Unidirectional Blood Flow Research Articles

Comparative anatomy of the heart–glomerulus complex of Cephalodiscus gracilis (Pterobranchia): structure, function, and phylogenetic implications

Cephalodiscus gracilis Harmer, 1905 is a semi-sessile deuterostome that shares with fish-like chordates pharyngeal gill slits and a dorsally situated brain. In order to reveal structures potentially homologous among deuterostomes and to infer their functional roles, we investigated the axial complex, associated blood vessels and structures of C. gracilis using transmission electron microscopy, light microscopy, and digital 3D reconstructions. We describe the smooth, bipartite cephalic shield retractor muscles that originate as solid compact muscles and fan out to traverse the protocoel as individual muscle cells. The axial complex consists of a cap-shaped coelomic sac, the pericardium that surrounds the central heart. The pericardium is constituted of myoepithelial cells, with the cells facing the heart being thicker and richer in myofilaments. A prominent dorsal median blood vessel opens into the heart, which gives rise to a short median ventral vessel that opens into the paired glomeruli connected to the ventral side of the stomochord. The tip of the curved stomochord rests precisely above the connection of the dorsal median vessel with the heart, a position that would allow the stomochord to function as a valve facilitating unidirectional blood flow. Glomeruli are lined by podocytes of the spacious protocoel and are considered to be the site of ultrafiltration. Two pairs of blood vessels enter the median dorsal blood vessel from the tentacles. The median dorsal blood vessel is separated from the brain by a thin basement membrane. This arrangement is consistent with the hypothesis that blood vessels in the tentacles increase oxygen supply for the brain. Based on detailed similarities, the heart–glomerulus complex of C. gracilis is considered homologous with the heart–glomerulus complex in Rhabdopleura spp., and Enteropneusta, and the axial complex in Echinodermata. In addition, we hypothesize homology to the excretory complex including Hatschek’s nephridium in Cephalochordata. Thus, the heart–glomerulus complex does not support a sister-group relationship between Echinodermata and Hemichordata, whereas the organization of the cephalic shield retractor muscles is consistent with the evolution of pterobranchs within enteropneusts.

Mitral valve size measurement in North Karnataka by using cardiac sizer: A cadaveric study

Background: Heart is a vital organ of circulatory system. Valves maintain the unidirectional flow of blood. Mitral valve (MV) prevents the backflow of blood into the left atrium. For the proper functioning of the heart, all valves should be intact. MV prolapse and regurgitation is the main cause of MV replacement. Mean circumference of MV varies from person to person. Aim of the present study is to measure the average size of the valve in the cadavers of North Karnataka region by using cardiac sizer, which would help in the selection of prosthetic valve in the cardiac surgery. Materials and Methods: This study was carried out on 50 cadaveric adult human hearts. Left atrium was opened along the left border of heart so as to expose the mitral orifice. Then, the diameter of the valve was measured by using cardiac sizer, whereas circumference was calculated manually. Number of mitral valve cusps and papillary muscles were observed. Results: The mean annular circumference and diameter of the mitral valve was found to be 8.03 ± 0.82 cm and 2.56 ± 0.32 cm, respectively. Majority (72%) of the mitral valves had the circumference ranging from 7.53 to 8.47 cm and the diameter ranging from 2.4 to 2.7 cm. Conclusion: The size of mitral valve in the North Karnataka region was found to be less as compared to the other studies. This study might help cardio-thoracic surgeon as well the prosthetic valve manufacturing companies for the rough estimation of the mitral valve size.

Serotonin Potentiates Transforming Growth Factor-beta3 Induced Biomechanical Remodeling in Avian Embryonic Atrioventricular Valves

Embryonic heart valve primordia (cushions) maintain unidirectional blood flow during development despite an increasingly demanding mechanical environment. Recent studies demonstrate that atrioventricular (AV) cushions stiffen over gestation, but the molecular mechanisms of this process are unknown. Transforming growth factor-beta (TGFβ) and serotonin (5-HT) signaling modulate tissue biomechanics of postnatal valves, but less is known of their role in the biomechanical remodeling of embryonic valves. In this study, we demonstrate that exogenous TGFβ3 increases AV cushion biomechanical stiffness and residual stress, but paradoxically reduces matrix compaction. We then show that TGFβ3 induces contractile gene expression (RhoA, aSMA) and extracellular matrix expression (col1α2) in cushion mesenchyme, while simultaneously stimulating a two-fold increase in proliferation. Local compaction increased due to an elevated contractile phenotype, but global compaction appeared reduced due to proliferation and ECM synthesis. Blockade of TGFβ type I receptors via SB431542 inhibited the TGFβ3 effects. We next showed that exogenous 5-HT does not influence cushion stiffness by itself, but synergistically increases cushion stiffness with TGFβ3 co-treatment. 5-HT increased TGFβ3 gene expression and also potentiated TGFβ3 induced gene expression in a dose-dependent manner. Blockade of the 5HT2b receptor, but not 5-HT2a receptor or serotonin transporter (SERT), resulted in complete cessation of TGFβ3 induced mechanical strengthening. Finally, systemic 5-HT administration in ovo induced cushion remodeling related defects, including thinned/atretic AV valves, ventricular septal defects, and outflow rotation defects. Elevated 5-HT in ovo resulted in elevated remodeling gene expression and increased TGFβ signaling activity, supporting our ex-vivo findings. Collectively, these results highlight TGFβ/5-HT signaling as a potent mechanism for control of biomechanical remodeling of AV cushions during development.

Akutes fetofetales Transfusionssyndrom - Fallbericht und Literaturübersicht

The perinatal morbidity and mortality risk in monochorionic twin pregnancies are 3-5-fold increased compared to those of dichorionic twin pregnancies. Partially, this is due to the higher rate of preterm delivery but also to the twin-to-twin transfusion syndrome (TTTS). Caused by unidirectional blood flow via placental anastomoses, the TTTS leads to weight differences of more than 20% between monochorial twins. The blood donor often shows oligohydramnios, whereas the recipient shows polyhydramnios. Lewi et al. demonstrated, in a study with 202 monochorionic twin pregnancies, a 9% rate of severe TTTS. The mortality of this complication is about 90% when untreated. In contrast to the chronic TTTS, little is known about the acute intrapartal one, which is characterised by anaemia and hypovolaemia of the donor and polyglobulia of the recipient without significant weight differences between the two. In most cases, anaemia occurred after normal delivery of the first twin. Still, there are no means or signs for early detection. We describe the case of a 30-year-old primigravida with a monochorionic diamniotic twin pregnancy. During pregnancy, no evidence of TTTS could be detected. At 37 + 1 weeks gestation labour was induced with prostaglandin-containing gel. Both foetuses showed cephalic presentation. The CTG of the first twin showed a conspicuous heart rate. After labour the first twin presented with anaemia and hypovolaemic shock, the APGAR was 2/7/8. The infant's haemoglobin was 13.7 g/dL. After delivery, the second twin with APGAR 10/10/10 showed a haemoglobin of 19.6 g/dL, which is in the upper normal range. Their birth weights differed by merely 10.4%. Acute TTTS is frequently characterised by anaemia and hypovolaemia of the second twin. In our case of a monochorionic twin delivery with acute TTTS the donor was born first. Early diagnosis and neonatal intervention is essential for reducing postnatal morbidity and mortality.

Cardiac morbidity in twin-twin transfusion syndrome?

Twin-to-twin transfusion syndrome (TTTS) affects about 10% of monochorionic pregnancies and develops when uncompensated unidirectional blood flow from one twin ('donor') to the other ('recipient') causes circulatory imbalance. The cardiac effect of the underlying hypervolemia or endocrine dysregulation, or both, manifests in the recipient as echocardiographic findings of the syndrome-related cardiomyopathy. The Quintero staging system for TTTS has recently been questioned, because more refined measurement of cardiac function may improve evaluation of disease severity and prediction of outcome. Much has been done to increase survival and diminish the cardiac morbidity associated with TTTS. The purpose of this paper was to review the literature on cardiac morbidity associated this syndrome.

Innovative PCG technique for Cardiac Spectral Analysis

Normally the ratio of population versus physician is so feeble in most of the economically under- developed and developing countries that cause delayed diagnosis and non-availability of on-time treatment of heart patients specifically in the rural areas. It forces to think about availability of a low cost equipment in the rural health centres which may readily diagnose and alarm the critical cardiac condition of patient in absence of cardiologist too, so that the patient can immediately be carried to nearby urban health centre for early treatment. This paper presents an effective and handy PCG device which is equally useful for urban health centres to assist the cardiologist in making faster decision and control of the ailment, which is vital and critical subject in treating such patients. The equipment developed is low cost, quiet affordable by anyone or the rural health centres, portable and easy to maneuver by anyone who possess even a little knowledge to handle it and read the analysis. It does not require any specialized medical person to use the equipment. The diagnosis is carried through computer- based inference system which counts for reliability and accuracy of the diagnosis. Keywords - Phonocardiograph, PCG device, Human Heart, Osculation, Spectral Analysis, I. Introduction With the advent of the stethoscope in the year 1816, the technique of heart auscultation entered the domain of modern medical analysis. Prior to the modern practice, a remarkable number of fresh medical practicener fail to diagnose heart sounds by just listening to it due to the restriction of the human ear to detect low frequency heart sounds, and therefore the proper diagnosis of the heart was not possible. This paved the way for Phonocardiogram equipment, where study of the heart sound waveform enabled professionals to determine the nature of heart disease. The Phonocardiogram (PCG) device is quite a well-known device, which is used to listen to the heart sounds of a human being and the output from the machine is compared with the ideal heart sounds of a human being of that age and the deviation from the ideal response is then analyzed to detect the nature of ailment. The PCG devices in use today are very expensive and usually detect three peaks of the heart sounds. While the PCG device described here is such that observation and analysis of the waveforms can be done with ease. Any trained personnel, which always may not be the doctor himself, can operate this device and analyze its waveforms. This device is extremely cost effective; doctors can use it in their clinics too. Along with a cost effective alternative to the expensive options, it is sufficiently sensitive also to catch even a minute change in the heart sound. It uses computer to display and analyze the waveform which is nowadays easily available everywhere. II. The Human Heart The heart is a muscular organ responsible for pumping blood through the blood vessels by repeated, rhythmic contractions. The heart is composed of the cardiac muscle, an involuntary muscle tissue which is found only within this organ. The cardiac valves maintain unidirectional flow of blood by opening and closing, depending on the difference in pressure on each side. There are four valves of the heart (not counting the valve of the coronary sinus and valve of the inferior vena cava). The two atrioventricular (AV) valves ensure that blood flows from the atria to the ventricles, and not the other way. The two semilunar (SL) valves are present in the arteries leaving the heart, and they prevent the blood flowing back from the arteries into the ventricles. The sound of heart valves shutting causes the heart sounds. Heart's sounds are generated within the heart during cardiac cycle. The main cause of these sounds is acceleration and deceleration of blood flow, and closing and opening of the heart valves. Normally there are two heart sounds, and any additional sounds indicate diseased condition of cardiac. If a third heart sound is present it could be a sign of cardiac failure whereas a murmur indicates defective valves or an orifice in the septal wall. There are four sounds produced in the heart, namely:

Tbx2 and Tbx3 induce atrioventricular myocardial development and endocardial cushion formation

A key step in heart development is the coordinated development of the atrioventricular canal (AVC), the constriction between the atria and ventricles that electrically and physically separates the chambers, and the development of the atrioventricular valves that ensure unidirectional blood flow. Using knock-out and inducible overexpression mouse models, we provide evidence that the developmentally important T-box factors Tbx2 and Tbx3, in a functionally redundant manner, maintain the AVC myocardium phenotype during the process of chamber differentiation. Expression profiling and ChIP-sequencing analysis of Tbx3 revealed that it directly interacts with and represses chamber myocardial genes, and induces the atrioventricular pacemaker-like phenotype by activating relevant genes. Moreover, mutant mice lacking 3 or 4 functional alleles of Tbx2 and Tbx3 failed to form atrioventricular cushions, precursors of the valves and septa. Tbx2 and Tbx3 trigger development of the cushions through a regulatory feed-forward loop with Bmp2, thus providing a mechanism for the co-localization and coordination of these important processes in heart development.Electronic supplementary materialThe online version of this article (doi:10.1007/s00018-011-0884-2) contains supplementary material, which is available to authorized users.

Design of a Cyclic Pressure Bioreactor for the <em>Ex Vivo</em> Study of Aortic Heart Valves

The aortic valve, located between the left ventricle and the aorta, allows for unidirectional blood flow, preventing backflow into the ventricle. Aortic valve leaflets are composed of interstitial cells suspended within an extracellular matrix (ECM) and are lined with an endothelial cell monolayer. The valve withstands a harsh, dynamic environment and is constantly exposed to shear, flexion, tension, and compression. Research has shown calcific lesions in diseased valves occur in areas of high mechanical stress as a result of endothelial disruption or interstitial matrix damage(1-3). Hence, it is not surprising that epidemiological studies have shown high blood pressure to be a leading risk factor in the onset of aortic valve disease(4). The only treatment option currently available for valve disease is surgical replacement of the diseased valve with a bioprosthetic or mechanical valve(5). Improved understanding of valve biology in response to physical stresses would help elucidate the mechanisms of valve pathogenesis. In turn, this could help in the development of non-invasive therapies such as pharmaceutical intervention or prevention. Several bioreactors have been previously developed to study the mechanobiology of native or engineered heart valves(6-9). Pulsatile bioreactors have also been developed to study a range of tissues including cartilage(10), bone(11) and bladder(12). The aim of this work was to develop a cyclic pressure system that could be used to elucidate the biological response of aortic valve leaflets to increased pressure loads. The system consisted of an acrylic chamber in which to place samples and produce cyclic pressure, viton diaphragm solenoid valves to control the timing of the pressure cycle, and a computer to control electrical devices. The pressure was monitored using a pressure transducer, and the signal was conditioned using a load cell conditioner. A LabVIEW program regulated the pressure using an analog device to pump compressed air into the system at the appropriate rate. The system mimicked the dynamic transvalvular pressure levels associated with the aortic valve; a saw tooth wave produced a gradual increase in pressure, typical of the transvalvular pressure gradient that is present across the valve during diastole, followed by a sharp pressure drop depicting valve opening in systole. The LabVIEW program allowed users to control the magnitude and frequency of cyclic pressure. The system was able to subject tissue samples to physiological and pathological pressure conditions. This device can be used to increase our understanding of how heart valves respond to changes in the local mechanical environment.

Analogue tracers and lumped constant in capillary beds

The lumped constant is a proportionality factor for converting a tracer analogue's metabolic rate to that of its mother substance. In a uniform system, it is expressed as the ratio of the tracer analogue's extraction fraction ( E ⁎) to the extraction fraction of its mother substance ( E). Here we show that, in capillary beds perfused by unidirectional blood flow, unequal concentration gradients of the tracer analogue and of the mother substance influence extraction fractions both locally and across the organ and that the direct proportionality of E ⁎ and E must be replaced by ln(1− E ⁎)/ln(1− E) to yield Λ, i.e. the lumped constant derived from first principles of bi-substrate enzyme and membrane kinetics. In other words, at a given capillary blood flow ( F), the ratio of systemic clearances (F E ⁎/FE), often used in compartmental kinetic analysis, must be replaced by the ratio of the intrinsic clearances, [− F ln(1− E ⁎)]/[− F ln(1− E)]. The conclusion is supported by 2-[ 18F]fluoro-2-deoxy- d-galactose removal kinetics in pig liver in vivo from previous publications by the dependence of E ⁎/ E and the independence of Λ, on blood galactose concentration. Moreover, our corrections to the results of compartmental kinetics are quantified for comparing extraction fractions in different regions of interest (e.g. by positron emission tomography) and for calculating Λ using whole-organ E ⁎ and E measured by arteriovenous concentration differences.

CFD 해석을 이용한 Balloon형 인공심폐기 설계를 위한 구조적 해석

본 연구는 기존의 인공심폐기의 단점을 보완하기 위하여 혈액펌프를 사용하지 않고 혈류의 흐름을 유도할 수 있는 기구(balloon)형 인공심폐기 설계를 위한 구조적 해석을 시도하였다. 가상의 모형 인공심폐기 내에서의 혈류의 흐름패턴을 분석하기 위하여 CFD 모델링 방법을 사용하였다. 이 시스템의 작동원리는 막 산화기 주위를 기구를 사용하여 압력하중을 인가하여 주기적으로 수축.이완되도록 하였으며, 시간에 따라 변화하는 시간 함수 값은 sine 반주기와 sine 주기를 계산하여 적용하였다. 이와 같은 방법으로 기구형 인공심폐기를 설계할 경우 한 방향에 대한 혈류의 움직임을 유도할 수 있다는 가정 하에 구조적 해석을 하였다. 실험결과 CFD 시뮬레이션을 통하여 인공심폐기의 입구와 출구에 서의 혈류의 속도와 압력을 측정하여 분석한 결과 한 방향에 대한 혈류의 유동이 발생하는 것을 확인하였다. 이와 같은 CFD 시뮬레이션은 혈류의 흐름특성을 미리 예측할 수 있어 인공심폐기 설계에 있어서 최적화된 디자인을 제공할 수 있을 것이라 판단된다. In this study, we attempted a structural analysis in order to design a balloon type extracorporeal membrane oxygenator that can induce blood flow without using blood pumps for the purpose of complementing the weakness in the existing extracorporeal membrane oxygenator. To analyze the flow characteristic of the blood flow within the virtual model of extracorporeal membrane oxygenator, computational fluid dynamics(CFD) modeling method was used. The operating principle of this system is to make the surface of the extracorporeal membrane oxygenator keep contracting and dilating regularly by applying pressure load using a balloon, and the 'ime Function Value'that changes according to the time was applied by calculating a half cycle of sine waveform and a cycle of sine.waveform Under the assumption that the uni-directional blood flow could be induced if the balloon type extracorporeal membrane oxygenator was designed as per the method described above, we conducted a structural analysis accordingly. We measured and analyzed the velocity and pressure of blood flow at both inlet and outlet of the extracorporeal membrane oxygenator through CFD simulation. As a result of the modeling, it was confirmed that there was a flow in accord with the direction of the blood by the contraction/dilation. With CFD simulation, the characteristics of blood flow can be predicted in advance, so it is judged that this will be able to provide the most optimized design in producing an extracorporeal membrane oxygenator.

A Hand for the Epicardium

See related article, pages 940–949 In mammals, formation of the properly septated 4-chambered heart and coronary vasculature is essential for unidirectional blood flow and survival of the organism. This process involves complex cell-cell interactions, the dysregulation of which can profoundly alter organogenesis, leading to a plethora of structural or functional cardiac defects. No wonder that congenital heart disease (CHD) represents the largest class of birth defects in humans. CHD, even the more subtle, subclinical form, is a major risk factor for early onset of serious cardiovascular complications and premature death. Despite important advances in diagnosis and surgical repair, preventive or therapeutic approaches have been hampered by our incomplete understanding of the molecular basis of most CHDs. Over the past 15 years, work in several model systems has identified genes required for normal heart development and started unraveling intricate regulatory relationships among many of them. Importantly, mutations in several of these cardiac regulators were subsequently linked to human CHD.1 Of those, the basic helix-loop-helix transcription factors Hand1 (eHAND) and Hand2 (dHAND) have emerged as important regulators of heart, limb, and neural crest cell development. Within the developing heart, Hand1 and Hand2 have overlapping expression in the cardiac crescent, but Hand1 expression becomes more restricted to the left ventricle after cardiac looping, whereas Hand2 becomes more localized to the right ventricle and derivatives of the secondary heart field (SHF).2 Gene targeting …

The role of blood flow in determining the sites of atherosclerotic plaques

Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipids and inflammatory cells along the inner walls of arteries, and is an underlying cause of cardiovascular disease. Atherosclerotic lesions develop predominantly at branches, bends, and bifurcations in the arterial tree because these sites are exposed to low or disturbed blood flow, which exerts low/oscillatory shear stress on the vessel wall. This mechanical environment alters endothelial cell physiology by enhancing inflammatory activation. In contrast, regions of the arterial tree that are exposed to uniform, unidirectional blood flow and experience high shear stress are protected from inflammation and lesion development. Shear stress is sensed by the endothelium via mechanoreceptors and is subsequently transduced into biochemical signals resulting in modulation of proinflammatory signaling pathways. In this article, we address the molecular mechanisms behind the spatial localization of vascular inflammation and atherosclerosis, with particular focus on studies by our own group of two key proinflammatory signaling pathways, the mitogen-activated protein kinase pathway and the nuclear factor-kappa-B pathway.

Isolation of Valvular Endothelial Cells

Heart valves are solely responsible for maintaining unidirectional blood flow through the cardiovascular system. These thin, fibrous tissues are subjected to significant mechanical stresses as they open and close several billion times over a lifespan. The incredible endurance of these tissues is due to the resident valvular endothelial (VEC) and interstitial cells (VIC) that constantly repair and remodel in response to local mechanical and biological signals. Only recently have we begun to understand the unique behaviors of these cells, for which in vitro experimentation has played a key role. Particularly challenging is the isolation and culture of VEC. Special care must be used from the moment the tissue is removed from the host through final plating. Here we present protocols for direct isolation, side specific isolation, culture, and verification of pure populations of VEC. We use enzymatic digestion followed by a gentle swab scraping technique to dislodge only surface cells. These cells are then collected into a tube and centrifuged into a pellet. The pellet is then resuspended and plated into culture flasks pre-coated with collagen I matrix. VEC phenotype is confirmed by contact inhibited growth and the expression of endothelial specific markers such as PECAM1 (CD31), Von Willebrand Factor (vWF), and negative expression of alpha-smooth muscle actin (α-SMA). The functional characteristics of VEC are associated with high levels of acetylated LDL. Unlike vascular endothelial cells, VEC have the unique capacity to transform into mesenchyme, which normally occurs during embryonic valve formation1. This can also occur during significantly prolonged post confluent in vitro culture, so care should be made to passage at or near confluence. After VEC isolation, pure populations of VIC can then be easily acquired.

Isolation of Valvular Endothelial Cells

Heart valves are solely responsible for maintaining unidirectional blood flow through the cardiovascular system. These thin, fibrous tissues are subjected to significant mechanical stresses as they open and close several billion times over a lifespan. The incredible endurance of these tissues is due to the resident valvular endothelial (VEC) and interstitial cells (VIC) that constantly repair and remodel in response to local mechanical and biological signals. Only recently have we begun to understand the unique behaviors of these cells, for which in vitro experimentation has played a key role. Particularly challenging is the isolation and culture of VEC. Special care must be used from the moment the tissue is removed from the host through final plating. Here we present protocols for direct isolation, side specific isolation, culture, and verification of pure populations of VEC. We use enzymatic digestion followed by a gentle swab scraping technique to dislodge only surface cells. These cells are then collected into a tube and centrifuged into a pellet. The pellet is then resuspended and plated into culture flasks pre-coated with collagen I matrix. VEC phenotype is confirmed by contact inhibited growth and the expression of endothelial specific markers such as PECAM1 (CD31), Von Willebrand Factor (vWF), and negative expression of alpha-smooth muscle actin (α-SMA). The functional characteristics of VEC are associated with high levels of acetylated LDL. Unlike vascular endothelial cells, VEC have the unique capacity to transform into mesenchyme, which normally occurs during embryonic valve formation. This can also occur during significantly prolonged post confluent in vitro culture, so care should be made to passage at or near confluence. After VEC isolation, pure populations of VIC can then be easily acquired.

How does the tubular embryonic heart work? Looking for the physical mechanism generating unidirectional blood flow in the valveless embryonic heart tube

The heart is the first organ to function in vertebrate embryos. The human heart, for example, starts beating around the 21st embryonic day. During the initial phase of its pumping action, the embryonic heart is seen as a pulsating blood vessel that is built up by (1) an inner endothelial tube lacking valves, (2) a middle layer of extracellular matrix, and (3) an outer myocardial tube. Despite the absence of valves, this tubular heart generates unidirectional blood flow. This fact poses the question how it works. Visual examination of the pulsating embryonic heart tube shows that its pumping action is characterized by traveling mechanical waves sweeping from its venous to its arterial end. These traveling waves were traditionally described as myocardial peristaltic waves. It has, therefore, been speculated that the tubular embryonic heart works as a technical peristaltic pump. Recent hemodynamic data from living embryos, however, have shown that the pumping function of the embryonic heart tube differs in several respects from that of a technical peristaltic pump. Some of these data suggest that embryonic heart tubes work as valveless "Liebau pumps." In the present study, a review is given on the evolution of the two above-mentioned theories of early cardiac pumping mechanics. We discuss pros and cons for both of these theories. We show that the tubular embryonic heart works neither as a technical peristaltic pump nor as a classic Liebau pump. The question regarding how the embryonic heart tube works still awaits an answer.

The Role Of Cell Biology And Leaflet Remodeling In The Progression Of Heart Valve Disease

Heart valves are complex tri-layered structures that ensure the unidirectional flow of blood. Scientists are actively investigating how characteristics of the two major cell types, valvular endothelial cells (VECs) and valvular interstitial cells (VICs), and their mechanical relationships with the valvular extracellular matrix promote structural integrity and age-related remodeling. Abnormal changes in VECs, VICs, and the extracellular matrix at the molecular level lead to gross tissue malformations and dysfunction. This review addresses current advances in the field of valve biology, mechanisms underlying valvular leaflet remodeling, and common pathological manifestations. Improving our understanding of heart valve biology, the impact of cardiovascular drugs, and remodeling changes will be critical to the development of novel therapies for heart valve diseases.

Endothelial Nitric Oxide Synthase Gene Expression During Murine Embryogenesis

To elucidate the role of endothelial NO synthase (eNOS)-derived NO during mammalian embryogenesis, we assessed the expression of the eNOS gene during development. Using transgenic eNOS promoter/reporter mice (with beta-galactosidase and green fluorescent protein reporters), in situ cRNA hybridization, and immunohistochemistry to assess transcription, steady-state mRNA levels, and protein expression, respectively, we noted that eNOS expression in the developing cardiovascular system was highly restricted to endothelial cells of medium- and large-sized arteries and the endocardium. The onset of transcription of the native eNOS gene and reporters coincided with the establishment of robust, unidirectional blood flow at embryonic day 9.5, as assessed by Doppler ultrasound biomicroscopy. Interestingly, reporter transgene expression and native eNOS mRNA were also observed in discrete regions of the developing skeletal musculature and the apical ectodermal ridge of developing limbs, suggesting a role for eNOS-derived NO in limb development. In vitro studies of promoter/reporter constructs indicated that similar eNOS promoter regions operate in both embryonic skeletal muscle and vascular endothelial cells. In summary, transcriptional activity of the eNOS gene in the murine circulatory system occurred following the establishment of embryonic blood flow. Thus, the eNOS gene is a late-onset gene in endothelial ontogeny.

A house with many rooms: how the heart got its chambers with foxn4: Figure 1.

The vertebrate heart is initially formed from two lateral domains of cardiogenic mesoderm that fuse at the ventral midline to form a simple heart tube that is similar to the hearts or dorsal vessels of invertebrates. As development proceeds, this initial heart tube undergoes a series of morphogenetic rearrangements that subdivides the heart into the distinct chambers found in adult vertebrates. In this issue of Genes & Development, Chi et al. (2008) describe a novel transcriptional pathway required for separation of the outflow (ventricular) portion from the inflow (atrial) portion of the two-chambered zebrafish heart. This separation takes place at the atrioventricular (AV) canal, which forms the valves separating the ventricular and atrial compartments required for unidirectional blood flow, as well as the electrical conduction system required for proper cardiac rhythm. Chi et al. (2008) identify a member of the forkhead box (fox) family of transcription factors, foxn4, which works in concert with tbx5 to direct the development of the AV boundary by regulating the expression of tbx2b. This study sheds new light on how the AV canal myocardium became specialized during vertebrate evolution to perform its function as both the gatekeeper of blood flow and regulator of cardiac rhythm.

Signal transduction in early heart development (II): ventricular chamber specification, trabeculation, and heart valve formation.

The formation of a four-chambered heart with ventricular chambers aligned in a left-right orientation begins with the rightward looping of the linear heart tube in accordance with the left-right embryonic axis. The functional specification of the ventricular chambers in the looped heart occurs with the formation of a trabeculated myocardium along the outer curvature of the realigned heart tube. Two major signal transduction pathways are involved in this process, the retinoic acid and neuregulin signaling pathways, with the retinoic acid pathway also participating in rightward heart tube looping. With the establishment of the atrial and ventricular chambers, maintenance of a unidirectional flow of blood between the two chambers must be ensured. To achieve this, heart valves develop at the atrioventricular juncture. This process begins with formation of endocardial cushions, the primordia of heart valves, and ends with formation of heart valve leaflets. Underlying this process is a complex network of signal transduction pathways that mediate communication between the endocardial and myocardial cell layers to form the endocardial cushions and nascent heart valve. Some of the signaling molecules involved are vascular endothelial growth factor, Wnts, bone morphogenetic proteins, epidermal growth factor, hyaluronic acid, neurofibromin, and calcium.

Transitions in Early Embryonic Atrioventricular Valvular Function Correspond With Changes in Cushion Biomechanics That Are Predictable by Tissue Composition

Endocardial cushions are critical to maintain unidirectional blood flow under constantly increasing hemodynamic forces, but the interrelationship between endocardial cushion structure and the mechanics of atrioventricular junction function is poorly understood. Atrioventricular (AV) canal motions and blood velocities of embryonic chicks at Hamburger and Hamilton (HH) stages 17, 21, and 25 were quantified using ultrasonography. Similar to the embryonic zebrafish heart, the HH17 AV segment functions like a suction pump, with the cushions expanding in a wave during peak myocardial contraction and becoming undetectable during the relaxation phase. By HH25, the AV canal contributes almost nothing to the piston-like propulsion of blood, but the cushions function as stoppers apposing blood flow with near constant thickness. Using a custom built mesomechanical testing system, we quantified the nonlinear pseudoelastic biomechanics of developing AV cushions, and found that both AV cushions increased in effective modulus between HH17 and HH25. Enzymatic digestion of major structural constituent collagens or glycosaminoglycans resulted in distinctly different stress-strain curves suggestive of their individual contributions. Mixture theory using histologically determined volume fractions of cells, collagen, and glycosaminoglycans showed good prediction of cushion material properties regardless of stage and cushion position. These results have important implications in valvular development, as biomechanics may play a larger role in stimulating valvulogenic events than previously thought.