Transient increase in VEGF-A leads to cardiac tube anomalies and increased risk of congenital heart malformations

Vascular endothelial growth factor (VEGF) plays a critical role during early heart development. Clinical evidence shows that conditions associated with changes in VEGF signaling in utero are correlated with an increased risk of congenital heart defects (CHD) in newborns. However, how malformations develop after abnormal VEGF exposure is unknown. During embryogenesis, a primitive heart, consisting of an endocardial tube enveloped by a myocardial mantle, is the first organ to function. This tubular heart ultimately transforms into a four-chambered heart. To determine how a transient increase in VEGF prior to heart tube formation affects heart development leading to CHD, we applied exogenous VEGF or a control (vehicle) solution to quail embryos in ovo at Hamburger-Hamilton (HH) stage 8 (28–30 hr of incubation), right before heart tube formation. Light microscopy analysis of embryos re-incubated after treatment for 13 hrs (to approximately HH11/HH12) showed that increased VEGF leads to impaired heart tube elongation accompanied by diameter expansion. Micro-CT analysis of embryos re-incubated for 9 days (to approximately HH38), when the heart is fully formed, showed that VEGF treatment increased the rate of cardiac malformations in surviving embryos. Despite no sex differences in survival, female embryos were more likely to develop cardiac malformations. Our results further suggest that heart tube malformations after a transient increase in VEGF right before heart tube formation may be reversible, leading to normal hearts.     

Echocardiographic and morphologic examination of left ventricular false tendons in human and animal hearts

False tendons are thin, fibrous or fibromuscular structures that traverse the cavity of the left ventricle with no connection to the valvular cusps; they may be single or multiple. We retrospectively analyzed echocardiograms for the prevalence of false tendons in the hearts of 368 (231 male, 137 female) newborns, infants, and children (mean age = 6.28 +/- 4.32 years) who were referred for echocardiography because of suspected acquired or congenital heart disease, but in whom no cardiac pathology was found. In addition, we studied the prevalence of false tendons in 90 hearts from three species of animals (dog, sheep, goat) and eight cadaveric human hearts. In our echocardiographic study, false tendons were detected in 97 of 368 hearts (26.4%). In our gross morphologic studies, false tendons were observed in most of the animal and human hearts: they were present in 5 of 8 (62.5%) human hearts, 14 of 20 (70%) dog hearts, 41 of 50 (82%) sheep hearts, and 16 of 20 (80%) goat hearts. The overall prevalence in animal hearts was 71 of 90 (78.8%). Histologic examination showed the false tendons to be composed of cardiac muscle, blood vessels, fibrous tissue, and Purkinje cells. The possible role of false tendons in innocent murmurs, cardiac rhythm disorders, or left ventricular dysfunction is discussed.     

The anatomy of cardiac looping: a step towards the understanding of the morphogenesis of several forms of congenital cardiac malformations

The early embryonic heart of vertebrates is a simple tubular pump. During the early phases of its development, the initially straight embryonic heart tube becomes transformed into a helically wound loop that is normally seen with a counterclockwise winding. This process is named cardiac looping. Such looping not only establishes the basic type of topological left-right asymmetry of the ventricular chambers but, additionally, is also said to bring the segments of the heart tube and the developing great vessels into an approximation of their definitive topographical relationships. Cardiac looping is, therefore, regarded as the key process in cardiac morphogenesis and pathologists have speculated since the beginning of the 20th century that several forms of congenital cardiac malformations (e.g., with mirror-imaged arrangement of the ventricular chambers) might result from disturbances in looping morphogenesis. In this article a review is given on (1) differences in the usage of the term cardiac looping; (2) our current knowledge of the dynamically changing anatomy of the looping embryonic heart; and (3) our current knowledge of the role of looping anomalies in the morphogenesis of congenital cardiac malformations.     

Method of investigation of deviations from the normal duration of the cardiac cycle

An electronic system for determining the frequency of deviations from the normal duration of the cardiac cycle is described.Department of Physics and Department of Pediatrics, Voroshilovgrad Medical Institute. (Presented by Academician V. N. Chernigovskii.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 78, No. 7, pp. 123–124, July, 1974.     

In vivo imaging of the cyclic changes in cross‐sectional shape of the ventricular segment of pulsating embryonic chick hearts at stages 14 to 17: A contribution to the understanding of the ontogenesis of cardiac pumping function

The cardiac cycle‐related deformations of tubular embryonic hearts were traditionally described as concentric narrowing and widening of a tube of circular cross‐section. Using optical coherence tomography (OCT), we have recently shown that, during the cardiac cycle, only the myocardial tube undergoes concentric narrowing and widening while the endocardial tube undergoes eccentric narrowing and widening, having an elliptic cross‐section at end‐diastole and a slit‐shaped cross‐section at end‐systole. Due to technical limitations, these analyses were confined to early stages of ventricular development (chick embryos, stages 10–13). Using a modified OCT‐system, we now document, for the first time, the cyclic changes in cross‐sectional shape of beating embryonic ventricles at stages 14 to 17. We show that during these stages (1) a large area of diminished cardiac jelly appears at the outer curvature of the ventricular region associated with formation of endocardial pouches; (2) the ventricular endocardial lumen acquires a bell‐shaped cross‐section at end‐diastole and becomes compressed like a fireplace bellows during systole; (3) the contracting portions of the embryonic ventricles display stretching along its baso‐apical axis at end‐systole. The functional significance of our data is discussed with respect to early cardiac pumping function. Developmental Dynamics 238:3273–3284, 2009. © 2009 Wiley‐Liss, Inc.     

体视显微镜下检查成人心房室传导轴

目的:建立一套采用体视显微镜检查房室传导轴的新方法,并结合组织学方法对房室传导轴的形态进行初步探究。方法:采用8例成人心进行实验,先在体视显微镜下行解剖检查,再用组织学方法,观察房室传导轴的特定形态。结果:新方法能全部(8/8)成功地检查房室传导轴,并获得它们的巨微解剖立体形态学资料,1~2个组织块(10张切片/组织块)即可获得足够的组织学信息;8例房室结头部与扩展区之间没有成形的绝缘膜,使得房室结头部不易被解剖分离;8例房室结在平行于心内膜切面上均为椭圆形;具有房室环形态学特征的传导组织和结间束在人心常规组织切片上得到体现。结论:新方法能准确、简便地定位房室传导轴,而且能获得传导轴的巨微解剖资料,为心脏病理学及法医学检查传导系统提供帮助。     

cDNA芯片法筛选压力负荷型心肌肥厚相关基因

应用cDNA芯片技术筛选腹主动脉绑扎后4周大鼠的压力负荷型心肌肥厚相关基因。在反转录来自假手术及腹主动脉绑扎（4周）的大鼠心肌细胞RNA的过程中，用α－^33P-dATP进行探针的标记。然后将探针与微阵列尼龙腹杂交，高严谨度洗涤后分析杂交图谱。通过所获某种特定基因信号的相对强度来比较其对照及腹主动脉绑扎的大鼠心肌组织中表达水平的差异。结果显示有235个基因片段在两组之间信号差别在3倍以上，其中5倍以上差异的基因有55个，而在这55个基因中有26个基因功能未知。所得差异自然包括TGFβ受体III，raf,ARF,clk2等重要的信号传导分子与心肌肥厚的发生密切相关。     

Depressed contractile reserve and impaired calcium handling of cardiac myocytes from chronically unloaded hearts are ameliorated with the administration of physiological treatment dose of T3 in rats

Aim: Chronic cardiac unloading causes a time‐dependent upregulation of phospholamban (PLB) and depression of myocyte contractility in normal rat hearts. As thyroid hormone is known to decrease PLB expression, we examined whether thyroid hormone restores the depressed contractile performance of myocytes from chronically unloaded hearts. Methods: Cardiac unloading was induced by heterotopic heart transplantation in isogenic rats for 5 weeks. Animals were treated with either vehicle or physiological treatment dose of 3,5,3′‐triiodo‐l ‐thyronine (T3) that does not cause hyperthyroidism for the last 3 weeks (n = 20 each). Results: In vehicle‐treated animals, myocyte relaxation and [Ca²⁺]_i decay were slower in unloaded hearts than in recipient hearts. Myocyte shortening in response to high [Ca²⁺]_o was also depressed with impaired augmentation of peak‐systolic [Ca²⁺]_i in unloaded hearts compared with recipient hearts. In vehicle‐treated rats, protein levels of PLB were increased by 136% and the phosphorylation level of PLB at Ser16 were decreased by 32% in unloaded hearts compared with recipient hearts. By contrast, in the T3‐treated animals, the slower relaxation, delayed [Ca²⁺]_i decay, and depressed contractile reserve in myocytes from unloaded hearts were all returned to normal levels. Furthermore, in the T3‐treated animals, there was no difference either in the PLB protein level or in its Ser16‐phosphorylation level between unloaded and recipient hearts. Conclusion: These results suggest that the treatment with physiological treatment dose of thyroid hormone rescues the impaired myocyte relaxation and depressed contractile reserve at least partially through the restoration of PLB protein levels and its phosphorylation state in chronically unloaded hearts.     

A postmortem review of congenital cardiac malformations in a series of 180 adults, over the age of 16 years, born between 1865 and 1980.

The evolution of diagnosis and treatment of congenital heart malformations can be traced through patients surviving into adulthood. We reviewed the heart specimens from 180 patients aged 16 to 86 years and considered the morphological features, the nature of any interventional procedures, and the events leading to death. Based on the mode of clinical presentation, 33 cases were considered covert, and the remaining 147 cases were known or suspected to have a cardiac abnormality during life. Of the symptomatic cases, 60 had no surgical intervention, whereas 167 surgical procedures had been performed in the remaining 87 cases. Acquired heart disease was noted in 7 of the covert cases and in 16 of the symptomatic cases. Overall, there were only 3 instances of errors in clinical identification of significant morphological abnormalities, and 2 cases related to surgical procedures. This review emphasizes the value of autopsy examination for clinicopathologic correlations and the case for retention of cardiac specimens for teaching purposes.     

空气细颗粒物暴露水平与健康成人大脑灰质体积和认知功能的关联研究

目的:应用磁共振成像(MRI)技术探究空气细颗粒物PM2.5暴露水平对健康成年人大脑灰质体积(GMV)和认知功能的影响。方法:选取487例健康成人,采集一般人口学信息及详细居住信息,并根据居住信息获取各受试近6个月和8岁～15岁期间的PM2.5暴露水平,对所有研究对象完成高分辨率结构MRI扫描,使用中文版精神分裂症认知功能成套测验-共识版(MCCB)进行认知测查,使用相关和回归分析探索空气PM2.5暴露水平与GMV和认知功能的关联。结果:近6个月PM2.5暴露水平与大脑右侧额下回三角部(brodmann分区[BA] 45)和右侧颞中回(BA 22)GMV存在负性关联(FWE校正,P<0.05,团块>10体素);与MCCB认知评估的信息处理速度-连线测试(r=-0.17,P<0.01)和推理和问题解决-迷宫测验评分(r=-0.22,P<0.01)负相关。8～15岁时的累积空气PM2.5暴露量与左侧梭状回(BA 18)和右侧舌回(BA 17)GMV负相关(FWE校正,P<0.05,团块>10体素),且与信息处理速度-连线测试、推理和问题解决-迷宫测验评分...     

Autonomic innervation of the human cardiac conduction system: Changes from infancy to senility—An immunohistochemical and histochemical analysis

In order to study the changes in the pattern of autonomic innervation of the human cardiac conduction system in relation to age, the innervation of the conduction system of 24 human hearts (the age of the individuals ranged from newborn to 80 years), freshly obtained at autopsy, was evaluated by a combination of immunofluorescence and histochemical techniques. The pattern of distribution and density of nerves exhibiting immunoreactivity against protein gene product 9.5 (PGP), a general neural marker, dopamine β‐hydroxylase (DBH) and tyrosine hydroxylase (TH), indicators for presumptive sympathetic neural tissue, and those demonstrating positive acetylcholinesterase (AChE) activity, were studied. All these nerves showed a similar pattern of distribution and developmental changes. The density of innervation, assessed semiquantitatively, was highest in the sinus node, and exhibited a decreasing gradient through the atrioventricular node, penetrating and branching bundle, to the bundle branches. Other than a paucity of those showing AChE activity, nerves were present in substantial quantities in infancy. They then increased in density to a maximum in childhood, at which time the adult pattern was achieved and then gradually decreased in density in the elders to a level similar to or slightly less than that in infancy. In contrast, only scattered AChE‐positive nerves were found in the sinus and atrioventricular nodes, but were absent from the bundle branches of the infant heart, whereas these conduction tissues themselves possessing a substantial amount of pseudocholinesterase. During maturation into adulthood, however, the conduction tissues gradually lost their content of pseudocholinesterase but acquired a rich supply of AChE‐positive nerves, comparable in density to those of DBH and TH nerves. The decline in density of AChE‐positive nerves in the conduction tissues in the elders was also similar to those of DBH and TH nerves. Our findings of initial sympathetic dominance in the neural supply to the human cardiac conduction system in infancy, and its gradual transition into a sympathetic and parasympathetic codominance in adulthood, correlate well with the physiologic alterations known to occur in cardiac rate during postnatal development. The finding of reduction in density of innervation of the conduction tissue with ageing is also in agreement with clinical and electrophysiological findings such as age‐associated reduction in cardiac response to parasympathetic stimulation. Finally, our findings also support the hypothesis that, in addition to the para‐arterial route, the parafascicular route of extension along the conduction tissue constitutes another pathway for the innervation of the conduction system of the human heart during development. Anat Rec 264:169–182, 2001. © 2001 Wiley‐Liss, Inc.     

Insights from the examination of verbal and spatial memory errors in relation to clinical symptoms of patients with recent-onset schizophrenia

Introduction. Memory deficits in patients with schizophrenia (SZ) are considered as a key feature of the clinical manifestations of the disease. In order to further examine the role and nature of memory deficits in SZ, the pattern of errors in verbal and spatial serial recall tasks committed by SZ patients was compared to that of healthy controls. We also tested the relationship between these memory errors and clinical symptoms.

Methods. Twenty-seven outpatients with recent-onset SZ and 27 age and gender matched healthy controls had to remember sequences of items (digits or localisations) in a serial recall task. Clinical symptoms were assessed with the PANSS and the SAPS.

Results. The results indicate that the number of omissions, intrusions, and transpositions can differentiate patients with SZ from healthy controls. Intrusions and transpositions committed in the verbal domain were associated with the negative subscale of the PANSS. Transposition errors were associated with delusions whether the to-be-remembered information was verbal or spatial.

Conclusion. The examination of the pattern of errors, in particular that of transpositions, is a more informative cognitive index than the mere analysis of overall performance, and provides a promising target for treatment.     

Anomalous origin of additional coronary artery arising from the pulmonary artery in complex congenital heart disease

Anomalous origin of coronary arteries is a rare congenital defect and usually presents as an isolated defect. In only 5% of cases, it may be associated with other cardiac anomalies. In this article, we present a case of a newborn with a very complex congenital cardiac disease accompanied with an anomalous origin of an additional coronary artery.     

Comparison of interpolation methods of predominant cardiomyocyte orientation from in vivo and ex vivo cardiac diffusion tensor imaging data

Cardiac electrophysiology and cardiac mechanics both depend on the average cardiomyocyte long-axis orientation. In the realm of personalized medicine, knowledge of the patient-specific changes in cardiac microstructure plays a crucial role. Patient-specific computational modelling has emerged as a tool to better understand disease progression. In vivo cardiac diffusion tensor imaging (cDTI) is a vital tool to non-destructively measure the average cardiomyocyte long-axis orientation in the heart. However, cDTI suffers from long scan times, rendering volumetric, high-resolution acquisitions challenging. Consequently, interpolation techniques are needed to populate bio-mechanical models with patient-specific average cardiomyocyte long-axis orientations. In this work, we compare five interpolation techniques applied to in vivo and ex vivo porcine input data. We compare two tensor interpolation approaches, one rule-based approximation, and two data-driven, low-rank models. We demonstrate the advantage of tensor interpolation techniques, resulting in lower interpolation errors than do low-rank models and rule-based methods adapted to cDTI data. In an ex vivo comparison, we study the influence of three imaging parameters that can be traded off against acquisition time: in-plane resolution, signal to noise ratio, and number of acquired short-axis imaging slices.     

Comparison of baroreceptor cardiac reflex sensitivity estimates from inter‐systolic and ECG R‐R intervals

Baroreceptor reflex sensitivity (BRS) is frequently evaluated using the spontaneous sequence method. Many of these studies use the inter‐systolic interval (ISI) derived from a blood pressure monitor (e.g., Finapres) as interbeat interval measure instead of the traditionally recommended R‐R series derived from the ECG. In this study, we examine possible differences between estimates of BRS from ISI and ECG R‐R intervals. BRS was evaluated in 35 participants under three conditions: rest, mental arithmetic, and recovery periods. Although correlations between the two estimates are very high (all rs>.9), small but significant differences were found: the measures from ISI systematically yield higher BRS values and result in the detection of a greater number of reflex sequences. The higher BRS values from measures of ISI are due to the effects of pulse transit time fluctuations associated with the sequences of change in blood pressure.