Transient pacing in pigs with complete heart block via myocardial injection of mRNA coding for the T-box transcription factor 18.

The adenovirus-mediated somatic transfer of the embryonic T-box transcription factor 18 (TBX18) gene can convert chamber cardiomyocytes into induced pacemaker cells. However, the translation of therapeutic TBX18-induced cardiac pacing faces safety challenges. Here we show that the myocardial expression of synthetic TBX18 mRNA in animals generates de novo pacing and limits innate and inflammatory immune responses. In rats, intramyocardially injected mRNA remained localized, whereas direct myocardial injection of an adenovirus carrying a reporter gene resulted in diffuse expression and in substantial spillover to the liver, spleen and lungs. Transient expression of TBX18 mRNA in rats led to de novo automaticity and pacemaker properties and, compared with the injection of adenovirus, to substantial reductions in the expression of inflammatory genes and in activated macrophage populations. In rodent and clinically relevant porcine models of complete heart block, intramyocardially injected TBX18 mRNA provided rate-adaptive cardiac pacing for one month that strongly correlated with the animal's sinus rhythm and physical activity. TBX18 mRNA may aid the development of biological pacemakers.

Pediatric Monitoring Technologies and Congenital Heart Disease: A Systematic Review.

Outpatient monitoring of infants with congenital heart disease has been shown to significantly reduce rates of mortality in the single ventricle population. Despite the accelerating development of miniaturized biosensors and electronics, and a growing market demand for at-home monitoring devices, the application of these technologies to infants and children is significantly delayed compared with the development of devices for adults. This article aims to review the current landscape of available monitoring technologies and devices for pediatric patients to describe the gap between technologies and clinical needs with the goal of progressing development of clinically and scientifically validated pediatric monitoring devices.

Contemporary Patterns of Care in Tetralogy of Fallot: Analysis of The Society of Thoracic Surgeons Data.

BACKGROUND: Against the background of earlier studies, recent patterns in surgical management of tetralogy of Fallot (TOF) were assessed. METHODS: A retrospective review of The Society of Thoracic Surgeons (STS) Congenital Database (2010-2020) was performed on patients aged <18 years with TOF or pulmonary stenosis and primary procedure TOF surgical repair or palliation. Procedural frequencies were examined by epoch. Demographics, clinical variables, and outcomes were compared between the initial palliation and primary repair groups. Among those operated on at 0 to 60 days of age, variation in palliation rates across hospitals was assessed. RESULTS: The 12,157 operations included 11,307 repairs (93.0%) and 850 palliations (7.0%); 68.5% of all palliations were modified Blalock-Taussig-Thomas shunts. Of 1105 operations on neonates, 45.4% (502) were palliations. Among neonates, palliations declined from 49.0% (331 of 675) in epoch 1 (2010-2015) to 39.8% (171 of 430) in epoch 2 (2016-2020; P = .0026). Overall, the most prevalent repair technique (5196 of 11,307; 46.0%) was ventriculotomy with transanular patch, which was also used in 520 of 894 (58.2%) of repairs after previous cardiac operations. Patients undergoing initial palliation demonstrated more preoperative STS risk factors (50.1% vs 24.3% respectively; P < .0001) and more major morbidity and mortality than patients undergoing primary repair (21.2% vs 7.46%; P < .0001). In the 0- to 60-day age group, risk factor-adjusted palliation rates across centers varied considerably, with 32 of 99 centers performing significantly more or significantly fewer palliations than predicted on the basis of their case mix. CONCLUSIONS: Surgical palliation rates have decreased across all age groups despite increasing prevalence of risk factors. Ventriculotomy with transanular patch remains the most prevalent repair type. The considerable center-level variation in rates of palliation was not completely explained by case mix.

Data Quality Degradation on Prediction Models Generated From Continuous Activity and Heart Rate Monitoring: Exploratory Analysis Using Simulation.

BACKGROUND: Limited data accuracy is often cited as a reason for caution in the integration of physiological data obtained from consumer-oriented wearable devices in care management pathways. The effect of decreasing accuracy on predictive models generated from these data has not been previously investigated. OBJECTIVE: The aim of this study is to simulate the effect of data degradation on the reliability of prediction models generated from those data and thus determine the extent to which lower device accuracy might or might not limit their use in clinical settings. METHODS: Using the Multilevel Monitoring of Activity and Sleep in Healthy People data set, which includes continuous free-living step count and heart rate data from 21 healthy volunteers, we trained a random forest model to predict cardiac competence. Model performance in 75 perturbed data sets with increasing missingness, noisiness, bias, and a combination of all 3 perturbations was compared to model performance for the unperturbed data set. RESULTS: The unperturbed data set achieved a mean root mean square error (RMSE) of 0.079 (SD 0.001) in predicting cardiac competence index. For all types of perturbations, RMSE remained stable up to 20%-30% perturbation. Above this level, RMSE started increasing and reached the point at which the model was no longer predictive at 80% for noise, 50% for missingness, and 35% for the combination of all perturbations. Introducing systematic bias in the underlying data had no effect on RMSE. CONCLUSIONS: In this proof-of-concept study, the performance of predictive models for cardiac competence generated from continuously acquired physiological data was relatively stable with declining quality of the source data. As such, lower accuracy of consumer-oriented wearable devices might not be an absolute contraindication for their use in clinical prediction models.

Perioperative Considerations for Pediatric Patients With Congenital Heart Disease Presenting for Noncardiac Procedures: A Scientific Statement From the American Heart Association.

Continuous advances in pediatric cardiology, surgery, and critical care have significantly improved survival rates for children and adults with congenital heart disease. Paradoxically, the resulting increase in longevity has expanded the prevalence of both repaired and unrepaired congenital heart disease and has escalated the need for diagnostic and interventional procedures. Because of this expansion in prevalence, anesthesiologists, pediatricians, and other health care professionals increasingly encounter patients with congenital heart disease or other pediatric cardiac diseases who are presenting for surgical treatment of unrelated, noncardiac disease. Patients with congenital heart disease are at high risk for mortality, complications, and reoperation after noncardiac procedures. Rigorous study of risk factors and outcomes has identified subsets of patients with minor, major, and severe congenital heart disease who may have higher-than-baseline risk when undergoing noncardiac procedures, and this has led to the development of risk prediction scores specific to this population. This scientific statement reviews contemporary data on risk from noncardiac procedures, focusing on pediatric patients with congenital heart disease and describing current knowledge on the subject. This scientific statement also addresses preoperative evaluation and testing, perioperative considerations, and postoperative care in this unique patient population and highlights relevant aspects of the pathophysiology of selected conditions that can influence perioperative care and patient management.

Growth Differentiation Factor 15: A Novel Growth Biomarker for Children With Congenital Heart Disease.

BACKGROUND: Failure to thrive (FTT), defined as weight or height less than the lowest 2.5 percentile for age, is prevalent in up to 66% of children with congenital heart disease (CHD). Risk stratification methods to identify those who would benefit from early intervention are currently lacking. We aimed to identify a novel growth biomarker to aid clinical decision-making in children with CHD. METHODS: This is a cross-sectional study of patients 2 months to 10 years of age with any CHD undergoing cardiac surgery. Preoperative weight-for-age Z scores (WAZ) and height-for-age Z scores (HAZ) were calculated and assessed for association with preoperative plasma biomarkers: growth differentiation factor 15 (GDF-15), fibroblast growth factor 21, leptin, prealbumin, and C-reactive protein (CRP). RESULTS: Of the 238 patients included, approximately 70% of patients had WAZ/HAZ < 0 and 34% had FTT. There was a moderate correlation between GDF-15 and WAZ/HAZ. When stratified by age, the correlation of GDF-15 to WAZ and HAZ was strongest in children under 2 years of age and persisted in the setting of inflammation (CRP > 0.5 mg/dL). Diagnoses commonly associated with congestive heart failure had high proportions of FTT and median GDF-15 levels. Prealbumin was not correlated with WAZ or HAZ. CONCLUSIONS: GDF-15 represents an important growth biomarker in children with CHD, especially those under 2 years of age who have diagnoses commonly associated with CHF. Our data do not support prealbumin as a long-term growth biomarker.

The Congenital Heart Technical Skill Study: Rationale and Design.

BACKGROUND: We report the rationale and design for a peer-evaluation protocol of attending congenital heart surgeon technical skill using direct video observation. METHODS: All surgeons contributing data to The Society of Thoracic Surgeons-Congenital Heart Surgery Database (STS-CHSD) are invited to submit videos of themselves operating, to rate peers, or both. Surgeons may submit Norwood procedures, complete atrioventricular canal repairs, and/or arterial switch operations. A HIPPA-compliant website allows secure transmission/evaluation. Videos are anonymously rated using a modified Objective Structured Assessment of Technical Skills score. Ratings are linked to five years of contemporaneous outcome data from the STS-CHSD and surgeon questionnaires. The primary outcome is a composite for major morbidity/mortality. RESULTS: Two hundred seventy-six surgeons from 113 centers are eligible for participation: 83 (30%) surgeons from 53 (45%) centers have agreed to participate, with recruitment ongoing. These surgeons vary considerably in years of experience and outcomes. Participants, both early and late in their careers, describe the process as "very rewarding" and "less time consuming than anticipated." An initial subset of 10 videos demonstrated excellent interrater reliability (interclass correlation = 0.85). CONCLUSIONS: This study proposes to evaluate the technical skills of attending pediatric cardiothoracic surgeons by video observation and peer-review. It is notable that over a quarter of congenital heart surgeons, across a range of experiences, from almost half of United States centers have already agreed to participate. This study also creates a mechanism for peer feedback; we hypothesize that feedback could yield broad and meaningful quality improvement.

The Transcriptional Signature of Growth in Human Fetal Aortic Valve Development.

BACKGROUND: In the second trimester of human fetal development, a tenfold increase in fetal size occurs while cardiac valves grow and retain their function. Patterns of transcription in normally growing human aortic valves are unknown. METHODS: Discarded human aortic valve samples were collected from the second trimester, 6 from early (14, 15, 17 weeks) and 6 from late (20, 21, 22 weeks) gestation. Network analysis of RNA sequencing data identified subnetworks of significantly increasing and decreasing transcripts. Subsequent cluster analysis identified patterns of transcription through the time course. Pathway enrichment analysis determined the predominant biological processes at each interval. RESULTS: We observed phasic transcription over the time course, including an early decrease in cell proliferation and developmental genes (14 to 15 weeks). Pattern specification, shear stress, and adaptive immune genes were induced early. Cell adhesion genes were increased from 14 to 20 weeks. A phase involving cell differentiation and apoptosis (17 to 20 weeks) was followed by downregulation of endothelial-to-mesenchymal transformation genes and then by increased extracellular matrix organization and stabilization (20 to 22 weeks). CONCLUSIONS: We present a unique data set, comprehensively characterizing human valve development after valve primordia are formed, focusing on key processes displayed by normal aortic valves undergoing significant growth. We build a time course of genes and processes in second trimester fetal valve growth and observe the sequential regulation of gene clusters over time. Critical valve growth genes are potential targets for therapeutic intervention in congenital heart disease and have implications for regenerative medicine and tissue engineering.

Advances in MALDI imaging mass spectrometry of proteins in cardiac tissue, including the heart valve.

Significant progress has been made for tissue imaging of proteins using matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI IMS). These advancements now facilitate mapping of a wide range of proteins, peptides, and post-translational modifications in a wide variety of tissues; however, the use of MALDI IMS to detect proteins from cardiac tissue is limited. This review discusses the most recent advances in protein imaging and demonstrates application to cardiac tissue, including the heart valve. Protein imaging by MALDI IMS allows multiplexed histological mapping of proteins and protein components that are inaccessible by antibodies and should be considered an important tool for basic and clinical cardiovascular research. This article is part of a Special Issue entitled: MALDI Imaging, edited by Dr. Corinna Henkel and Prof. Peter Hoffmann.