Effect of left atrial ligation-driven altered inflow hemodynamics on embryonic heart development: clues for prenatal progression of hypoplastic left heart syndrome

Congenital heart defects (CHDs) are abnormalities in the heart structure present at birth. One important condition is hypoplastic left heart syndrome (HLHS) where severely underdeveloped left ventricle (LV) cannot support systemic circulation. HLHS usually initiates as localized tissue malformations with no underlying genetic cause, suggesting that disturbed hemodynamics contribute to the embryonic development of these defects. Left atrial ligation (LAL) is a surgical procedure on embryonic chick resulting in a phenotype resembling clinical HLHS. In this study, we investigated disturbed hemodynamics and deteriorated cardiac growth following LAL to investigate possible mechanobiological mechanisms for the embryonic development of HLHS. We integrated techniques such as echocardiography, micro-CT and computational fluid dynamics (CFD) for these analyses. Specifically, LAL procedure causes an immediate flow disturbance over atrioventricular (AV) cushions. At later stages after the heart septation, it causes hemodynamic disturbances in LV. As a consequence of the LAL procedure, the left-AV canal and LV volume decrease in size, and in the opposite way, the right-AV canal and right ventricle volume increase. According to our CFD analysis, LAL results in an immediate decrease in the left AV canal WSS levels for 3.5-day (HH21) pre-septated hearts. For 7-day post-septated hearts (HH30), LAL leads to further reduction in WSS levels in the left AV canal, and relatively increased WSS levels in the right AV canal. This study demonstrates the critical importance of the disturbed hemodynamics during the heart valve and ventricle development.

     

In vitro hemodynamic investigation of the embryonic aortic arch at late gestation

This study focuses on the dynamic flow through the fetal aortic arch driven by the concurrent action of right and left ventricles. We created a parametric pulsatile computational fluid dynamics (CFD) model of the fetal aortic junction with physiologic vessel geometries. To gain a better biophysical understanding, an in vitro experimental fetal flow loop for flow visualization was constructed for identical CFD conditions. CFD and in vitro experimental results were comparable. Swirling flow during the acceleration phase of the cardiac cycle and unidirectional flow following mid-deceleration phase were observed in pulmonary arteries (PA), head-neck vessels, and descending aorta. Right-to-left (oxygenated) blood flowed through the ductus arteriosus (DA) posterior relative to the antegrade left ventricular outflow tract (LVOT) stream and resembled jet flow. LVOT and right ventricular outflow tract flow mixing had not completed until approximately 3.5 descending aorta diameters downstream of the DA insertion into the aortic arch. Normal arch model flow patterns were then compared to flow patterns of four common congenital heart malformations that include aortic arch anomalies. Weak oscillatory reversing flow through the DA junction was observed only for the Tetralogy of Fallot configuration. PA and hypoplastic left heart syndrome configurations demonstrated complex, abnormal flow patterns in the PAs and head-neck vessels. Aortic coarctation resulted in large-scale recirculating flow in the aortic arch proximal to the DA. Intravascular flow patterns spatially correlated with abnormal vascular structures consistent with the paradigm that abnormal intravascular flow patterns associated with congenital heart disease influence vascular growth and function.     

Multiscale models of the hybrid palliation for hypoplastic left heart syndrome

A less-invasive procedure that combines interventional stent placement in the ductus arteriosus and surgical banding of the branch pulmonary arteries has been recently introduced in the treatment of the hypoplastic left heart syndrome (HLHS). The hemodynamic behaviour of this hybrid approach has not been examined before in a mathematical model. In this study, a mathematical model of the hybrid procedure for HLHS is described, applying a multiscale approach that couples 3D models of the area of the surgical operation and lumped parameter models of the remaining circulation. The effects of various degrees of pulmonary banding and different stent sizes inserted in the ductus arteriosus on pulmonary-systemic flow ratio, cardiac output and oxygen delivery were assessed. Computational results suggest that balanced systemic and pulmonary blood flow and optimal systemic oxygen delivery are sensitive to the degree of pulmonary arterial banding and not to the size of the ductal stent.     

A case of nonimmune hydrops fetalis with a rare cardiac anomaly in a rhesus monkey

A case of nonimmune hydrops fetalis in a rhesus monkey was identified by ultrasound. The 68-day fetus exhibited generalized edema, pleural effusion, and mild ascites. Intrauterine fetal demise occurred between 75 and 80 days gestation. Necropsy revealed marked anasarca and a rare cardiac anomaly characterized by aortic and left atrioventricular valve atresia, hypoplasia of the ascending aorta and arch, and absence of the left ventricle.     

Epidemiology of noncomplex left ventricular outflow tract obstruction malformations (aortic valve stenosis, coarctation of the aorta, hypoplastic left heart syndrome) in Texas, 1999-2001

BACKGROUND: The left ventricular outflow tract (LVOT) malformations aortic valve stenosis (AVS), coarctation of the aorta (CoA), and hypoplastic left heart syndrome (HLHS) contribute significantly to infant mortality due to birth defects. Previous epidemiology data showed rate differences between male and female and white and black ethnic groups. The Texas Birth Defects Registry, an active surveillance program, enables study in a large, diverse population including Hispanics. METHODS: Records of children up to 1 year old with AVS, CoA, and HLHS born in Texas from 1999 to 2001, were collected from the registry. Those including additional heart defects or a chromosomal anomaly were excluded. Multivariate analysis included: infant sex; United States-Mexico border county residence; and maternal age, race/ethnicity, birthplace, and education. RESULTS: There were 910 cases among 1.08 million live births, of which 499 met inclusion criteria. Multivariate modeling of all LVOT malformations combined demonstrated lower prevalence rate ratios (PRRs) for black males (0.26) and Hispanic males (0.70). Similar results were found for CoA but not AVS or HLHS. Higher PRRs were noted for increased maternal age for LVOT (1.3 for 24-34 years; 1.7 for >34 years), AVS, and HLHS, but not CoA, and higher PRRs across all diagnoses for males (LVOT PRR, 2.4) were noted. CoA PRRs were higher in border county vs. non-border county residents (PRR, 2.1). Maternal education and birthplace were not significant factors. CONCLUSIONS: There are rate differences for males among all 3 ethnic groups. Sex and ethnic differences suggest genetic etiologies, where the ethnic differences could be used to find susceptibility loci with mapping by admixture linkage disequilibrium. Increased CoA rates along the U.S.-Mexico border suggest environmental causes that will require further monitoring.     

A computational study of aortic reconstruction in single ventricle patients

Biomechanics and Modeling in Mechanobiology - Patients with hypoplastic left heart syndrome (HLHS) are born with an underdeveloped left heart. They typically receive a sequence of surgeries that...     

Congenital heart disease cyanotic children

Cyanosis is often the only apparent symptom of congenital heart disease for which a child is brought to a physician. Some of the more common anomalies can be diagnosed from this and other symptoms by a general practitioner. Squatting after exertion is a sign of tetralogy of Fallot; severe disability with relatively mild cyanosis may indicate pure pulmonary stenosis. A brisk, short, rasping systolic murmur is characteristic of these conditions and of tricuspid atresia. Tetralogy of Fallot is further symptomatized by a boot-shaped heart, not greatly enlarged, and right axis deviation on electrocardiograms. Typically the lung fields are clear. The author's treatment of choice is aortic-pulmonary or subclavian-pulmonary anastomosis as indicated, preferably done after the child is three years old if the condition is not so severe as to require earlier operation. Pure pulmonary stenosis, which in some cases cannot be distinguished from tetralogy of Fallot except by cardiac catheterization and angiocardiography, may in more typical cases be diagnosed by convexity rather than concavity in the pulmonary segment and by differences in electrocardiograms. An expanding valvulotome is used to open the stenosed pulmonary valve, which is then dilated.A systolic murmur, a round heart and left axis deviation are usually found in tricuspid atresia. Shunt operations performed for relief of this condition may lead to later heart failure because of the devious rerouting of blood through the heart. The operations here outlined and others are statistically evaluated.     

大鼠心力衰竭模型的构建与鉴定

目的比较主动脉弓缩窄和腹主动脉缩窄复制心力衰竭衰模型的异同,探索快速有效的心衰动物模型。方法将大鼠分为主动脉缩窄手术组,腹主动脉缩窄手术组和对照组（C组）。主动脉缩窄手术组实施颈部手术,在主动脉弓处缩窄动脉直径;腹主动脉缩窄手术组实施腹部手术,在腹主动脉处缩窄动脉直径;C组实施颈部手术但不实施动脉缩窄手术。各组实验动物均正常喂养4～6周后进行心脏的超声检测和心脏血流动力学检测。结果心脏超声结果显示：主动脉弓缩窄手术组左心室壁厚度和左心室腔内径在术后4周明显高于正常组;而腹主动脉缩窄手术组左心室壁厚度和左心室腔内径在术后4周较正常组没有明显增加。术后6周,腹主动脉缩窄手术组左心室壁厚度和左心室腔内径都明显增加,而主动脉弓缩窄手术组左心室壁厚度没有明显改变,左心室腔内经明显增加。血流动力学指标显示：主动脉弓缩窄手术组LVESP、LVEDP、LVDP、±dp/dtmax都明显低于腹主动脉缩窄手术组。结论主动脉弓缩窄手术复制心肌肥大导致心功能衰竭模型效果明显快于腹主动脉缩窄手术复制的心肌肥大导致心功能衰竭模型。     

An Angiocardiographic Analysis of the Central Circulation in the Air Breathing Teleost Channa argus

The unique anatomy of the double ventral aorta outflow system in the air breathing teleost Channa argus (Ophiocephalus) showing an anterior and posterior ventral aorta is described. The marked trabeculation of the ventricle and bulbus arteriosus and the arrangement of central veins are used as a basis for the hypothesis that Channa may selectively channel the well oxygenated blood draining the air breathing organs via the anterior cardinal vein to the posterior ventral aorta, which forms the systemic arterial circulation. An angiocardiographic technique was used to test this hypothesis, as well as to delineate the functional role of the heart chambers in the cardiac cycle. No reflux of contrast to the sinus venosus during atrial filling and no ventricular filling before atrial contraction were apparent, which makes the atrium the main determinant of the ventricular end-diastolic volume. Ventricular contraction left a small or no residual volume. The ventricular ejectate was initially nearly completely absorbed by the very elastic bulbus arteriosus, acting as a pressure chamber (Windkessel) stabilizing and prolonging ventral aortic blood flow. Contrast medium was not selectively passed from the anterior cardinal vein to the posterior ventral aorta. However, the diameter of this vessel and its density of contrast were greater than in the anterior aorta, suggesting a preference for a greater blood flow from the air breathing organ through the heart to the posterior aorta.     

CONGENITAL HEART DISEASE IN CYANOTIC CHILDREN

Cyanosis is often the only apparent symptom of congenital heart disease for which a child is brought to a physician. Some of the more common anomalies can be diagnosed from this and other symptoms by a general practitioner. Squatting after exertion is a sign of tetralogy of Fallot; severe disability with relatively mild cyanosis may indicate pure pulmonary stenosis. A brisk, short, rasping systolic murmur is characteristic of these conditions and of tricuspid atresia.Tetralogy of Fallot is further symptomatized by a boot-shaped heart, not greatly enlarged, and right axis deviation on electrocardiograms. Typically the lung fields are clear. The author''s treatment of choice is aortic-pulmonary or subclavian-pulmonary anastomosis as indicated, preferably done after the child is three years old if the condition is not so severe as to require earlier operation.Pure pulmonary stenosis, which in some cases cannot be distinguished from tetralogy of Fallot except by cardiac catheterization and angiocardiography, may in more typical cases be diagnosed by convexity rather than concavity in the pulmonary segment and by differences in electrocardiograms. An expanding valvulotome is used to open the stenosed pulmonary valve, which is then dilated.A systolic murmur, a round heart and left axis deviation are usually found in tricuspid atresia. Shunt operations performed for relief of this condition may lead to later heart failure because of the devious rerouting of blood through the heart.The operations here outlined and others are statistically evaluated.     

A fast computational model for circulatory dynamics: effects of left ventricle–aorta coupling

The course of diseases such as hypertension, systolic heart failure and heart failure with a preserved ejection fraction is affected by interactions between the left ventricle (LV) and the vasculature. To study these interactions, a computationally efficient, biophysically based mathematical model for the circulatory system is presented. In a four-chamber model of the heart, the LV is represented by a previously described low-order, wall volume-preserving model that includes torsion and base-to-apex and circumferential wall shortening and lengthening, and the other chambers are represented using spherical geometries. Active and passive myocardial mechanics of all four chambers are included. The cardiac model is coupled with a wave propagation model for the aorta and a closed lumped-parameter circulation model. Parameters for the normal heart and aorta are determined by fitting to experimental data. Changes in the timing and magnitude of pulse wave reflections by the aorta are demonstrated with changes in compliance and taper of the aorta as seen in aging (decreased compliance, increased diameter and length), and resulting effects on LV pressure–volume loops and LV fiber stress and sarcomere shortening are predicted. Effects of aging of the aorta combined with reduced LV contractile force (failing heart) are examined. In the failing heart, changes in aortic properties with aging affect stroke volume and sarcomere shortening without appreciable augmentation of aortic pressure, and the reflected pressure wave contributes an increased proportion of aortic pressure.

     

Occult aortic stenosis as cause of intractable heart failure

During a three-year period 10 patients with critical aortic stenosis were referred to a cardiac referral centre with symptoms and signs of intractable cardiac failure and low cardiac output. In nine patients the correct diagnosis was not suspected at the referring hospital, and in the remaining patient the true severity of the aortic stenosis was not appreciated and cardiomyopathy was suggested as an additional diagnosis. The most common referral diagnoses were severe mitral regurgitation (four patients), congestive cardiomyopathy (two patients), or both (three patients). Only two patients had soft ejection systolic murmurs at the base of the heart radiating into the neck, and such a murmur appeared in a third patient during medical treatment. The carotid pulses were of small volume but the characteristic slow-rising, anacrotic nature of the pulse could not be appreciated clinically. The diagnosis was suspected in nine patients because of aortic valve calcification detected by lateral chest x-ray examination in seven patients and by x-ray screening of the heart in two, and because of abnormal aortic valve echoes in the echocardiogram of all five patients in whom the aortic valve could be seen. Eight patients underwent aortic valve replacement despite seemingly poor preoperative left ventricular function. Three patients died, of whom two had severe coexistent coronary artery disease. The five survivors all returned to normal lives and needed little or no medication.Critical aortic stenosis should be actively sought in patients with severe heart failure of unknown cause since surgery may enable them to resume their normal lives.     

Comparison of Central Aortic and Peripheral Artery Pressure Curves

Brachial artery and central aortic pressures were compared in 50 consecutive patients subjected to retrograde left heart catheterization in order to re-emphasize the fact that the two pressures are not necessarily identical. In 43 cases the systemic systolic pressure peaks exceeded those in the central aorta while in seven these pressures were equal. The average pressure difference was 22.6 mm. Hg. The greatest differences occurred in cases of aortic regurgitation and could be extreme, the brachial artery systolic pressure exceeding that in the aorta by more than 100 mm. Hg in some instances. The least differences occurred in cases of aortic stenosis but significant differences occasionally existed, leading to erroneous estimation of valve orifice size if the systemic rather than the aortic systolic pressure was used.     

Acidaemia reduces cardiac output and left ventricular contractility in conscious lambs

We studied the effects of HCI-induced metabolic acidaemia on cardiac output, contractile function, myocardial blood flow, and myocardial oxygen consumption in nine unanaesthetized newborn lambs. Through a left thoracotomy, catheters were placed in the aorta, left atrium and coronary sinus. A pressure transducer was placed in the left ventricle. Three to four days after surgery, we measured cardiac output, dP/dt, left ventricular end diastolic and aortic mean blood pressures, heart rate, aortic and coronary sinus blood oxygen contents, and left ventricular myocardial blood flow during a control period, during metabolic acidaemia, and after the aortic pH was restored to normal. We calculated systemic vascular resistance, myocardial oxygen consumption and left ventricular work. Acidaemia was associated with reduction in cardiac output, maximal dP/dt, and aortic mean blood pressure. Left ventricular end diastolic pressure and systemic vascular resistance increased, and heart rate did not change significantly. The reduction in myocardial blood flow and oxygen consumption was accompanied by fall in cardiac work. Cardiac output returned to control levels after the pH had been normalized but maximal dP/dt was incompletely restored. Myocardial blood flow and oxygen consumption increased beyond control levels. This study demonstrates that HCI-induced metabolic acidaemia in conscious newborn lambs is associated with a reduction in cardiac output which could have been mediated by the reduction in contractile function and/or the increase in systemic vascular resistance. The decreases in myocardial blood flow and oxygen consumption appear to reflect diminished cardiac work. The restoration of a normal cardiac output after normalization of the pH appears to have resulted from the increases in heart rate and left ventricular filling pressures in conjunction with an incomplete restoration of contractile function.     

Cardiac neural crest is dispensable for outflow tract septation in Xenopus

In vertebrate embryos, cardiac precursor cells of the primary heart field are specified in the lateral mesoderm. These cells converge at the ventral midline to form the linear heart tube, and give rise to the atria and the left ventricle. The right ventricle and the outflow tract are derived from an adjacent population of precursors known as the second heart field. In addition, the cardiac neural crest contributes cells to the septum of the outflow tract to separate the systemic and the pulmonary circulations. The amphibian heart has a single ventricle and an outflow tract with an incomplete spiral septum; however, it is unknown whether the cardiac neural crest is also involved in outflow tract septation, as in amniotes. Using a combination of tissue transplantations and molecular analyses in Xenopus we show that the amphibian outflow tract is derived from a second heart field equivalent to that described in birds and mammals. However, in contrast to what we see in amniotes, it is the second heart field and not the cardiac neural crest that forms the septum of the amphibian outflow tract. In Xenopus, cardiac neural crest cells remain confined to the aortic sac and arch arteries and never populate the outflow tract cushions. This significant difference suggests that cardiac neural crest cell migration into the cardiac cushions is an amniote-specific characteristic, presumably acquired to increase the mass of the outflow tract septum with the evolutionary need for a fully divided circulation.     

A family-based association study of congenital left-sided heart malformations and 5,10 methylenetetrahydrofolate reductase

BACKGROUND: Aortic valve stenosis (AVS), coarctation of the aorta (CoA), and hypoplastic left heart syndrome (HLHS) are obstructive malformations of the left ventricular outflow tract that account for a significant proportion of infant mortality. Two previous small case-control studies suggested methylenetetrahydrofolate reductase (MTHFR) polymorphisms may be associated with this group of malformations. METHODS: We used a family-based association design with inclusion criteria of nonsyndromic diagnosis of AVS, CoA, and HLHS, powered to detect an odds ratio for the heterozygote of <1.5. A total of 207 affected offspring-parent trios were genotyped by restriction fragment length polymorphisms at the two common polymorphic loci C677T and A1298C. RESULTS: Error rate estimation based on replicate samples was 0.76%. Mendelian inconsistency at either polymorphism was noted in 10 trios, for a calculated undetected error rate of 1.95%. A total of 197 trios were analyzed using the transmission disequilibrium test. Significant association was not found between both the C677T or A1298C polymorphisms and presence of a heart defect, whether analyzed as a group, or by sex, ethnicity, or specific diagnosis. A log-linear analysis did not find increased relative risk based on the maternal genotype. CONCLUSIONS: We were unable to replicate previous association studies and concluded that neither the affected nor the maternal MTHFR genotype, by itself, is a major risk factor for congenital left ventricular outflow tract malformations.     

Effect of hyperbaric oxygenation on several functional and morphologic properties of the heart and catecholamine metabolism in the presence of compensatory myocardial hypertrophy]

Rabbits subjected to hyperbaric oxygenation (HBO) for one month following ascending aorta stenosis developed less distinct hypertrophy and signs of myocardial dystrophy with a more distinct enhancement of the left ventricular contractility than animals with aortic stenosis kept under normal pressure. In rabbits with heart hypertrophy developing under HBO the increasing adaptive capacity of the myocardium was accompanied by an elevation in functional reserve of the sympathetic regulation apparatus. Apparently HBO aided the development of the optimum cardiac adaptation to a high afterload.     

Atrioventricular canal defect and hypoplastic left heart syndrome as discordant congenital heart defects in twins.

We report on a twin pair presenting with atrioventricular canal defect (AVCD) with right ventricular dominance in one twin, and classic hypoplastic left heart syndrome (HLHS) in the other. According to the developmental-mechanistic approach, AVCDs belong to the group of extracellular matrix abnormalities, whereas classic HLHS is included among flow lesions. Twin pairs with congenital heart defect (CHD) generally have concordant defects by mechanistic group. The occurrence of AVCD and classic HLHS in twins or siblings has never been reported. Interestingly, hypoplasia of the left ventricle is the anatomic characteristic which unifies the discordant CHDs observed in our twins. The occurrence of CHD in both members of the twin pair implies a strong influence of genetic factors. At present, the genetic basis determining the different cardiac phenotypes observed in our twins is unknown. The report of these peculiar associations may be useful to stimulate further studies and shed light on the etiology of CHDs.     

DiGeorge syndrome presenting as severe congenital heart disease in the newborn.

In seven infants with DiGeorge syndrome the major clinical manifestation was cardiac failure in the 1st week of life. All had severe congenital heart disease: five had interruption of the aortic arch and associated lesions, one had a ventricular septal defect and a cervical aorta, and one had truncus arteriosus. All but one died by 2 weeks of age. Necropsy data lent support to the hypothesis of a relation between the cardiovascular anomalies and defective development of structures derived from the third and fourth pharyngeal pouches.