians should be well-trained and educated to use the VASCADE closure device because improper utilization is a common cause of device failure, and complications with the VASCADE device can have profound clinical implications.

Real-world experience of suture-based closure devices: Insights from the FDA Manufacturer and User Facility Device Experience.

OBJECTIVES: We analyzed post-marketing surveillance data from the United States Food and Drug Administration (FDA) Manufacturer and User Facility Device Experience (MAUDE) database for suture-based vascular closure devices (VCDs) - Perclose ProGlide (Abbott, Chicago, Illinois) and Prostar XL (Abbott). BACKGROUND: Suture-based VCDs are mostly used for large-bore femoral arterial access-site closure. Real-world, contemporary experience on the most commonly reported complications and modes of failure associated with these devices is limited. METHODS: Post-marketing surveillance data from the FDA MAUDE database, for the ProGlide system and for the Prostar XL system, were analyzed, yielding 827 Perclose ProGlide reports and 175 Prostar XL reports. RESULTS: Of the 827 reports of major complications involving the Perclose ProGlide devices, 404 reports involved injury, and one involved death related to the device. In the Prostar XL analysis, 94 reports involved injury, and one involved death. Bleeding from vessel injury was the most common adverse outcome described with both devices, followed by hematoma and thrombus. Surgical repair was the most commonly used treatment strategy. In terms of device malfunction, suture-related malfunction (212 reports) was most commonly seen in the Perclose ProGlide group, while failed deployment was most commonly seen in the Prostar XL group. CONCLUSIONS: Our analysis of the MAUDE database demonstrates that in real-world practice, suture-based VCDs were found to be associated with complications, including vascular injury, difficulties with the device itself, and even death. Ongoing user education and pre-procedural patient selection are important to minimize risks associated with suture-based vascular closure devices.

GLP-1 RA for cardiometabolic risk reduction in obesity - How do we best describe benefit and value?

How do we assess the overall benefit and value of GLP1-RAs? Current clinical trials often focus narrowly on individual atherosclerotic cardiovascular endpoints like MACE, potentially missing broader GLP-1 RA benefits across multiple comorbidities. Herein, we set out a framework for expanding outcome analyses in large trials that we believe will provide a more holistic understanding of GLP-1 RA benefits across the cardio-kidney-metabolic (CKM) spectrum, guiding patient care, guidelines, and insurance coverage decisions.

Advanced methods for gene network identification and noise decomposition from single-cell data.

Central to analyzing noisy gene expression systems is solving the Chemical Master Equation (CME), which characterizes the probability evolution of the reacting species' copy numbers. Solving CMEs for high-dimensional systems suffers from the curse of dimensionality. Here, we propose a computational method for improved scalability through a divide-and-conquer strategy that optimally decomposes the whole system into a leader system and several conditionally independent follower subsystems. The CME is solved by combining Monte Carlo estimation for the leader system with stochastic filtering procedures for the follower subsystems. We demonstrate this method with high-dimensional numerical examples and apply it to identify a yeast transcription system at the single-cell resolution, leveraging mRNA time-course experimental data. The identification results enable an accurate examination of the heterogeneity in rate parameters among isogenic cells. To validate this result, we develop a noise decomposition technique exploiting time-course data but requiring no supplementary components, e.g., dual-reporters.

Frailty and Metabolic Vulnerability in Heart Failure: A Community Cohort Study.

BACKGROUND: Frailty is common in heart failure (HF) and is associated with death but not routinely captured clinically. Frailty is linked with inflammation and malnutrition, which can be assessed by a novel plasma multimarker score: the metabolic vulnerability index (MVX). We sought to evaluate the associations between frailty and MVX and their prognostic impact. METHODS AND RESULTS: In an HF community cohort (2003-2012), we measured frailty as a proportion of deficits present out of 32 physical limitations and comorbidities, MVX by nuclear magnetic resonance spectroscopy, and collected extensive longitudinal clinical data. Patients were categorized by frailty score (≤0.14, >0.14 and ≤0.27, >0.27) and MVX score (≤50, >50 and ≤60, >60 and ≤70, >70). Cox models estimated associations of frailty and MVX with death, adjusted for Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) score and NT-proBNP (N-terminal pro-B-type natriuretic peptide). Uno's C-statistic measured the incremental value of MVX beyond frailty and clinical factors. Weibull's accelerated failure time regression assessed whether MVX mediated the association between frailty and death. We studied 985 patients (median age, 77; 48% women). Frailty and MVX were weakly correlated (Spearman's ρ=0.21). The highest frailty group experienced an increased rate of death, independent of MVX, MAGGIC score, and NT-proBNP (hazard ratio, 3.3 [95% CI, 2.5-4.2]). Frailty improved Uno's c-statistic beyond MAGGIC score and NT-proBNP (0.69-0.73). MVX only mediated 3.3% and 4.5% of the association between high and medium frailty groups and death, respectively. CONCLUSIONS: In this HF cohort, frailty and MVX are weakly correlated. Both independently contribute to stratifying the risk of death, suggesting that they capture distinct domains of vulnerability in HF.

Heart failure without a reduced ejection fraction.

Heart failure (HF) substantially impacts the health and financial security of an increasing proportion of the US population. It worsens debility and quality of life and may lead to hospitalization and death. HF is a clinical syndrome with diverse symptomatic presentations. Physicians generally divide patients with HF into 2 groups: those with a left ventricular ejection fraction (LVEF) greater than or equal to 50% and those with an LVEF less than 49%. This review focuses on the group of patients whose LVEF is greater than or equal to 50%. This classification of HF is referred to as HF with a preserved ejection fraction (HFpEF). Few beneficial therapies have been identified for this condition, possibly because of its heterogenous etiologies (eg, myocardial, vascular, metabolic, and other physiologic derangements). Clinicians should focus on diagnosing, treating, and preventing the etiologies that are known to cause HFpEF. Results from a small proportion of randomized controlled trials have shown therapeutic benefit for small molecules, although limited, if any, demonstrated mortality benefit has been noted. More research and investment are needed to decrease the burden of HFpEF and to discover lifesaving treatments for this growing population.

Diya - A universal light illumination platform for multiwell plate cultures.

Recent progress in protein engineering has established optogenetics as one of the leading external non-invasive stimulation strategies, with many optogenetic tools being designed for in vivo operation. Characterization and optimization of these tools require a high-throughput and versatile light delivery system targeting micro-titer culture volumes. Here, we present a universal light illumination platform - Diya, compatible with a wide range of cell culture plates and dishes. Diya hosts specially designed features ensuring active thermal management, homogeneous illumination, and minimal light bleedthrough. It offers light induction programming via a user-friendly custom-designed GUI. Through extensive characterization experiments with multiple optogenetic tools in diverse model organisms (bacteria, yeast, and human cell lines), we show that Diya maintains viable conditions for cell cultures undergoing light induction. Finally, we demonstrate an optogenetic strategy for in vivo biomolecular controller operation. With a custom-designed antithetic integral feedback circuit, we exhibit robust perfect adaptation and light-controlled set-point variation using Diya.

Characterization of Myocardial Injury With High-Sensitivity Troponin.

BACKGROUND: High-sensitivity troponin I, cardiac form (hs-cTnI) accelerates the assessment of acute coronary syndrome. Little has been documented about its performance, how it relates to different types of myocardial injury, and its impact on morbidity and mortality. This study sought to expand understanding of hs-cTnI by characterizing types of myocardial injury, the impact of comorbidities, and 30-day outcomes. METHODS: The study retrospectively evaluated 1,975 patients with hs-cTnI levels obtained in the emergency department or inpatient setting from June to September 2020. Troponin was considered elevated if it was higher than the 99th percentile for either sex. Charts were reviewed to determine the presence of myocardial injury. Troponin elevation was adjusted for demographics, comorbidities, and kidney dysfunction. Thirty-day mortality and readmission rates were calculated. RESULTS: Of 1,975 patients, 468 (24%) had elevated hs-cTnI, and 330 (17%) had at least 1 type of myocardial injury, type 2 myocardial infarction being the most frequent. Sensitivity and specificity using the 99th percentile as a cutoff were 99% and 92%, respectively. The average maximum hs-cTnI level was significantly higher for type 1 myocardial infarction (P < .001). Being male, Black, non-Hispanic, and a hospital inpatient were all associated with higher initial and peak hs-cTnI levels (P < .001). Elevated hs-cTnI level, age, heart disease, kidney dysfunction, and inpatient status were predictive of 30-day mortality on multivariate analysis. CONCLUSION: Elevated hs-cTnI levels in emergency department and inpatient settings occurs most commonly because of type 2 myocardial infarction. Maximum hs-cTnI level is associated with the patient's particular type of myocardial injury, certain demographics, and cardiovascular comorbidities, and it may be a predictor of 30-day outcomes.

In-Hospital Heart Failure in Patients With Takotsubo Cardiomyopathy Due to Coronary Artery Disease: An Artificial Intelligence and Optical Coherence Tomography Study.

BACKGROUND: Takotsubo syndrome (TTS) is often associated with symptoms of heart failure (HF) during the acute phase of the disease. 3-dimensional optical coherence tomography (OCT) may be used to assess the extent of angiographically silent underlying coronary artery disease (CAD). This study aims to use an artificial intelligence algorithm to analyze OCT findings and to determine whether the presence of pre-existing CAD predisposes TTS patients to present HF at admission. METHODS: This is an observational and retrospective study that enrolled TTS patients who underwent coronary angiography and OCT examination of left anterior descending (LAD) coronary artery. Plaque characterization was automatically analyzed via an artificial intelligence model from OCT images. An angiography-derived index of microcirculatory resistance (IMRangio) using the optic flow ratio (OFR) was calculated to assess its correlation with plaque volumes. RESULTS: Thirty-seven patients were included (94.6 % women) with a median age of 82.0 years. Ten patients (27 %) showed some degree of HF at admission. Sixty-seven coronary non-obstructive plaques were analyzed. Tissue compositional analysis showed that patients with HF had an increased overall plaque volume (79.0 mm3 vs 28.6 mm3; p = 0.011) and longer plaque lesion length (12.8 mm vs 7.2 mm; p = 0.006). Patients with HF also showed an increased percentage of lipidic and calcified plaque tissue (26.4 % vs 13.4 %; p = 0.019 and 4.5 % vs 0.0 %; p = 0.001, respectively). A moderate positive correlation was found between global overall plaque volume and IMRangio. CONCLUSION: Increased overall plaque volume was associated with the development of HF during the acute phase of TTS, suggesting that the presence of angiographically silent underlying CAD may play a prognostic role in these patients.

Imaging modality for left ventricular ejection fraction estimation and effect of implantable cardioverter-defibrillator on mortality in patients with heart failure.

BACKGROUND: Implantable cardioverter-defibrillators (ICDs) improve outcomes in patients with heart failure (HF) with left ventricular ejection fraction (LVEF) ≤35%. Less is known about whether outcomes varied between the 2 noninvasive imaging modalities used to estimate LVEF-2-dimensional echocardiography (2DE) and multigated acquisition radionuclide ventriculography (MUGA)-which use different principles (geometric vs count-based, respectively). OBJECTIVE: The purpose of this study was to examine whether the effect of ICD on mortality in patients with HF and LVEF ≤35% varied on the basis of LVEF measured by 2DE or MUGA. METHODS: Of the 2521 patients with HF with LVEF ≤35% in the Sudden Cardiac Death in Heart Failure Trial, 1676 (66%) were randomized to either placebo or ICD, of whom 1386 (83%) had LVEF measured by 2DE (n = 971) or MUGA (n = 415). Hazard ratios (HRs) and 97.5% confidence intervals (CIs) for mortality associated with ICD were estimated overall, checking for interaction, and within the 2 imaging subgroups. RESULTS: Of the 1386 patients in the present analysis, all-cause mortality occurred in 23.1% (160 of 692) and 29.7% (206 of 694) of patients randomized to ICD or placebo, respectively (HR 0.77; 97.5% CI 0.61-0.97), which is consistent with that in 1676 patients in the original report. HRs (97.5% CIs) for all-cause mortality in the 2DE and MUGA subgroups were 0.79 (0.60-1.04) and 0.72 (0.46-1.11), respectively (P = .693 for interaction). Similar associations were observed for cardiac and arrhythmic mortalities. CONCLUSION: We found no evidence that in patients with HF and LVEF ≤35%, the effect of ICD on mortality varied by the noninvasive imaging method used to measure LVEF.

Fractional flow reserve use in coronary artery revascularization: A systematic review and meta-analysis.

Fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) is recommended in revascularization guidelines for intermediate lesions. However, recent studies comparing FFR-guided PCI with non-physiology-guided revascularization have reported conflicting results. PubMed and Embase were searched for studies comparing FFR-guided PCI with non-physiology-guided revascularization strategies (angiography-guided, intracoronary imaging-guided, coronary artery bypass grafting). Data were pooled by meta-analysis using random-effects model. 26 studies enrolling 78,897 patients were included. FFR-guided PCI as compared to non-physiology-guided coronary revascularization had lower risk of all-cause mortality (odds ratio [OR] 0.79 95% confidence interval [CI] 0.64-0.99, I2 = 53%) and myocardial infarction (MI) (OR 0.74 95% CI 0.59-0.93, I2 = 44.7%). However, no differences between groups were found in terms of major adverse cardiac events (MACEs) (OR 0.86 95% CI 0.72-1.03, I2 = 72.3%) and repeat revascularization (OR 1 95% CI 0.82-1.20, I2 = 43.2%). Among patients with coronary artery disease (CAD), FFR-guided PCI as compared to non-physiology-guided revascularization was associated with a lower risk of all-cause mortality and MI.

Cardiovascular risk stratification among individuals with obesity: The Coronary Artery Calcium Consortium.

OBJECTIVE: The effectiveness of coronary artery calcification (CAC) for risk stratification in obesity, in which imaging is often limited because of a reduced signal to noise ratio, has not been well studied. METHODS: Data from 9334 participants (mean age: 53.3 ± 9.7 years; 67.9% men) with BMI ≥ 30 kg/m2 from the CAC Consortium, a retrospectively assembled cohort of individuals with no prior cardiovascular diseases (CVD), were used. The predictive value of CAC for all-cause and cause-specific mortality was evaluated using multivariable-adjusted Cox proportional hazards and competing-risks regression. RESULTS: Mean BMI was 34.5 (SD 4.4) kg/m2 (22.7% Class II and 10.8% Class III obesity), and 5461 (58.5%) had CAC. Compared with CAC = 0, those with CAC = 1-99, 100-299, and ≥300 Agatston units had higher rates (per 1000 person-years) of all-cause (1.97 vs. 3.5 vs. 5.2 vs. 11.3), CVD (0.4 vs. 1.1 vs. 1.5 vs. 4.2), and coronary heart disease (CHD) mortality (0.2 vs. 0.6 vs. 0.6 vs. 2.5), respectively, after mean follow-up of 10.8 ± 3.0 years. After adjusting for traditional cardiovascular risk factors, CAC ≥ 300 was associated with significantly higher risk of all-cause (hazard ratio [HR]: 2.05; 95% CI: 1.49-2.82), CVD (subdistribution HR: 3.48; 95% CI: 1.81-6.70), and CHD mortality (subdistribution HR: 5.44; 95% CI: 2.02-14.66), compared with CAC = 0. When restricting the sample to individuals with BMI ≥ 35 kg/m2 , CAC ≥ 300 remained significantly associated with the highest risk. CONCLUSIONS: Among individuals with obesity, including moderate-severe obesity, CAC strongly predicts all-cause, CVD, and CHD mortality and may serve as an effective cardiovascular risk stratification tool to prioritize the allocation of therapies for weight management.

Platforms for Optogenetic Stimulation and Feedback Control.

Harnessing the potential of optogenetics in biology requires methodologies from different disciplines ranging from biology, to mechatronics engineering, to control engineering. Light stimulation of a synthetic optogenetic construct in a given biological species can only be achieved via a suitable light stimulation platform. Emerging optogenetic applications entail a consistent, reproducible, and regulated delivery of light adapted to the application requirement. In this review, we explore the evolution of light-induction hardware-software platforms from simple illumination set-ups to sophisticated microscopy, microtiter plate and bioreactor designs, and discuss their respective advantages and disadvantages. Here, we examine design approaches followed in performing optogenetic experiments spanning different cell types and culture volumes, with induction capabilities ranging from single cell stimulation to entire cell culture illumination. The development of automated measurement and stimulation schemes on these platforms has enabled researchers to implement various in silico feedback control strategies to achieve computer-controlled living systems-a theme we briefly discuss in the last part of this review.

A hierarchy of biomolecular proportional-integral-derivative feedback controllers for robust perfect adaptation and dynamic performance.

Proportional-Integral-Derivative (PID) feedback controllers are the most widely used controllers in industry. Recently, the design of molecular PID-controllers has been identified as an important goal for synthetic biology and the field of cybergenetics. In this paper, we consider the realization of PID-controllers via biomolecular reactions. We propose an array of topologies offering a compromise between simplicity and high performance. We first demonstrate that different biomolecular PI-controllers exhibit different performance-enhancing capabilities. Next, we introduce several derivative controllers based on incoherent feedforward loops acting in a feedback configuration. Alternatively, we show that differentiators can be realized by placing molecular integrators in a negative feedback loop, which can be augmented by PI-components to yield PID-controllers. We demonstrate that PID-controllers can enhance stability and dynamic performance, and can also reduce stochastic noise. Finally, we provide an experimental demonstration using a hybrid setup where in silico PID-controllers regulate a genetic circuit in single yeast cells.

Dynamic cybergenetic control of bacterial co-culture composition via optogenetic feedback.

Communities of microbes play important roles in natural environments and hold great potential for deploying division-of-labor strategies in synthetic biology and bioproduction. However, the difficulty of controlling the composition of microbial consortia over time hinders their optimal use in many applications. Here, we present a fully automated, high-throughput platform that combines real-time measurements and computer-controlled optogenetic modulation of bacterial growth to implement precise and robust compositional control of a two-strain E. coli community. In addition, we develop a general framework for dynamic modeling of synthetic genetic circuits in the physiological context of E. coli and use a host-aware model to determine the optimal control parameters of our closed-loop compositional control system. Our platform succeeds in stabilizing the strain ratio of multiple parallel co-cultures at arbitrary levels and in changing these targets over time, opening the door for the implementation of dynamic compositional programs in synthetic bacterial communities.

Physiologic and compositional coronary artery disease extension in patients with takotsubo syndrome assessed using artificial intelligence: an optical coherence tomography study.

BACKGROUND: Takotsubo syndrome (TTS) is an acute and reversible ventricular motion abnormality without epicardial coronary obstruction. Optical flow ratio (OFR) is an approach to evaluate the coronary stenosis significance based on three-dimensional optical coherence tomography (3D-OCT). The aim of this study is to utilize OCT and an artificial intelligence plaque characterization model to show the prevalence and composition of atherosclerotic disease in coronary vessels of patients with TTS. METHODS: This is a retrospective and observational study which enrolled patients with TTS who underwent coronary angiography and OCT examination. OCT images were analyzed for tissue characterization and OFR computation using a novel artificial intelligence algorithm. RESULTS: A total of 37 patients and 49 vessels were studied. All patients were imaged in the left anterior descending coronary artery (LAD) and about two-thirds were also imaged in the left circumflex coronary artery (LCX). Most patients were women ( n = 35), and apical was the most common takotsubo type. Tissue composition analysis yielded the following overall plaque types: fibrous (67.1%), lipid (15.5%), and calcium (3.77%). The mean OFR for LAD and LCX was 0.97 ± 0.04 and 0.98 ± 0.02, respectively. CONCLUSION: Utilizing automatic plaque characterization on OCT images by artificial intelligence, we found that TTS patients have coronary artery disease (i.e. presence of lipid, calcified, or fibrous tissue). The advent of artificial intelligence methods may allow for large-scale studies of patients with TTS.

Rapid prototyping and design of cybergenetic single-cell controllers.

The design and implementation of synthetic circuits that operate robustly in the cellular context is fundamental for the advancement of synthetic biology. However, their practical implementation presents challenges due to low predictability of synthetic circuit design and time-intensive troubleshooting. Here, we present the Cyberloop, a testing framework to accelerate the design process and implementation of biomolecular controllers. Cellular fluorescence measurements are sent in real-time to a computer simulating candidate stochastic controllers, which in turn compute the control inputs and feed them back to the controlled cells via light stimulation. Applying this framework to yeast cells engineered with optogenetic tools, we examine and characterize different biomolecular controllers, test the impact of non-ideal circuit behaviors such as dilution on their operation, and qualitatively demonstrate improvements in controller function with certain network modifications. From this analysis, we derive conditions for desirable biomolecular controller performance, thereby avoiding pitfalls during its biological implementation.

Real-World Experience of the MANTA Closure Device: Insights From the FDA Manufacturer and User Facility Device Experience (MAUDE) Database.

BACKGROUND/PURPOSE: The MANTA vascular closure device (VCD) is the first commercially available dedicated closure device for large-bore femoral arterial access-site closure and was approved by the United States Food and Drug Administration (FDA) in February 2019. Real-world data on the most commonly reported complications and modes of failure associated with the MANTA closure device are limited. We analyzed post-marketing surveillance data from FDA's Manufacturer and User Facility Device Experience (MAUDE) database for the MANTA VCD (Teleflex, Wayne, Pennsylvania). METHODS/MATERIALS: Post-marketing surveillance data from the FDA MAUDE database from February 2019 through March 2020 were analyzed, yielding 170 reports. RESULTS: Of the 170 reports of major complications involving MANTA devices, 141 reports involved either injury (136) or death (5) related to the device. Of the 141 reports, bleeding was the most common adverse outcome described (45), followed by vessel occlusion (30) and vessel dissection (21). Device malfunction incidents (29 reports) were reported in 4 main categories: failed deployment (16 reports), malposition of the collagen (9), insufficient information (3), and device dislocation (1). CONCLUSIONS: Our analysis of the MAUDE database demonstrates that in real-world practice, the MANTA VCD was found to be associated with complications, including death, vascular injury, and difficulties with the device itself. Ongoing user education, proctoring, and pre-procedural patient selection are important to minimize risks associated with the MANTA VCD.

Utility of Routine Invasive Coronary Angiography Prior to Transcatheter Aortic Valve Replacement.

BACKGROUND/PURPOSE: Despite the high prevalence of coronary artery disease (CAD) in patients with severe aortic stenosis (AS), the optimal management of concomitant CAD, including revascularization before transcatheter aortic valve replacement (TAVR), remains controversial. Contemporary, real-world practice patterns have not yet been described. We aimed to characterize the burden of CAD in contemporary TAVR patients and evaluate revascularization practices at a high-volume center. METHODS/MATERIALS: We retrospectively analyzed all adult patients referred for TAVR at our center between January 2019 and January 2020. Presence of significant CAD and subsequent management were recorded. Presenting symptoms, use of non-invasive and invasive ischemia testing, and pre-TAVR computed tomography (CT) imaging were analyzed. RESULTS: A total of 394 patients with severe AS were referred for TAVR. Thirty-nine patients (9.9%) instead underwent surgery, of whom only 5 (1.3%) received coronary artery bypass grafting. Of the remaining 355 patients, 218 patients (61.4%) had insignificant CAD. Of the 137 patients (38.6%) with significant CAD, only 30 (8.5%) underwent percutaneous coronary intervention (PCI). Of these, less than half had anginal symptoms, a third had CAD in proximal segments, and a third underwent ischemia testing before PCI. Pre-TAVR CT accurately identified significant CAD in 28/30 patients (93.3%) who underwent PCI. CONCLUSIONS: Only 1 in 25 contemporary TAVR patients had significant CAD and angina requiring intervention, calling into question the utility of routine invasive coronary angiography before TAVR. A Heart Team approach integrating anginal symptoms, ischemia testing and possibly pre-TAVR CT is needed to guide the need, timing, and strategy of revascularization.