Hemodynamics During Development and Postnatal Life.

A well-developed heart is essential for embryonic survival. There are constant interactions between cardiac tissue motion and blood flow, which determine the heart shape itself. Hemodynamic forces are a powerful stimulus for cardiac growth and differentiation. Therefore, it is particularly interesting to investigate how the blood flows through the heart and how hemodynamics is linked to a particular species and its development, including human. The appropriate patterns and magnitude of hemodynamic stresses are necessary for the proper formation of cardiac structures, and hemodynamic perturbations have been found to cause malformations via identifiable mechanobiological molecular pathways. There are significant differences in cardiac hemodynamics among vertebrate species, which go hand in hand with the presence of specific anatomical structures. However, strong similarities during development suggest a common pattern for cardiac hemodynamics in human adults. In the human fetal heart, hemodynamic abnormalities during gestation are known to progress to congenital heart malformations by birth. In this chapter, we discuss the current state of the knowledge of the prenatal cardiac hemodynamics, as discovered through small and large animal models, as well as from clinical investigations, with parallels gathered from the poikilotherm vertebrates that emulate some hemodynamically significant human congenital heart diseases.

Association between patent ductus arteriosus flow and home oxygen therapy in extremely preterm infants.

BACKGROUND: Central blood flow measurements include the estimation of right and left ventricular output (RVO, LVO), superior vena cava (SVC) flow, and calculated patent ductus arteriosus (PDA) flow. We aimed to provide an overview of the maturation patterns of these values and the relationship between PDA flow and the need for home oxygen therapy. METHODS: This prospective single-center study was conducted in infants born at <26 weeks of gestation. We performed echocardiographic measurements five times during their life (from the 4th post-natal day to the 36th postmenstrual week). RESULTS: Sixty patients with a mean birth weight of 680 (590, 760) g were included. Postnatal development of LVO and PDA flow peaked at the end of the second postnatal week (427 and 66 mL/kg/min, respectively). The RVO increased between days 4 and 7-8. The SVCF was most stable. The development curves of PDA flow differed between the groups with (n = 28; 47%) and without home oxygen therapy. CONCLUSION: We present the central blood flow values and their postnatal development in infants <26 weeks of gestation. This study demonstrates the association between PDA flow and the future need for home oxygen therapy. IMPACT: This study enriches our knowledge of the long-term development of central blood flow parameters and derived patent ductus arteriosus (PDA) flow in extremely preterm infants (<26 weeks). While pulmonary resistance decreased, PDA flow continued to increase from day 4 to the end of the second week of life. Similarly, left ventricular output increased as a marker of preload. The superior vena cava flow remained stable. The observed association between PDA flow and an unfavorable respiratory outcome is important for future studies focusing on the prevention of chronic lung disease.

Pregnancy Termination and Postnatal Major Congenital Heart Defect Prevalence After Introduction of Prenatal Cardiac Screening.

Importance: Prenatal cardiac screening of the first and second trimesters has had a major impact on postnatal prevalence of congenital heart defects (CHDs), rates of termination of pregnancy (TOP), and outcomes among children born alive with CHDs. Objective: To examine the prenatal and postnatal incidence of major CHDs (ie, necessitating intervention within the first year of life), detection rate trends, rates of TOP, and the association of cardiac screening with postnatal outcomes. Design, Settings, and Participants: In this cross-sectional study, 3827 fetuses with antenatally diagnosed major CHDs in the Czech Republic (population 10.7 million) between 1991 and 2021 were prospectively evaluated with known outcomes and associated comorbidities. Prenatal and postnatal prevalence of CHD in an unselected population was assessed by comparison with a retrospective analysis of all children born alive with major CHDs in the same period (5454 children), using national data registry. Data analysis was conducted from January 1991 to December 2021. Main Outcomes and Measures: Prenatal detection and postnatal prevalence of major CHDs and rate of TOPs in a setting with a centralized health care system over 31 years. Results: A total of 3 300 068 children were born alive during the study period. Major CHD was diagnosed in 3827 fetuses, of whom 1646 (43.0%) were born, 2069 (54.1%) resulted in TOP, and 112 (2.9%) died prenatally. The prenatal detection rate increased from 6.2% in 1991 to 82.8% in 2021 (P < .001). Termination of pregnancy decreased from 70% in 1991 to 43% (P < .001) in 2021. Of 627 fetuses diagnosed in the first trimester (introduced in 2007), 460 were terminated (73.3%). Since 2007, of 2066 fetuses diagnosed in the second trimester, 880 (42.6%) were terminated, resulting in an odds ratio of 3.6 (95% CI, 2.8-4.6; P < .001) for TOP in the first trimester compared with the second trimester. Postnatal prevalence of major CHDs declined from 0.21% to 0.14% (P < .001). The total incidence (combining prenatal detection of terminated fetuses with postnatal prevalence) of major CHD remained at 0.23% during the study period. Conclusions and Relevance: In this cross-sectional study, the total incidence of major CHD did not change significantly during the 31-year study period. The prenatal detection of major CHD approached 83% in the current era. Postnatal prevalence of major CHD decreased significantly due to early TOPs and intrauterine deaths. The introduction of first trimester screening resulted in a higher termination rate in the first trimester but did not revert the overall decreasing trend of termination for CHDs in general.

Long-Term Results of Congenital Aortic Stenosis Treatment in the Era of Percutaneous Balloon Valvuloplasty: Up to 33 Years Follow-Up.

Background The goal of this study was to evaluate long-term results of percutaneous balloon valvuloplasty (BVPL) used exclusively for initial management of congenital aortic stenosis in children. Methods and Results A total of 409 consecutive pediatric patients (134 newborns, 275 older patients) who underwent BVPL as initial treatment of aortic stenosis in a single nationwide pediatric center were subjected to a retrospective follow-up study. The resulting follow-up time reached a median of 18.5 (interquartile range, 12.2-25.1) years. Successful BVPL was defined by residual Doppler gradient <70/40 (systolic/mean) mm Hg. The primary end point was death; secondary end points included any valve reintervention, balloon revalvuloplasty, any aortic valve surgery, and aortic valve replacement, respectively. BVPL effectively reduced the peak and mean gradient both immediately and at the latest follow-up (P<0.001). There was significant procedure-related progression of aortic insufficiency (P<0.001). Higher aortic annulus z score was predictive for severe aortic regurgitation (P<0.05) and lower z score for insufficient gradient reduction (P<0.05). The actuarial probability of survival/survival free from any valve reintervention was 89.9%/59.9%, 85.9%/35.2%, and 82.0%/26.7% at 10, 20, and 30 years after first BVPL, respectively. Left ventricular dysfunction or arterial duct dependency as the indication for BVPL was predictive of both worse survival and survival free from any reintervention (P<0.001). Lower aortic annulus z score and lower balloon-to-annulus ratio were predictive of a need for revalvuloplasty (P<0.001). Conclusions Percutaneous BVPL provides good initial palliation. In patients with hypoplastic annuli and left ventricular or mitral valve comorbidity, the results are less favorable.

Impact of liver fibrosis and nodules formation on hemodynamics in young adults after total cavopulmonary connection. A magnetic resonance study.

Background: The aim of this study was to analyze the relation between the hepatic fibrosis markers, liver morphology and hemodynamics assessed by magnetic resonance imaging (MRI) after total cavopulmonary connection (TCPC). Materials and methods: Adult patients after TCPC performed in childhood between 1993 and 2003 are the subjects of this observational study. The follow-up protocol consisted of clinical and echocardiographic examination, liver elastography, cardiopulmonary exercise test, MRI hemodynamics and liver morphology assessment and direct enhanced liver fibrosis (ELF) test. Results: The cohort consisted of 39 patients (46% female) with a median age at study 26 (IQR 23-28) years and interval from TCPC 21 (IQR 20-23) years. There was no correlation between ELF test and any MRI variables, but procollagen III amino-terminal peptide (PIIINP), a single component of ELF test, correlated significantly with ventricular end-diastolic volume (r = 0.33; p = 0.042) and inferior vena cava flow (r = 0.47; p = 0.003). Fifteen (38%) patients with liver nodules had compared to other 24 patients higher end-diastolic volume (ml/m2) 102.8 ± 20.0 vs. 88.2 ± 17.7; p = 0.023, respectively. PIIINP correlated significantly with inferior vena cava flow (r = 0.56; p = 0.030) and with end-diastolic volume (r = 0.53; p = 0.043), but only in patients with liver nodules. Conclusion: Gradual progression of liver fibrosis, particularly hepatic arterialization caused by liver nodules formation, increases inferior vena cava flow and subsequent ventricular volume overload may further compromise single ventricle functional reserve in adult patients after TCPC.

The aorto-left ventricular tunnel from a fetal perspective: Original case series and literature review.

INTRODUCTION: Aorto-left ventricular tunnel (ALVT) accounts for <0.1% of congenital heart defects. Evidence on the prognosis from a fetal perspective is limited. With this retrospective international case series, we provide information on the outcome of fetuses with ALVT. METHODS: All members of the Association for European Pediatric and Congenital Cardiology's (AEPC) fetal working group and fetal medicine units worldwide were invited for participation. We observed antenatal parameters, neonatal outcome and postnatal follow-up. Additionally, a systematic search of the literature was performed. RESULTS: Twenty fetuses with ALVT were identified in 10 participating centers (2001-2019). Fetal echocardiographic characteristics of ALVT included an increased cardiac-thorax ratio (95%), left ventricular end-diastolic diameter (90%) and a dysplastic aortic valve (90%). Extracardiac malformations were rare (5%). Eight fetuses died at a median gestational age (GA) of 21 + 6 weeks (range, 19-24): all showed signs of hydrops prior to 24 weeks or at autopsy. All others (60%, 12/2) were live-born (median GA 38 + 4, range 37-40), underwent surgery and were alive at last follow up (median 3.2 years, range 0.1-17). The literature reported 22 ALVT fetuses with similar outcome. CONCLUSIONS: In the absence of fetal hydrops, ALVT carries a good prognosis. Fetuses who survive to 24 weeks without hydrops are likely to have a good outcome.

Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.

Congenital heart disease is the most common type of birth defect, accounting for one-third of all congenital anomalies. Using whole-exome sequencing of 2718 patients with congenital heart disease and a search in GeneMatcher, we identified 30 patients from 21 unrelated families of different ancestries with biallelic phospholipase D1 (PLD1) variants who presented predominantly with congenital cardiac valve defects. We also associated recessive PLD1 variants with isolated neonatal cardiomyopathy. Furthermore, we established that p.I668F is a founder variant among Ashkenazi Jews (allele frequency of ~2%) and describe the phenotypic spectrum of PLD1-associated congenital heart defects. PLD1 missense variants were overrepresented in regions of the protein critical for catalytic activity, and, correspondingly, we observed a strong reduction in enzymatic activity for most of the mutant proteins in an enzymatic assay. Finally, we demonstrate that PLD1 inhibition decreased endothelial-mesenchymal transition, an established pivotal early step in valvulogenesis. In conclusion, our study provides a more detailed understanding of disease mechanisms and phenotypic expression associated with PLD1 loss of function.

Spectrum of postmortem autopsy findings in native and surgically corrected hearts with congenital malformations: a 10-year single-center experience.

OBJECTIVES: We reviewed a spectrum of congenital heart defects assessed in our center between 1/2010 and 4/2020, evaluated their gross anatomy, assessed the age distribution, evaluated performed surgical procedures, and correlated gross and ultrasound findings. METHODS: All necroptic cases and explanted hearts that underwent specialized cardiac autopsy were included in this study. Autopsy findings including gross description of congenital heart defects together with echocardiographic findings were retrospectively assessed. In surgically corrected hearts, the operation records were included as well. All congenital heart defects and surgical procedures were subclassified into main and additional category. RESULTS: The study included 92 necroptic cases of live-born children, 7 stillbirths, 2 cases of young adults, 50 induced abortions, and 5 explanted hearts, with median age 36 weeks. The most frequently encountered leading congenital heart defects were hypoplastic left heart syndrome, aortic stenosis, septal defects, or persistent arterial trunk. Fifty-one patients underwent surgical repair represented mainly by valvuloplasties, aortoplasty, and procedures leading to univentricular circulation. In the native hearts, 4 postnatal and 16 abortion/stillbirth cases showed discordance between gross and sonographic findings, mainly attributed to missed ventricular septal defect. Gestational age of the discordant group was significantly lower compared to the concordant group (P= .007). CONCLUSIONS: Autopsy continues to provide essential information about the morphology of congenital heart defects. However, the encountered congenital heart defects were usually complex, often surgically corrected or evaluated as a result of induced abortion or still birth. Cardiac autopsy therefore places high demands on pathologists with regards to proper gross heart assessment. It is also an invaluable part of quality control in prenatal cardiology.

Is left bundle branch block pattern on the ECG caused by variable ventricular activation sequence?

BACKGROUND: The presence and extent of ventricular dyssynchrony are currently assessed from the QRS complex morphology and width. However, similar electrocardiography (ECG) pattern may be caused by variable ventricular activation sequence. This may then contribute to interindividually different response to cardiac resynchronization therapy (CRT). METHODS: Electroanatomical mapping and magnetic resonance imaging scan were performed in 11 patients with left bundle branch block (LBBB, QRS 170 ± 14 ms) and heart failure of ischemic (coronary artery disease (CAD), n = 2) and nonischemic (dilated cardiomyopathy (DCM), n = 9) etiology. Ventricular activation sequence was studied during LBBB and final CRT programming. Presence and extent of scarring were analyzed in the 17-segment left-ventricular (LV) model. RESULTS: Regardless of etiology, presence of typical LBBB was associated with diffuse prolongation of impulse conduction with right-to-left activation sequence. Basal lateral wall was constant site of late activation. This activation pattern was present in "true LBBB," but also in LBBB-like pattern (persistent S wave in V5-6) and left axis deviation. Activation started in right vetricular (RV) apex in patients with left axis deviation at RV free wall in normal axis. Individuals with CAD and DCM patient displayed focal scar. Despite that they exhibited typical LBBB and activation sequence mirrored findings in other LBBB individuals. Reverse remodeling (∆LVESV > 15% after 6 months) was evident in 10 patients. CONCLUSIONS: Both typical LBBB and LBBB-like pattern might be associated with constant activation sequence regardless of etiology and scar localization. Activation initiation in RV apex, not LV activation sequence can be surrogate for left axis deviation. CRT caused inter- and intraventricular LV resynchronization without significantly changed RV activation sequence and duration.

Left ventricular apical pacing in children: feasibility and long-term effect on ventricular function.

AIMS: Left ventricular apical pacing (LVAP) has been reported to preserve left ventricular (LV) function in chronically paced children with complete atrioventricular block (CAVB). We sought to evaluate long-term feasibility of LVAP and the effect on LV mechanics and exercise capacity as compared to normal controls. METHODS AND RESULTS: Thirty-six consecutive paediatric patients with CAVB and LVAP in the absence (N = 22) or presence of repaired structural heart disease (N = 14, systemic LV in all) and 25 age-matched normal controls were cross-sectionally studied after a median of 3.9 (interquartile range 2.1-6.8) years of pacing using echocardiography and exercise stress testing. Pacemaker implantation was uneventful and there was no death. Probability of the absence of pacemaker-related surgical revision (elective generator replacement excluded) was 89.0% at 5 years after implantation. Left ventricular apical pacing patients had lower maximum oxygen uptake (P = 0.009), no septal to lateral but significant apical to basal LV mechanical delay (P < 0.001) which correlated with decreased LV contraction efficiency (P = 0.001). Left ventricular ejection fraction and global longitudinal LV strain were, however, not different from controls. Results were similar in both the presence and absence of structural heart disease. CONCLUSION: Left ventricular apical pacing is technically feasible with a low reintervention rate. Mechanical synchrony between LV septum and free wall is maintained at the price of an apical to basal mechanical delay associated with LV contraction inefficiency as compared to healthy controls. Global LV systolic function is, however, not negatively affected by LVAP.

Pulmonary Right Ventricular Resynchronization in Congenital Heart Disease: Acute Improvement in Right Ventricular Mechanics and Contraction Efficiency.

BACKGROUND: Electromechanical discoordination may contribute to long-term pulmonary right ventricular (RV) dysfunction in patients after surgery for congenital heart disease. We sought to evaluate changes in RV function after temporary RV cardiac resynchronization therapy. METHODS AND RESULTS: Twenty-five patients aged median 12.0 years after repair of tetralogy of Fallot and similar lesions were studied echocardiographically (n=23) and by cardiac catheterization (n=5) after primary repair (n=4) or after surgical RV revalvulation for significant pulmonary regurgitation (n=21). Temporary RV cardiac resynchronization therapy was applied in the presence of complete right bundle branch block by atrial-synchronized RV free wall pacing in complete fusion with spontaneous ventricular depolarization using temporary electrodes. The q-RV interval at the RV free wall pacing site (mean 77.2% of baseline QRS duration) confirmed pacing from a late activated RV area. RV cardiac resynchronization therapy carried significant decrease in QRS duration (P<0.001) along with elimination of the right bundle branch block QRS morphology, increase in RV filling time (P=0.002), pulmonary artery velocity time integral (P=0.006), and RV maximum +dP/dt (P<0.001), and decrease in RV index of myocardial performance (P=0.006). RV mechanical synchrony improved: septal-to-lateral RV mechanical delay decreased (P<0.001) and signs of RV dyssynchrony pattern were significantly abolished. RV systolic stretch fraction reflecting the ratio of myocardial stretching and contraction during systole diminished (P=0.001). CONCLUSIONS: In patients with congenital heart disease and right bundle branch block, RV cardiac resynchronization therapy carried multiple positive effects on RV mechanics, synchrony, and contraction efficiency.

Does First-Trimester Screening Modify the Natural History of Congenital Heart Disease? Analysis of Outcome of Regional Cardiac Screening at 2 Different Time Periods.

BACKGROUND: The study analyzed the impact of first-trimester screening on the spectrum of congenital heart defects (CHDs) later in pregnancy and on the outcome of fetuses and children born alive with a CHD. METHODS: The spectrum of CHDs, associated comorbidities, and outcome of fetuses, either diagnosed with a CHD in the first trimester (Group I, 127 fetuses) or only in the second-trimester screening (Group II, 344 fetuses), were analyzed retrospectively between 2007 and 2013. Second-trimester fetuses diagnosed with a CHD between 2007 and 2013 were also compared with Group III (532 fetuses diagnosed with a CHD in the second trimester from 1996 to 2001, the period before first-trimester screening was introduced). RESULTS: The spectrum of CHDs diagnosed in the first and second trimesters in the same time period differed significantly, with a greater number of comorbidities (P<0.0001), CHDs with univentricular outcome (P<0.0001), intrauterine deaths (P=0.01), and terminations of pregnancy (P<0.0001) in Group I compared with Group II. In Group III, significantly more cases of CHDs with univentricular outcome (P<0.0001), intrauterine demise (P=0.036), and early termination (P<0.0001) were identified compared with fetuses diagnosed with CHDs in the second trimester between 2007 and 2013. The spectrum of CHDs seen in the second-trimester groups differed after first-trimester screening was implemented. CONCLUSIONS: First-trimester screening had a significant impact on the spectrum of CHDs and the outcomes of pregnancies with CHDs diagnosed in the second trimester. Early detection of severe forms of CHDs and significant comorbidities resulted in an increased pregnancy termination rate in the first trimester.

Flecainide versus digoxin for fetal supraventricular tachycardia: Comparison of two drug treatment protocols.

BACKGROUND: The optimal treatment for fetal supraventricular tachycardia (SVT) with 1:1 atrioventricular relationship is unclear. OBJECTIVE: We compared the effectiveness of transplacental treatment protocols used in 2 centers. METHODS: Pharmacologic treatment was used in 84 fetuses. Maternal oral flecainide was the primary therapy in center 1 (n = 34) and intravenous maternal digoxin in center 2 (n = 50). SVT mechanism was classified by mechanical ventriculoatrial (VA) time intervals as short VA or long VA. Treatment success was defined as conversion to sinus rhythm (SR), or rate control, defined as >15% rate reduction. RESULTS: Short VA interval occurred in 67 fetuses (80%) and long VA in 17 (20%). Hydrops was present 28 of 84 (33%). For short VA SVT, conversion to SR was 29 of 42 (69%) for digoxin and 24 of 25 (96%) for flecainide (P = .01). For long VA SVT, conversion to SR and rate control was 4 of 8 (50%) and 0 of 8, respectively, for digoxin, and 6 of 9 (67%) and 2 of 9 (cumulative 89%) for flecainide (P = .13). In nonhydropic fetuses, digoxin was successful in 23 of 29 (79%) and flecainide in 26 of 27 (96%) (P = .10). In hydrops, digoxin was successful in 8 of 21 (38%), flecainide alone in 6 of 7 (86%, P = .07 vs digoxin), and flecainide ± amiodarone in 7 of 7 (100%) (P = .01). Intrauterine or neonatal death occurred in 9 of 21 hydropic fetuses treated with digoxin (43%), compared to 0 of 7 (P = .06) treated with flecainide. CONCLUSIONS: Flecainide was more effective than digoxin, especially when hydrops was present. No adverse fetal outcomes were attributed to flecainide.

Prolonged repolarization in atrial septal defect: An example of mechanoelectrical feedback due to right ventricular volume overload.

BACKGROUND: Prolonged corrected QT (QTc) intervals are frequently observed in children before atrial septal defect (ASD) closure in our department. OBJECTIVE: The aim of the study was to assess the effect of long-term right ventricular volume overload on repolarization. METHODS: QRS, QT, and JT intervals were measured manually in leads II and V5 of a standard 12-lead electrocardiogram in 45 children with an isolated ASD a day before and at least 6 months after ASD closure. QT intervals were corrected for heart rate using the Bazett, Fridericia, Framingham, and Hodges formulas. Each QTc interval calculated using the Bazett formula was compared to sex- and age-matched normal values. RESULTS: Individual QTc intervals shortened significantly (P < .001) using all correction formulas, whereas the QRS duration did not change. The prevalence of prolonged QTc interval decreased from 22.2% to 2.2% after shunt closure (P = .007). CONCLUSION: The QTc interval shortens significantly after the closure of a hemodynamically relevant ASD in childhood. This phenomenon is independent of the used QT correction formula and may reflect a mechanoelectrical feedback associated with right ventricular volume overload.

Experience with the surgical treatment of atrioventricular septal defect with left ventricular outflow tract obstruction.

OBJECTIVES: We sought to determine the prevalence, morphology, surgical methods and results of surgery for left ventricular outflow tract obstruction (LVOTO) associated with atrioventricular septal defect (AVSD). METHODS: Correction of AVSD was performed in 615 patients. Twenty-three (3.7%) patients with LVOTO were identified. Sixteen (70%) of them had partial and 7 (30%) had complete AVSD. Surgery for AVSD was performed at a median of 0.6 years (mean 2.1 ± 3.0 years), and surgery for LVOTO at a median of 3.4 years (mean 4.7 ± 3.5 years). The point and period prevalence of LVOTO in AVSD were determined. Detailed morphological study, individualized repair of AVSD with LVOTO and long-term follow-up were performed. Early and long-term results were analysed. RESULTS: The point prevalence of LVOTO at the time of AVSD repair was 1.3%. The period prevalence of LVOTO was 3.7% in course of 8.3 ± 6.0 (0-18.4) years and 191.4 patient-years following AVSD repair. Causes of LVOTO were fibromuscular membrane (n = 17), septal hypertrophy (n = 17), abnormal atrioventricular (AV) valve (n = 9), muscular bands (n = 3), fibrous strands (n = 4) and stenotic aortic valve (n = 2). Usually, a combination of several obstructive lesions was present. LVOTO was present at the time of AVSD repair in 8 patients (35%) and developed after repair in 15 (65%) patients. Membrane excision (n = 17), myectomy (n = 17), excision of abnormal AV valvar tissue (n = 8), excision of muscular bands and fibrous strands (n = 6), AV valve replacement (n = 2) and aortic valvotomy (n = 2) were required. There was 1 (4%) early and 1 (4%) late death. Six (29%) survivors required reoperation for recurrence of LVOTO at an average interval of 6.3 ± 3.2 years after surgery. The actuarial survival at 1 and 10 years was 96 and 88%, respectively. The actuarial freedom from reoperation for LVOTO was 80, 40 and 20% at 6, 10 and 15 years after surgery, respectively. Eighteen (78%) patients remain in good condition at mean 6.0 ± 5.5 years after surgery. CONCLUSIONS: The point prevalence of LVOTO at the time of AVSD repair was 1.3%, and period prevalence 3.7%. Fibromuscular membrane, septal hypertrophy and valvar attachments represent the most common causes of LVOTO. Usually, more structures are involved. The repair must be individualized. The presence of LVOTO increases the need for reoperation.