Validation of smartwatch electrocardiogram intervals in children compared to standard 12 lead electrocardiograms.

Lay people are now able to obtain one-lead electrocardiograms (ECG) using smartwatches, which facilitates documentation of arrhythmias. The accuracy of smartwatch derived ECG intervals has not been validated in children though. Home-based monitoring of ECG intervals using a smartwatch could improve monitoring of children, e.g. when taking QTc prolonging medications. The aim of this study was to validate the ECG intervals measured by smartwatch in comparison to standard 12-lead ECGs in children and adolescents. Prospective study of children (age 5-17 years) at the outpatient clinic of a national pediatric heart center. Patients underwent a smartwatch ECG (ScanWatch, Withings) and a simultaneous standard 12-lead ECG. ECG intervals were measured both automatically and manually from the smartwatch ECG and the 12-lead ECG. Intraclass correlation coefficients and Bland-Altman plots were performed. 100 patients (54% male, median age 12.9 (IQR 8.7-15.6) were enrolled. The ICC calculated from the automated smartwatch and automated 12-lead ECG were excellent for heart rate (ICC 0.97, p < 0.001), good for the PR and QT intervals (ICC 0.86 and 0.8, p < 0.001), and moderate for the QRS duration and QTc interval (ICC 0.7 and 0.53, p < 0.001). When using manual measurements for the smartwatch ECG, validity was improved for the PR interval (ICC 0.93, p < 0.001), QRS duration (ICC 0.92, p < 0.001), QT (ICC 0.95, p < 0.001) and QTc interval (ICC 0.84, p < 0.001). CONCLUSION: Automated smartwatch intervals are most reliable measuring the heart rate. The automated smartwatch QTc intervals are less reliable, but this may be improved by manual measurements. WHAT IS KNOWN: In adults, smartwatch derived ECG intervals measured manually have previously been shown to be accurate, though agreement for automated QTc may be fair. WHAT IS NEW: In children, automated smartwatch QTc intervals are less reliable than RR, PR, QRS and uncorrected QT interval. Accuracy of the QTc can be improved by peroforming manual measurements.

Photon-counting computed tomography for paediatric congenital heart defects yields images of high diagnostic quality with low radiation doses at both 70 kV and 90 kV.

BACKGROUND: Photon-counting computed tomography (PCCT) is a new clinical method that may show better diagnostic quality at lower radiation doses than conventional CT. OBJECTIVE: To investigate the diagnostic quality and radiation dose of paediatric cardiovascular PCCT for diagnosis of congenital heart defects at 70 kV and 90 kV. MATERIALS AND METHODS: This retrospective assessment included clinical non-gated paediatric PCCT examinations for assessment of congenital heart defects. Radiation doses were recorded, and overall and specific diagnostic quality (1-4) were scored by four paediatric radiologists. Agreement, differences, and trends were assessed by percent rater agreement, intraclass correlation, Mann-Whitney tests, and Jonckheere-Terpstra tests. RESULTS: Seventy children with congenital heart defects were examined at 70 kV (n = 35; age 2 days-16 years; 63% boys) or 90 kV (n = 35; age 2 days-17 years; 51% boys). All observers gave a median score of 4 (high diagnostic quality) for both 70 kV and 90 kV, with no difference in median values between tube voltages (all P > 0.06). Agreement for overall scores was 66-94% for 70 kV and 60-77% for 90 kV. Agreement for specific scores was 80-97% for 70 kV and 83-89% for 90 kV. Size-dependent dose estimate was 0.68 mGy (0.25-2.02 mGy) for 70 kV and 1.10 mGy (0.58-2.71 mGy; P < 0.001) for 90 kV. Effective dose was 0.30 mSv (0.15-0.82 mSv) for 70 kV and 0.39 mSv (0.22-1.51 mSv; P = 0.01) for 90 kV. CONCLUSION: Paediatric cardiovascular PCCT yields images for congenital heart defects of high diagnostic quality with low radiation dose at both 70 kV and 90 kV.

Impact of Underweight, Overweight, and Obesity on Health-Related Quality of Life in Children with Tetralogy of Fallot Variants.

Traditional cardiovascular risk factors put patients with congenital heart disease (CHD) at increased risk for cardiovascular morbidity and mortality. The aim of this study was to evaluate whether body mass index (BMI) is associated with health-related quality of life (HRQoL) in patients with variants of Tetralogy of Fallot (TOF). Patients and parents of children with variants of TOF-CHD were asked to fill out the PedsQL 4.0 questionnaire and provide weight and length. Patients were categorized into low, normal, and high BMI percentiles. Other demographic data were obtained from the Swedish national registry for congenital heart disease (SWEDCON). Statistical analyses included non-parametric Mann-Whitney U test, Fisher exact, and Chi-square tests. Eighty-five patients were included. Twelve were overweight or obese, 57 had a normal BMI, and 16 were underweight. There was a significant difference in age and gender between the groups. Comparing overweight/obese children to those with normal BMI, physical and social functioning were impaired, while emotional and school function were comparable between the groups. This applied to both child and parental assessment. When comparing underweight to normal weight children, school functioning assessed by the parent was the only domain significantly different from patients with a normal BMI. Children with variants of TOF and overweight/obesity have lower HRQoL, particularly in physical and social functioning, while underweight children may have impaired school functioning. We suggest that preventive measures aimed at maintaining a normal weight should be taken early in life to reduce long-term cardiovascular risk in the CHD population.

Left Ventricular Diastolic Function in Children with Atrial Septal Defects Improves After Closure by Means of Increased Hydraulic Force.

Hydraulic force aids diastolic filling of the left ventricle (LV) by facilitating basal movement of the atrioventricular plane. The short-axis atrioventricular area difference (AVAD) determines direction and magnitude of this force. Patients with atrial septal defect (ASD) have reduced LV filling due to the left-to-right shunt across the atrial septum and thus potentially altered hydraulic force. The aims were therefore to use cardiac magnetic resonance images to assess whether AVAD and thus the hydraulic force differ in children with ASD compared to healthy children, and if it improves after ASD closure. Twenty-two children with ASD underwent cardiac magnetic resonance before ASD closure. Of these 22 children, 17 of them repeated their examination also after ASD closure. Twelve controls were included. Left atrial and ventricular areas were delineated in short-axis images, and AVAD was defined as the largest ventricular area minus the largest atrial area at each time frame and normalized to body height (AVADi). At end diastole AVADi was positive in all participants, suggesting a force acting towards the atrium assisting the diastolic movement of the atrioventricular plane; however, lower in children both before (6.3 cm2/m [5.2-8.0]; p < 0.0001) and after ASD closure (8.7 cm2/m [6.6-8.5]; p = 0.0003) compared to controls (12.2 cm2/m [11.3-13.9]). Left ventricular diastolic function improves after ASD closure in children by means of improved hydraulic force assessed by AVAD. Although AVADi improved after ASD closure, it was still lower than in controls, indicating diastolic abnormality even after ASD closure. In patients where AVADi is low, ASD closure may help avoid diastolic function deterioration and improve outcome. This could likely be important also in patients with small shunt volumes, especially if they are younger, who currently do not undergo ASD closure. Changes in clinical routine may be considered pending larger outcome studies.

Atrioventricular Area Difference Aids Diastolic Filling in Patients with Repaired Tetralogy of Fallot.

A hydraulic force aids diastolic filling of the left ventricle (LV) and is proportional to the difference in short-axis area between the left ventricle and atrium; the atrioventricular area difference (AVAD). Patients with repaired Tetralogy of Fallot (rToF) and pulmonary regurgitation (PR) have reduced LV filling which could lead to a negative AVAD and a hydraulic force impeding diastolic filling. The aim was to assess AVAD and to determine whether the hydraulic force aids or impedes diastolic filling in patients with rToF and PR, compared to controls. Twelve children with rToF (11.5 [9-13] years), 12 pediatric controls (10.5 [9-13] years), 12 adults with rToF (21.5 [19-27] years) and 12 adult controls (24 [21-29] years) were retrospectively included. Cine short-axis images were acquired using cardiac magnetic resonance imaging. Atrioventricular area difference was calculated as the largest left ventricular short-axis area minus the largest left atrial short-axis area at beginning of diastole and end diastole and indexed to height (AVADi). Children and adults with rToF and PR had higher AVADi (0.3 cm2/m [- 1.3 to 0.8] and - 0.6 [- 1.5 to - 0.2]) at beginning of diastole compared to controls (- 2.7 cm2/m [- 4.9 to - 1.7], p = 0.015) and - 3.3 cm2/m [- 3.8 to - 2.8], p = 0.017). At end diastole AVADi did not differ between patients and controls. Children and adults with rToF and pulmonary regurgitation have an atrioventricular area difference that do not differ from controls and thus a net hydraulic force that contributes to left ventricular diastolic filling, despite a small underfilled left ventricle due to pulmonary regurgitation.

Circulating leptin is associated with adverse vascular changes in young adult survivors of childhood cancer.

INTRODUCTION: Proteomics may help discover novel biomarkers and underlying mechanisms for cardiovascular disease. This could be useful for childhood cancer survivors as they show an increased risk of cardiovascular disease. The aim of this study was to investigate circulating cardiovascular proteins in young adult survivors of childhood cancer and their relationship to previously reported subclinical cardiovascular disease. METHODS: Ninety-two cardiovascular proteins were measured in 57 childhood cancer survivors and in 52 controls. For proteins that were significantly different between childhood cancer survivors and controls, we performed correlations between protein levels and measures of peripheral arterial stiffness (carotid distensibility and stiffness index, and augmentation index) and endothelial dysfunction (reactive hyperemia index). RESULTS: Leptin was significantly higher in childhood cancer survivors compared to controls (normalized protein expression units: childhood cancer survivors 6.4 (1.5) versus 5.1 (1.7), p < 0.0000001) after taking multiple tests into account. Kidney injury molecule-1, MER proto-oncogene tyrosine kinase, selectin P ligand, decorin, alpha-1-microglobulin/bikunin precursor protein, and pentraxin 3 showed a trend towards group differences (p < 0.05). Among childhood cancer survivors, leptin was associated with anthracycline treatment after adjustment for age, sex, and body mass index (p < 0.0001). Higher leptin correlated with lower carotid distensibility after adjustment for age, sex, body mass index, and treatments with radiotherapy and anthracyclines (p = 0.005). CONCLUSION: This proteomics approach identified that leptin is higher in young asymptomatic adult survivors of childhood cancer than in healthy controls and is associated with adverse vascular changes. This could indicate a role for leptin in driving the cardiovascular disease burden in this population.

Biomarkers and Proteomics in Sarcomeric Hypertrophic Cardiomyopathy in the Young-FGF-21 Highly Associated with Overt Disease.

Background: Any difference in biomarkers between genotype-positive individuals with overt hypertrophic cardiomyopathy (HCM), and genotype-positive but phenotype-negative individuals (G+P-) in HCM-associated pathways might shed light on pathophysiological mechanisms. We studied this in young HCM patients. Methods: 29 HCM patients, 17 G+P--individuals, and age- and sex-matched controls were prospectively included. We analyzed 184 cardiovascular disease-associated proteins by two proximity extension assays, categorized into biological pathways, and analyzed with multivariate logistic regression analysis. Significant proteins were dichotomized into groups above/below median concentration in control group. Results: Dichotomized values of significant proteins showed high odds ratio (OR) in overt HCMphenotype for Fibroblast growth factor-21 (FGF-21) 10 (p = 0.001), P-selectin glycoprotein ligand-1 (PSGL-1) OR 8.6 (p = 0.005), and Galectin-9 (Gal-9) OR 5.91 (p = 0.004). For G+P-, however, angiopoietin-1 receptor (TIE2) was notably raised, OR 65.5 (p = 0.004), whereas metalloproteinase inhibitor 4 (TIMP4) involved in proteolysis, in contrast, had reduced OR 0.06 (p = 0.013). Conclusions: This study is one of the first in young HCM patients and G+P- individuals. We found significantly increased OR for HCM in FGF-21 involved in RAS-MAPK pathway, associated with cardiomyocyte hypertrophy. Upregulation of FGF-21 indicates involvement of the RAS-MAPK pathway in HCM regardless of genetic background, which is a novel finding.

Ceramides: a potential cardiovascular biomarker in young adult childhood cancer survivors?

Aims: The aim of this study was to investigate circulating ceramides involved in cardiovascular disease (CVD) in young adult childhood cancer survivors (CCS) and their correlations to previously reported adverse cardiovascular changes in this cohort. Methods and results: Fifty-seven CCS and 53 healthy controls (age 20-30 years) were studied. Plasma long-chain ceramides, known to be cardiotoxic (C16:0, C18:0, C24:0, and C24:1), were analysed by mass spectrometry. The coronary event risk test 2 (CERT2) score was calculated from the ceramide data. Cardiac and carotid artery ultrasound data and lipid data available from previous studies of this cohort were used to study partial correlations with ceramide and CERT2 score data. All four analysed ceramides were elevated in CCS compared with controls (P ≤ 0.012). The greatest difference was noted for C18:0, which was 33% higher in CCS compared with controls adjusted for sex, age, and body mass index (BMI) (P < 0.001). The CERT2 score was higher in CCS compared with controls (P < 0.001). In the CCS group, 35% had a high to very high CERT2 score (7-12) when compared with 9% in the control group (P < 0.001). The CCS subgroup with a CERT2 score ≥ 7 had higher heart rate, systolic blood pressure, and higher levels of apolipoprotein B compared with CCS with a CERT2 score < 6 (P ≤ 0.011). When adjusted for age, sex, and BMI, CERT2 score was significantly correlated with arterial stiffness, growth hormone, and cranial radiotherapy (P < 0.044). Conclusion: Ceramides could be important biomarkers in understanding the pathophysiology of CVD and in predicting CVD disease risk in young adult CCS.

Validation of fluid-structure interaction simulations of the opening phase of phantom mitral heart valves under physiologically inspired conditions.

BACKGROUND AND OBJECTIVE: Atrioventricular valve disease is a common cause of heart failure, and successful surgical or interventional outcomes are crucial. Patient-specific fluid-structure interaction (FSI) modeling may provide valuable insights into valve dynamics and guidance of valve repair strategies. However, lack of validation has kept FSI modeling from clinical implementation. Therefore, this study aims to validate FSI simulations against in vitro benchmarking data, based on clinically relevant parameters for evaluating heart valve disease. METHODS: An FSI model that mimics the left heart was developed. The domain included a deformable mitral valve of different stiffnesses run with different inlet velocities. Five different cases were simulated and compared to in vitro data based on the pressure difference across the valve, the valve opening, and the velocity in the flow domain. RESULTS: The simulations underestimate the pressure difference across the valve by 6.8-14 % compared to catheter measurements. Evaluation of the valve opening showed an underprediction of 5.4-7.3 % when compared to cine MRI, 2D Echo, and 3D Echo data. Additionally, the simulated velocity through the valve showed a 7.9-8.4 % underprediction in relation to Doppler Echo measurements. Qualitative assessment of the velocity profile in the ventricle and the streamlines of the flow in the domain showed good agreement of the flow behavior. CONCLUSIONS: Parameters relevant to the diagnosis of heart valve disease estimated by FSI simulations showed good agreement when compared to in vitro benchmarking data, with differences small enough not to affect the grading of heart valve disease. The FSI model is thus deemed good enough for further development toward patient-specific cases.

Long-Term Survival After Single-Ventricle Palliation: A Swedish Nationwide Cohort Study.

BACKGROUND: Long-term survival after single-ventricle palliation and the effect of dominant ventricle morphology in large, unselected series of patients are scarcely reported. METHODS AND RESULTS: This nationwide cohort study included all children undergoing operation with single-ventricle palliation during their first year of life in Sweden between January 1994 and December 2019. Data were obtained from institutional records and assessment of underlying cardiac anomaly and dominant ventricular morphology was based on complete review of medical records, surgical reports, and echocardiographic examinations. Data on vital status and date of death were retrieved from the Swedish Cause of Death Register, allowing for complete data on survival. Among 766 included patients, 333 patients (43.5%) were classified as having left or biventricular dominance, and 432 patients (56.4%) as having right ventricular (RV) dominance (of whom 231 patients had hypoplastic left heart syndrome). Follow-up was 98.7% complete (10 patients emigrated). Mean follow-up was 11.3 years (maximum, 26.7 years). Long-term survival was significantly higher in patients with left ventricular compared with RV dominance (10-year survival: 91.0% [95% CI, 87.3%-93.6%] versus 71.1% [95% CI, 66.4%-75.2%]). RV dominance had a significant impact on outcomes after first-stage palliation but was also associated with impaired survival after completed total cavopulmonary connection. In total, 34 (4.4%) patients underwent heart transplantation. Of these 34 patients, 25 (73.5%) had predominant RV morphology. CONCLUSIONS: This study provides clinically relevant knowledge about the long-term prognosis in patients with different underlying cardiac anomalies undergoing single-ventricle palliation. RV dominance had a significant impact on outcomes after initial surgical treatment but was also associated with impaired survival after completed Fontan circulation. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03356574.

Longitudinal ECG changes in tetralogy of Fallot and association with surgical repair.

Background: ECG abnormalities have been linked to adverse changes in right ventricular (RV) morphology and poor clinical outcomes in repaired Tetralogy of Fallot (rTOF). Our aim was to describe how ECG changes progress in early and intermediate follow-up and whether types of surgical strategy at the time of primary repair affected these changes. Methods: We studied patients with rTOF born 2000-2018 operated at our institution. Seven time points in relation to primary repair, follow-up, and pulmonary valve replacement (PVR) were identified. Patients correct with valve sparing repair (VSR), trans-annular patch (TAP) including with a monocusp valve (TAP + M) and with at least 3 ECGs were included. PQ interval, QRS duration, dispersion, and fragmentation, QTc duration and dispersion, JTc as well as presence of a right bundle branch block (RBBB) were analyzed. Medical records were reviewed for demographic and surgical data. Results: Two hundred nineteen patients with 882 ECGs were analyzed with a median follow-up time of 12.3 years (8.4, 17) with 41 (19%) needing PVR during the study period. QRS duration increased at time of primary repair to discharge from 66 msec (IQR 12) to 129 msec (IQR 27) (p < 0.0001) and at 1- and 6- year follow-up but showed only a modest and temporary decrease after PVR. QTc increased at the time of primary repair as well as prior to PVR. PQ interval showed a small increase at the time of primary repair, was at its highest prior to PVR and decreased with PVR. Type of surgical repair affected mainly QTc and JTc and was consistently longer in the TAP + M group until PVR. In VSR, QTc and JTc were prolonged initially compared to TAP but were similar after 1 year. After PVR, there were no differences in adverse ECG changes between surgical groups. Conclusions: PQ interval and QRS duration best correspond to the assumed volume load whereas the relationship with QTc and JTc is more complex, suggesting that these represent more complex remodeling of the myocardium. Before PVR, QTc and JTc are longer in the TAP + M group which may be due to a longer surgical incision.

Newborn Screening for High-Risk Congenital Heart Disease by Dried Blood Spot Biomarker Analysis.

Importance: Congenital heart disease (CHD) is the most common human organ malformation, affecting approximately 1 of 125 newborns globally. Objectives: Assessing the performance of 2 diagnostic tests using minimal amounts of dried blood spots (DBS) to identify high-risk CHD compared with controls in a Swedish cohort of neonates. Design, Setting, and Participants: This diagnostic study took place in Sweden between 2019 and 2023 and enrolled full-term babies born between 2005 and 2023. All cases were identified through centralized pediatric cardiothoracic surgical services in Lund and Gothenburg, Sweden. Controls were followed up for 1 year to ensure no late presentations of high-risk CHD occurred. Cases were verified through surgical records and echocardiography. Exposure: High-risk CHD, defined as cases requiring cardiac surgical management during infancy due to evolving signs of heart failure or types in which the postnatal circulation depends on patency of the arterial duct. Using 3-µL DBS samples, automated quantitative tests for NT-proBNP and interleukin 1 receptor-like 1 (IL-1 RL1; formerly known as soluble ST2) were compared against established CHD screening methods. Main Outcomes and Measures: Performance of DBS tests to detect high-risk CHD using receiver operating characteristic curves; Bland-Altman and Pearson correlation analyses to compare IL-1 RL1 DBS with plasma blood levels. Results: A total of 313 newborns were included (mean [SD] gestational age, 39.4 [1.3] weeks; 181 [57.8%] male). Mean (SD) birthweight was 3495 (483) grams. Analyzed DBS samples included 217 CHD cases and 96 controls. Among the CHD cases, 188 participants (89.3%) were high-risk types, of which 73 (38.8%) were suspected prenatally. Of the 188 high-risk cases, 94 (50.0%) passed pulse oximetry screening and 36 (19.1%) were initially discharged after birth without diagnoses. Combining NT-proBNP and IL-1 RL1 tests performed well in comparison with existing screening methods and enabled additional identification of asymptomatic babies with receiver operating characteristic area under the curve 0.95 (95% CI, 0.93-0.98). Conclusions and relevance: In this diagnostic study, NT-proBNP and IL-1 RL1 DBS assays identified high-risk CHD in a timely manner, including in asymptomatic newborns, and improved overall screening performance in this cohort from Sweden. Prospective evaluation of this novel approach is warranted.

Multi-Modal in Vitro Experiments Mimicking the Flow Through a Mitral Heart Valve Phantom.

PURPOSE: Fluid-structure interaction (FSI) models are more commonly applied in medical research as computational power is increasing. However, understanding the accuracy of FSI models is crucial, especially in the context of heart valve disease in patient-specific models. Therefore, this study aimed to create a multi-modal benchmarking data set for cardiac-inspired FSI models, based on clinically important parameters, such as the pressure, velocity, and valve opening, with an in vitro phantom setup. METHOD: An in vitro setup was developed with a 3D-printed phantom mimicking the left heart, including a deforming mitral valve. A range of pulsatile flows were created with a computer-controlled motor-and-pump setup. Catheter pressure measurements, magnetic resonance imaging (MRI), and echocardiography (Echo) imaging were used to measure pressure and velocity in the domain. Furthermore, the valve opening was quantified based on cine MRI and Echo images. RESULT: The experimental setup, with 0.5% cycle-to-cycle variation, was successfully built and six different flow cases were investigated. Higher velocity through the mitral valve was observed for increased cardiac output. The pressure difference across the valve also followed this trend. The flow in the phantom was qualitatively assessed by the velocity profile in the ventricle and by streamlines obtained from 4D phase-contrast MRI. CONCLUSION: A multi-modal set of data for validation of FSI models has been created, based on parameters relevant for diagnosis of heart valve disease. All data is publicly available for future development of computational heart valve models.

Fetal cardiac magnetic resonance imaging of the descending aorta in suspected left-sided cardiac obstructions.

Background: Severe left-sided cardiac obstructions are associated with high morbidity and mortality if not detected in time. The correct prenatal diagnosis of coarctation of the aorta (CoA) is difficult. Fetal cardiac magnetic resonance imaging (CMR) may improve the prenatal diagnosis of complex congenital heart defects. Flow measurements in the ascending aorta could aid in predicting postnatal CoA, but its accurate visualization is challenging. Objectives: To compare the flow in the descending aorta (DAo) and umbilical vein (UV) in fetuses with suspected left-sided cardiac obstructions with and without the need for postnatal intervention and healthy controls by fetal phase-contrast CMR flow. A second objective was to determine if adding fetal CMR to echocardiography (echo) improves the fetal CoA diagnosis. Methods: Prospective fetal CMR phase-contrast flow in the DAo and UV and echo studies were conducted between 2017 and 2022. Results: A total of 46 fetuses with suspected left-sided cardiac obstructions [11 hypoplastic left heart syndrome (HLHS), five critical aortic stenosis (cAS), and 30 CoA] and five controls were included. Neonatal interventions for left-sided cardiac obstructions (n = 23) or comfort care (n = 1 with HLHS) were pursued in all 16 fetuses with suspected HLHS or cAS and in eight (27%) fetuses with true CoA. DAo or UV flow was not different in fetuses with and without need of intervention. However, DAo and UV flows were lower in fetuses with either retrograde isthmic systolic flow [DAo flow 253 (72) vs. 261 (97) ml/kg/min, p = 0.035; UV flow 113 (75) vs. 161 (81) ml/kg/min, p = 0.04] or with suspected CoA and restrictive atrial septum [DAo flow 200 (71) vs. 268 (94) ml/kg/min, p = 0.04; UV flow 89 vs. 159 (76) ml/kg/min, p = 0.04] as well as in those without these changes. Adding fetal CMR to fetal echo predictors for postnatal CoA did not improve the diagnosis of CoA. Conclusion: Fetal CMR-derived DAo and UV flow measurements do not improve the prenatal diagnosis of left-sided cardiac obstructions, but they could be important in identifying fetuses with a more severe decrease in blood flow across the left side of the heart. The physiological explanation may be a markedly decreased left ventricular cardiac output with subsequent retrograde systolic isthmic flow and decreased total DAo flow.