Clinical Interpretation of Genetic Variants in the Evaluation and Management of Thoracic Aortic Aneurysm and Dissection.

BACKGROUND: We aimed to elucidate clinical implications of genetic variant interpretation in assessing disease severity and progression in thoracic aortic aneurysm and dissection (TAAD) patients. METHODS: Consecutive TAAD patients with aortic root and/or ascending aortic aneurysms seen between 2011 and 2020 were included. Serial echocardiography, family history of TAAD, and management information were retrospectively collected and analyzed. Patients were classified into gene-positive (Gen-P), variants of uncertain significance, and gene-negative (Gen-N) groups. RESULTS: A total of 407 patients were included: mean age 53.7 ± 15.4 years, 64.4% men, and 38% with reported family history of TAAD. Thirty-seven (9.1%) were Gen-P; 147 (36.1%) had a variant of uncertain significance. The maximal aneurysm diameter was 4.78 mm larger in Gen-P than the other groups (P < .001). In 162 unoperated TAAD patients with serial echocardiographic measurements, aneurysms enlarged at a significantly higher rate in the Gen-P (1.36 mm/year, 95% CI: 0.77-1.95) than variants of uncertain significance and Gen-N groups (0.83 mm/year vs 0.89 mm/year, respectively; P < .001). Aneurysms were 20% more likely to require surgical intervention for every millimeter increase in diameter. When considered on an individual basis, the highest growth rates were found in the variants of uncertain significance group. CONCLUSIONS: While aneurysms linked to variants of uncertain significance demonstrate average growth rates comparable to those in Gen-N, close follow-up and genetic counseling in the variants of uncertain significance group are recommended for assessment of pathogenicity on a case-by-case basis. Early familial gene testing in TAAD is important to develop individualized preventive and therapeutic criteria.

Differences and Disparities Among Self-Referred and Physician-Referred Populations Undergoing Coronary Artery Calcium Scanning.

BACKGROUND: Coronary artery calcium computed tomography (CAC) is an important tool for identifying subclinical atherosclerosis and cardiovascular risk stratification. Despite robust evidence and inclusion in current guidelines, CAC is considered investigational by some US insurance carriers and requires out-of-pocket expenses. CAC can be obtained via self-referral (SR) or physician referral (PR). We aimed to examine differences in patient, socioeconomic, and CAC characteristics between referral groups. METHODS: We evaluated demographic, medical history, and CAC results of consecutive patients with a CAC completed at one of multiple Wisconsin sites from March 1, 2019, to June 30, 2021. We separated patients into SR and PR groups. Through census data, we analyzed socioeconomic variables at the block level including race and ethnicity, median income, average household size, and high school completion in the areas where patients resided at the time of CAC. RESULTS: The final analysis included 19 726 patients: 13 835 (70.1%) PR and 5891 (29.9%) SR. Most patients in both groups were White (95.2% versus 95.1%), with the Black/African American population representing 2.7% (SR) and 2.3% (PR). The PR group had a higher prevalence of cardiovascular risk factors. SR patients were more likely to have a score of 0 (41.2% versus 38.1%; P<0.001); PR patients had a higher prevalence of CAC >300 (16.8% versus 14.8%; P<0.001). SR patients were more likely to be women (55.1% versus 48.9%; P<0.001) and were found to live in higher income areas (19.5% versus 16.4%; P<0.001). Patients from low-income areas comprised the smallest proportion in both groups (7.5%). CONCLUSIONS: Patients who obtain out-of-pocket CAC live predominantly in medium- and high-income areas, and patients from lower income locations are less likely to obtain CAC despite having more cardiovascular disease risk factors. Consideration should be made from a policy perspective to promote health equity and improve utilization of CAC testing among underrepresented groups.

Racial Disparities in Diagnostic Evaluation and Revascularization in Patients With Acute Myocardial Infarction-A 15-Year Longitudinal Study.

We aimed to evaluate longitudinal trends of racial and ethnic disparities in the utilization of diagnostic angiograms, percutaneous coronary intervention (PCI), and coronary artery bypass graft surgery (CABG) for non-ST elevation myocardial infarction (NSTEMI) and ST elevation myocardial infarction (STEMI). We retrospectively analyzed the National Inpatient Sample (2005-2019). The 15-year period was divided into 5, 3-year periods. Our study included 9 million adult patients (NSTEMI, 72%; STEMI, 28%). No improvement in utilization of these procedures was seen in period 5 (2017-2019) vs period 1 (2005-2007) for both NSTEMI and STEMI in non-White patients vs White patients (P > 0.05 for all comparisons), excepting in CABG for STEMI in Black patients vs White patients (difference in CABG rate: period 1, 2.6%; period 5, 1.4%; P = 0.03). Reducing disparities in PCI for NSTEMI and both PCI and CABG for STEMI in Black patients vs White patients was associated with improved outcomes.

Sex Disparities in Diagnostic Evaluation and Revascularization in Patients With Acute Myocardial Infarction-A 15-Year Nationwide Study.

Background Although sex disparities in the diagnostic evaluation and revascularization of patients with acute myocardial infarction are well documented, no study has evaluated longitudinal trends in these disparities. Methods and Results Using the National Inpatient Sample from 2005 to 2019, 9 259 932 patients with acute myocardial infarction were identified. We divided 15 years into five 3-year periods. The primary objective was to evaluate sex-based trends in the use of diagnostic angiography, percutaneous coronary intervention, and coronary artery bypass graft (CABG) among patients with non-ST-segment-elevation myocardial infarction and ST-segment-elevation myocardial infarction (STEMI) over 15 years. The secondary objective was to evaluate sex disparities in mortality, length of stay, and cost. For non-ST-segment-elevation myocardial infarction, we saw a small reduction in sex disparity in the use of all diagnostic angiography in period 5 versus period 1 (4% versus 5.3%; P<0.01), no change in sex disparity in percutaneous coronary intervention use in period 5 versus period 1 (5.6% versus 5%; P=0.16), and a widening sex disparity in CABG in period 5 versus period 1 (5.4% versus 4.4%; P<0.01). However, we noted decreasing sex disparities in the use of diagnostic angiography, percutaneous coronary intervention, and CABG for ST-segment-elevation myocardial infarction in mostly all periods compared with period 1 (P<0.05, all comparisons), but differences still existed in period 5. Risk-adjusted in-hospital mortality was higher after CABG for non-ST-segment-elevation myocardial infarction and after percutaneous coronary intervention and CABG for ST-segment-elevation myocardial infarction in women than men. Conclusions Despite variable trends in sex disparities in diagnostic and revascularization procedures for acute myocardial infarction, disparities still exist.

Thirty-Day Readmission Rate Among Patients With Hypertensive Crisis: A Nationwide Analysis.

BACKGROUND: Hypertensive crisis is a life-threatening condition, further classified as hypertensive emergency and hypertensive urgency based on the presence or absence of acute or progressive end-organ damage, respectively. Readmissions in hypertensive emergency have been studied before. We aimed to analyze 30-day readmissions using recent data and more specific ICD-10-CM coding in patients with hypertensive crisis. METHODS: In a retrospective study using the National Readmission Database 2018, we collected data on 129,239 patients admitted with the principal diagnosis of hypertensive crisis. The primary outcome was the all-cause 30-day readmission rate. Secondary outcomes were common causes of readmission, in-hospital mortality, resource utilization, and independent predictors of readmission. We also compared outcomes between patients with hypertensive urgency and hypertensive emergency. RESULTS: Among 128,942 patients discharged alive, 13,768 (10.68%) were readmitted within 30 days; the most common cause of readmission was hypertensive crisis (19%). In-hospital mortality for readmissions (1.5%) was higher than for index admissions (0.2%, P < 0.01). Mean length of stay for readmissions was 4.5 days. The mean hospital cost associated with readmissions was $10,950, and total hospital costs were $151 million. Age <65 years and female sex were independent predictors of higher readmission rates. Subgroup analysis revealed a higher readmission rate for hypertensive emergency than hypertensive urgency (11.7% vs. 10%, P < 0.01). CONCLUSIONS: All-cause 30-day readmission rates are high in patients admitted with hypertensive crisis, especially patients with hypertensive emergency. Higher in-hospital mortality and resource utilization are associated with readmission in these patients.

Clinical Characteristics, Risk Factors, and Outcomes Among a Large Midwestern U.S. Cohort of Patients Hospitalized With COVID-19 Prior to Vaccine Availability.

Purpose: The COVID-19 pandemic posed unprecedented demands on health care. This study aimed to characterize COVID-19 inpatients and examine trends and risk factors associated with hospitalization duration, intensive care unit (ICU) admission, and in-hospital mortality. Methods: This retrospective study analyzed patients with SARS-CoV-2 infection hospitalized at an integrated health system between February 2, 2020, and December 12, 2020. Patient characteristics and clinical outcomes were obtained from medical records. Backward stepwise logistic regression analyses were used to identify independent risk factors of ICU admission and in-hospital mortality. Cox proportional hazards models were used to evaluate relationships between ICU admission and in-hospital mortality. Results: Overall, 9647 patients were analyzed. Mean age was 64.6 ± 18 years. A linear decrease was observed for hospitalization duration (0.13 days/week, R2=0.71; P<0.0001), ICU admissions (0.35%/week, R2=0.44; P<0.001), and hospital mortality (0.16%/week, R2=0.31; P<0.01). Bacterial co-infections, male sex, history of chronic lung and heart disease, diabetes, and Hispanic ethnicity were identified as independent predictors of ICU admission (P<0.001). ICU admission and age of ≥65 years were the strongest independent risk factors associated with in-hospital mortality (P<0.001). The in-hospital mortality rate was 8.3% (27.4% in ICU patients, 2.6% in non-ICU patients; P<0.001). Conclusions: Results indicate that, over the pandemic's first 10 months, COVID-19 carried a heavy burden of morbidity and mortality in older patients (>65 years), males, Hispanics, and those with bacterial co-infections and chronic comorbidities. Although disease severity has steadily declined following administration of COVID-19 vaccines along with improved understanding of effective COVID-19 interventions, these study findings reflect a "natural history" for this novel infectious disease in the U.S. Midwest.

COVID-19 Deliveries: Maternal Features and Neonatal Outcomes.

Integrated, data-driven criteria are necessary to evaluate delivery outcomes in pregnancies affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the ongoing COVID-19 pandemic. This study analyzed maternal demographics, clinical characteristics, treatments, and delivery outcomes of 85 ethnically diverse, adult pregnant women who tested positive for SARS-CoV-2 at the time of delivery. Median maternal and gestational ages were 27 years (interquartile range [IQR]: 23-31) and 39 weeks (IQR: 37.3-40.0), respectively. Of the 85 SARS-CoV-2-positive participants, 67 (79%) had no COVID-19 symptoms at the time of routine COVID-19 admission testing, 14 (16%) reported mild COVID-19 symptoms, and 4 (5%) presented severe COVID-19 symptoms that required hospitalization. Patients in the severe COVID-19 group had significantly longer hospitalizations than those with nonsevere COVID-19 (7 [IQR: 4.5-9.5] vs 2 [IQR: 2-3] days; P<0.01). Neonatal outcomes included 100% live births with a median 1-minute Apgar score of 8 and 15% preterm births. No neonatal deaths or vertical transmissions were reported, and all neonatal intensive care unit admissions were related to prematurity. Overall, maternal symptom prevalence and peripartum complication rates were low, suggesting a generally good prognosis for pregnant women with SARS-CoV-2 infections at the time of delivery.

Automated feature extraction from large cardiac electrophysiological data sets.

RATIONALE: A new multi-electrode array-based application for the long-term recording of action potentials from electrogenic cells makes possible exciting cardiac electrophysiology studies in health and disease. With hundreds of simultaneous electrode recordings being acquired over a period of days, the main challenge becomes achieving reliable signal identification and quantification. OBJECTIVE: We set out to develop an algorithm capable of automatically extracting regions of high-quality action potentials from terabyte size experimental results and to map the trains of action potentials into a low-dimensional feature space for analysis. METHODS AND RESULTS: Our automatic segmentation algorithm finds regions of acceptable action potentials in large data sets of electrophysiological readings. We use spectral methods and support vector machines to classify our readings and to extract relevant features. We are able to show that action potentials from the same cell site can be recorded over days without detrimental effects to the cell membrane. The variability between measurements 24 h apart is comparable to the natural variability of the features at a single time point. CONCLUSIONS: Our work contributes towards a non-invasive approach for cardiomyocyte functional maturation, as well as developmental, pathological and pharmacological studies. As the human-derived cardiac model tissue has the genetic makeup of its donor, a powerful tool for individual drug toxicity screening emerges.

Sustained perfusion of revascularized bioengineered livers heterotopically transplanted into immunosuppressed pigs.

Implanted bioengineered livers have not exceeded three days of continuous perfusion. Here we show that decellularized whole porcine livers revascularized with human umbilical vein endothelial cells and implanted heterotopically into immunosuppressed pigs whose spleens had been removed can sustain perfusion for up to 15 days. We identified peak glucose consumption rate as a main predictor of the patency of the revascularized bioengineered livers (rBELs). Heterotopic implantation of rBELs into pigs in the absence of anticoagulation therapy led to sustained perfusion for three days, followed by a pronounced immune responses directed against the human endothelial cells. A 10 day steroid-based immunosuppression protocol and a splenectomy at the time of rBEL implantation reduced the immune responses and resulted in continuous perfusion of the rBELs for over two weeks. We also show that the human endothelial cells in the perfused rBELs colonize the liver sinusoids and express sinusoidal endothelial markers similar to those in normal liver tissue. Revascularized liver scaffolds that can maintain blood perfusion at physiological pressures might eventually help to overcome the chronic shortage of transplantable human livers.

Author Correction: Sustained perfusion of revascularized bioengineered livers heterotopically transplanted into immunosuppressed pigs.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Human iPSC-Derived Cardiomyocyte Networks on Multiwell Micro-electrode Arrays for Recurrent Action Potential Recordings.

Cardiac safety screening is of paramount importance for drug discovery and therapeutics. Therefore, the development of novel high-throughput electrophysiological approaches for hiPSC-derived cardiomyocyte (hiPSC-CM) preparations is much needed for efficient drug testing. Although multielectrode arrays (MEAs) are frequently employed for field potential measurements of excitable cells, a recent publication by Joshi-Mukherjee and colleagues described and validated its application for recurrent action potential (AP) recordings from the same hiPSC-CM preparation over days. The aim here is to provide detailed step-by-step methods for seeding CMs and for measuring AP waveforms via electroporation with high precision and a temporal resolution of 1 µs. This approach addresses the lack of easy-to-use methodology to gain intracellular access for high-throughput AP measurements for reliable electrophysiological investigations. A detailed work flow and methods for plating of hiPSC-CMs on multiwell MEA plates are discussed emphasizing critical steps wherever relevant. In addition, a custom-built MATLAB script for rapid data handling, extraction and analysis is reported for comprehensive investigation of the waveform analysis to quantify subtle differences in morphology for various AP duration parameters implicated in arrhythmia and cardiotoxicity.

A Multiwell Cardiac µGMEA Platform for Action Potential Recordings from Human iPSC-Derived Cardiomyocyte Constructs.

Multielectrode array (MEA) technology has been extensively used for field potential recordings from excitable cells. However, its application for action potential (AP) measurements has not been harnessed. Here, we report a novel platform for high-resolution intracellular AP recordings from induced pluripotent stem cell-cardiomyocyte constructs derived from human cardiac fibroblasts. To gain intracellular access, micro-gold MEAs were used to electroporate multiple constructs simultaneously. High-throughput AP measurements were obtained from 41 multicellular constructs. Repeated electroporations of the same cells did not affect the signal stability. Our model has the capability to distinguish subtle differences in AP morphology to characterize the network profile. Furthermore, we confirm the reliability of the system by recapitulating known drug-induced physiological and arrhythmogenic responses. Overall, the model provides a unique cardio-electronic interface for non-invasive measurements of AP dynamics for drug screening and disease modeling. This technology opens the door for identifying novel cardio-factors to enhance electrophysiological maturation.