Role of artificial-intelligence-assisted automated cardiac biometrics in prenatal screening for coarctation of aorta.

OBJECTIVE: Although remarkable strides have been made in fetal medicine and the prenatal diagnosis of congenital heart disease, around 60% of newborns with isolated coarctation of the aorta (CoA) are not identified prior to birth. The prenatal detection of CoA has been shown to have a notable impact on survival rates of affected infants. To this end, implementation of artificial intelligence (AI) in fetal ultrasound may represent a groundbreaking advance. We aimed to investigate whether the use of automated cardiac biometric measurements with AI during the 18-22-week anomaly scan would enhance the identification of fetuses that are at risk of developing CoA. METHODS: We developed an AI model capable of identifying standard cardiac planes and conducting automated cardiac biometric measurements. Our data consisted of pregnancy ultrasound image and outcome data spanning from 2008 to 2018 and collected from four distinct regions in Denmark. Cases with a postnatal diagnosis of CoA were paired with healthy controls in a ratio of 1:100 and matched for gestational age within 2 days. Cardiac biometrics obtained from the four-chamber and three-vessel views were included in a logistic regression-based prediction model. To assess its predictive capabilities, we assessed sensitivity and specificity on receiver-operating-characteristics (ROC) curves. RESULTS: At the 18-22-week scan, the right ventricle (RV) area and length, left ventricle (LV) diameter and the ratios of RV/LV areas and main pulmonary artery/ascending aorta diameters showed significant differences, with Z-scores above 0.7, when comparing subjects with a postnatal diagnosis of CoA (n = 73) and healthy controls (n = 7300). Using logistic regression and backward feature selection, our prediction model had an area under the ROC curve of 0.96 and a specificity of 88.9% at a sensitivity of 90.4%. CONCLUSIONS: The integration of AI technology with automated cardiac biometric measurements obtained during the 18-22-week anomaly scan has the potential to enhance substantially the performance of screening for fetal CoA and subsequently the detection rate of CoA. Future research should clarify how AI technology can be used to aid in the screening and detection of congenital heart anomalies to improve neonatal outcomes. © 2024 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Prevalence and detection rate of major congenital heart disease in twin pregnancies in Denmark.

OBJECTIVE: To investigate the national prevalence and prenatal detection rate (DR) of major congenital heart disease (mCHD) in twin pregnancies without twin-to-twin transfusion syndrome (TTTS)-associated CHD in a Danish population following a standardized prenatal screening program. METHODS: This was a national registry-based study of data collected prospectively over a 10-year period. In Denmark, all women with a twin pregnancy are offered standardized screening and surveillance programs in addition to first- and second-trimester screening for aneuploidies and malformation, respectively: monochorionic (MC) twins every 2 weeks from gestational week 15 and dichorionic (DC) twins every 4 weeks from week 18. The data were retrieved from the Danish Fetal Medicine Database and included all twin pregnancies from 2009-2018, in which at least one fetus had a pre- and/or postnatal mCHD diagnosis. mCHD was defined as CHD requiring surgery within the first year of life, excluding ventricular septal defects. All pregnancy data were pre- and postnatally validated in the local patient files at the four tertiary centers covering the entire country. RESULTS: A total of 60 cases from 59 twin pregnancies were included. The prevalence of mCHD was 4.6 (95% CI, 3.5-6.0) per 1000 twin pregnancies (1.9 (95% CI, 1.3-2.5) per 1000 live births). The prevalences for DC and MC were 3.6 (95% CI, 2.6-5.0) and 9.2 (95% CI, 5.8-13.7) per 1000 twin pregnancies, respectively. The national prenatal DR of mCHD in twin pregnancies for the entire period was 68.3%. The highest DRs were in cases with univentricular hearts (100%) and the lowest with aortopulmonary window, total anomalous pulmonary venous return, Ebstein's anomaly, aortic valve stenosis and coarctation of the aorta (0-25%). Mothers of children with prenatally undetected mCHD had a significantly higher body mass index (BMI) compared to mothers of children with a prenatally detected mCHD (median, 27 kg/m2 and 23 kg/m2 , respectively; P = 0.02). CONCLUSIONS: The prevalence of mCHD in twins was 4.6 per 1000 pregnancies and was higher in MC than DC pregnancies. The prenatal DR of mCHD in twin pregnancies was 68.3%. Maternal BMI was higher in cases of prenatally undetected mCHD. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Cardiovascular function in 8- to 9-year-old singletons born after ART with frozen and fresh embryo transfer.

STUDY QUESTION: Do 8- to 9-year-old singletons conceived after frozen embryo transfer (FET) or fresh embryo transfer (Fresh-ET) have increased arterial stiffness compared to naturally conceived (NC) children? SUMMARY ANSWER: The process of FET or Fresh-ET is not associated with altered cardiovascular function in 8- to 9-year-old singletons, including arterial stiffness, as compared to NC children. WHAT IS KNOWN ALREADY: ART has been suggested to influence cardiovascular risk factors (i.e. endothelial dysfunction, increased arterial blood pressure and insulin resistance). It is not known if ART procedures alter arterial stiffness in singletons. STUDY DESIGN, SIZE, DURATION: A cohort study was carried out, including 8- to 9-year-old singletons conceived after FET, Fresh-ET and NC children (50 children in each group). This study was conducted between November 2018 and August 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: In total, 150 singletons were identified through the Danish IVF Registry and the Medical Birth Registry. They underwent cardiac magnetic resonance imaging (CMR) and anthropometric measurements. Parental data were collected using questionnaires. NC children were matched by sex and birth year with FET/Fresh-ET children. Exclusion criteria were congenital heart disease, maternal gestational diabetes or maternal diabetes mellitus. Our primary outcome was arterial stiffness, which is assessed from noninvasive arterial blood pressure and aortic ascendens distensibility. The secondary outcome was the pulse wave velocity of total aorta and exploratory outcomes were left ventricular ejection fraction, mean arterial pressure, cardiac output and total peripheral resistance. Measurements and analyses were performed blinded to the child group. MAIN RESULTS AND THE ROLE OF CHANCE: Aortic ascendens distensibility of children conceived after FET and Fresh-ET did not differ from NC children (mean (SD): FET 11.1 (3.6) 10-3 mmHg-1, Fresh-ET 11.8 (3.0) 10-3 mmHg-1, NC 11.4 (2.8) 10-3 mmHg-1, P > 0.05). Multivariate linear regression was performed to adjust for potential confounders (i.e. child sex and age, maternal BMI at early pregnancy and maternal educational level). Data showed no statistically significant differences between study groups and aortic ascendens distensibility. However, the fully adjusted model showed a non-significant tendency of lowered aortic ascendens distensibility in children born after FET compared to Fresh-ET (ß estimate (95% CI): -0.99 10-3 mmHg-1 (-2.20; 0.21)) and NC children (ß estimate (95% CI): -0.77 10-3 mmHg-1 (-1.98; 0.44)). Lastly, secondary and exploratory outcomes did not differ between the groups. Primary and secondary outcomes showed good intra-rater reliability. LIMITATIONS, REASONS FOR CAUTION: This study is possibly limited by potential selection bias as the participation rate was higher in the ART compared to the NC group. Also, in some variables, the study groups differed slightly from the non-participant population. The non-participant population (n = 1770) included those who were excluded, not invited to CMR scan, or declined to participate in this study. WIDER IMPLICATIONS OF THE FINDINGS: Our findings indicate that children born after FET or Fresh-ET do not have altered cardiovascular function, including arterial stiffness. This is reassuring for the future use of ART. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Novo Nordisk Foundation (grant reference number: NNF19OC0054340) and The Research Foundation of Rigshospitalet. All authors declared no conflict of interests. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT03719703.

Nitroglycerin-mediated vasorelaxation is modulated by endothelial calcium-activated potassium channels.

OBJECTIVE: Recent in vitro data suggest, large conductance calcium-activated K+ channels (BKCa) modulate the vascular response to nitric oxide (NO). The in vivo implications and the characteristics of this interaction are not clear. This study firstly investigates whether modulation of BKCa affects the vascular response to nitroglycerin (NTG)-derived NO in vivo and in the isolated heart and secondly examines the influence of endothelial BKCa on NTG-mediated vasodilation in vitro. METHODS: The hypotensive effect of NTG was measured in conscious, chronically catheterized rats during i.v. infusions of iberiotoxin (IbTX, a selective inhibitor of BKCa) or placebo. Similarly, NTG-induced flow-changes in the isolated perfused rat heart were examined before and after IbTX treatment (0.1 microM). Concentration-relaxation curves to NTG in the presence of various K+ channel modulating agents were performed in vitro on porcine coronary arteries with and without intact endothelium. RESULTS: I.v. infusion of IbTX reduced the in vivo hypotensive effect of NTG by 55% (before IbTX: 32.0 +/- 3.0 mmHg, vs. after IbTX: 14.5 +/- 3.2 mmHg, P < 0.05) and nearly abolished NTG-induced increase in coronary flow in the isolated perfused heart (P < 0.05). In vitro, this effect depended on an intact endothelium (endothelium intact segments; NTG: pD2 = 5.8 +/- 0.1, Emax = 97.6 +/- 3.2% vs. NTG + IbTX: pD2 = 4.9 +/- 0.2, Emax = 49.7 +/- 6.2%, P < 0.05; endothelium denuded segments; NTG: pD2 = 6.9 +/- 0.1, Emax = 104.0 +/- 1.4% vs. NTG + IbTX: pD2 = 6.7 +/- 0.1, Emax = 100 +/- 1.2%, P > 0.05). CONCLUSION: The results suggest, that modulation of endothelial BKCa significantly affects NTG-induced vasorelaxation in vitro, in the isolated perfused heart and in vivo.

Inducible nitric oxide synthase (iNOS) in the human heart: expression and localization in congestive heart failure.

The inducible nitric oxide (NO) synthase (iNOS or NOS2) generates a prolonged release of large amounts of NO which may be cytotoxic and/or inhibit myocyte contractility. It has been suggested that this mechanism specifically contributes to heart failure caused by dilated cardiomyopathy (DCM). To test this hypothesis we compared the myocardial amount and localization of iNOS in myocardial biopsies from patients with heart failure caused by either DCM or ischemic heart disease (IHD). During heart transplantation, myocardial biopsies collected from the diseased heart after explantation were frozen in liquid nitrogen. Twenty-two patients in NYHA class III-IV were included (DCM: n = 8; IHD: n = 14). In each biopsy, iNOS expression was assessed using reverse transcription polymerase chain reaction (RT-PCR), and visualized by immunohistochemistry. iNOS was detected in all biopsies. Intriguingly, the amount of iNOS mRNA (shown as iNOS cDNA normalized to GADPH cDNA) did not differ significantly between the two groups (DCM 30 +/- 7; IHD 20 +/- 6, mean +/- S.E.M., P > 0.05). Similarly, no inter-group differences in the amount of iNOS protein (Western) were observed. iNOS was invariably located to vascular endothelial and smooth muscle cells. In addition, an iNOS reaction in relation to the myocyte membrane was found in 4 of the 22 patients. These four patients (two from each group) had significantly (P < 0.05) higher iNOS/GADPH ratios (54 +/- 20) than patients without myocyte membrane iNOS reaction (17 +/- 15). In conclusion, iNOS is expressed in the myocardium of all patients with heart failure caused by either DCM or IHD. iNOS is located primarily and invariably in the endothelium and vascular smooth muscle cells of the myocardial vasculature and its expression appears to be associated with the condition of heart failure per se rather than related to the heart failure etiology.

Time course of hypoxic pulmonary vasoconstriction: a rabbit model of regional hypoxia.

There is disagreement in the literature about the time required for hypoxic constriction of pulmonary vessels to reach its full intensity. Some studies suggest that only minutes are required, others that several hours are needed. We examined the time course over 6 h of changes in pulmonary shunt (as a fraction of cardiac output) following induction of unilateral hypoxia by collapse or liquid filling of the left lung in 47 anesthetized rabbits. The time course was examined at four degrees of lung inflation: during collapse and at airway pressures of 0.3 kPa, 0.6 kPa, and 0.9 kPa. The respective volumes (mean +/- SD) of the liquid-filled lung were estimated to be 6.4 +/- 1.0, 12.8 +/- 2.5, and 15.8 +/- 1.6 ml/kg body weight (BW). During sustained hypoxia (the period from 150 to 360 min after inducing hypoxia), shunt declined at a slow linear rate of 2.37 x 10(-4)/min, which was independent of lung inflation (p = 0.65 analysis of variance [ANOVA]) and significantly different from zero (p < 0.001). The stability of cardiac output in this animal model, as measured sequentially by thermodilution, was confirmed in a further 20 animals. The experiments provide evidence for a slow intensification of blood-flow diversion at a rate that does not depend upon the degree of lung inflation. Whether this change is a feature of hypoxic constriction itself, or some modulation of it, remains unclear.

Dependence of pulmonary venous admixture on inspired oxygen fraction and time during regional hypoxia in the rabbit.

In order to examine the value of assuming constant pulmonary venous admixture with respect to changes in inspired oxygen fraction (FIO2) and time during sustained unilateral hypoxia, we studied venous admixture for 6 h in 27 anaesthetized rabbits in which the left lung was filled with liquid, isosmotic with plasma. In one group of 10 rabbits the right lung was ventilated for 6 h with FIO2 = 1; in a second group of 10 the right lung was ventilated with FIO2 = 1 for 2.5 h and then with FIO2 = 0.3 for 3.5 h. A third group was similarly studied by changing from FIO2 = 1 to FIO2 = 0.5. We found that hypoxic pulmonary vasoconstriction continued to intensify over 3 h. At 3-6 h, with FIO2 = 0.3, venous admixture (0.32 (SEM 0.03)) was higher than baseline (0.13 (0.01), t = 0 min during bilateral oxygenation) by twice the elevation above baseline of the venous admixture (0.22 (0.01)) in the group with FIO2 = 1. The finding of a marked increase in venous admixture with decreasing FIO2 is discussed in relation to current models of hypoxic pulmonary vasoconstriction.

Effect of lung inflation on active and passive liquid clearance from in vivo rabbit lung.

Active sodium transport contributes to liquid clearance from the alveoli. We hypothesized that the magnitude of active transport of alveolar liquid depends on the extent to which the alveolar epithelium is stretched and, consequently, on the degree of alveolar inflation. In a study on 38 adult rabbits, the left lung was filled in vivo with a solution of glucose (10 mmol/l) made isosmotic with plasma, using sodium chloride, and held at a constant airway pressure of 3, 6, or 9 cmH2O for 6 h. Alveolar liquid clearance was measured directly as a flow into a left main bronchial catheter. Control animals were compared with animals in which active epithelial sodium transport was inhibited by adding amiloride and phloridzin (both 1 mmol/l) to the instillate. At low inflation, active sodium transport reversed a secretion of liquid into the alveoli; at high inflation, active sodium transport made little or no contribution to transepithelial flow. Hydraulic conductance of the left lung was 1.57 microliters.min-1.cmH2O-1.kg body wt-1. The experiments suggest that pulmonary inflation renders active liquid clearance ineffective.

Intense slow hypoxic pulmonary vasoconstriction in gas-filled and liquid-filled lungs: an in vivo study in the rabbit.

To examine the hypothesis that hypoxic pulmonary vasoconstriction may have a slower time course and greater intensity than is currently recognized, experiments were conducted in twelve anaesthetized rabbits subjected to unilateral lung hypoxia for 6 h. Endobronchial cannulation was used to maintain apnoea of one lung at constant airway pressure whilst inflating the lung with nitrogen or liquid. The second lung was ventilated with oxygen to maintain normocapnia and oxygen transfer. A pulmonary ventilated with oxygen to maintain normocapnia and oxygen transfer. A pulmonary artery catheter was introduced non-invasively. Pulmonary shunt was derived from mixed venous and arterial blood gas parameters. Pulmonary artery pressure was monitored continuously and cardiac output was estimated from oxygen uptake measurements before and after 6 h unilateral hypoxia. The experiments show that a rapid phase of hypoxic pulmonary vasoconstriction is followed by a slow phase which develops over hours. The slow phase is associated with a massive blood flow diversion from the hypoxic lung, such that pulmonary shunt after 6 h unilateral hypoxia is indistinguishable from baseline shunt during bilateral ventilation with oxygen. The response is reversible, but with a similarly slow time course. Results from nitrogen and liquid filling of the lung are similar. These findings are consistent with early experiments by Dirken and Heemstra in 1948 (Quart F Exp Physiol 34, 193-211), and challenge the prevailing notion that hypoxic pulmonary vasoconstriction is always a rapid and relatively weak physiological response to hypoxia.