Early prenatal diagnosis of alveolar capillary dysplasia with misalignment of pulmonary veins due to a 16q24.1 deletion.

First trimester ultrasound screening is an essential fetal examination performed generally at 11-13 weeks of gestation (WG). However, it does not allow for an accurate description of all fetal organs, partly due to their development in progress. Meanwhile, increased nuchal translucency (INT) is a widely used marker known to be associated with chromosomal deleterious rearrangements. We report on a 14 WG fetus with an association of INT and univentricular congenital heart malformation (CHM) leading to chorionic villous sampling (CVS). Cytogenetic investigations performed using array-Comparative Genomic Hybridization (CGH) and fluorescence in situ hybridization (FISH) demonstrated a 1.17 Mb deletion in 16q24.1 encompassing FOXF1 arisen de novo on maternal inherited chromosome. Fetopathological study confirmed CHM with hypoplastic left heart syndrome (HLHS) associating aortic atresia, mitral stenosis, and left ventricular hypoplasia and revealed in addition specific lung lesions corresponding to alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). This is so far the first case of first trimester prenatal diagnosis of ACDMPV due to the deletion of FOXF1 gene. An interpretation of the complex genomic data generated by ultrasound markers is facilitated considerably by the genotype-phenotype correlations on fetopathological examination.

Deferoxamine Improves Alveolar and Pulmonary Vascular Development by Upregulating Hypoxia-inducible Factor-1α in a Rat Model of Bronchopulmonary Dysplasia.

Fetal lung development normally occurs in a hypoxic environment. Hypoxia-inducible factor (HIF)-1α is robustly induced under hypoxia and transactivates many genes that are essential for fetal development. Most preterm infants are prematurely exposed to hyperoxia, which can halt hypoxia-driven lung maturation. We were to investigate whether the HIF-1α inducer, deferoxamine (DFX) can improve alveolarization in a rat model of bronchopulmonary dysplasia (BPD). A rat model of BPD was produced by intra-amniotic lipopolysaccharide (LPS) administration and postnatal hyperoxia (85% for 7 days), and DFX (150 mg/kg/d) or vehicle was administered to rat pups intraperitoneally for 14 days. On day 14, the rat pups were sacrificed and their lungs were removed and examined. A parallel in vitro study was performed with a human small airway epithelial cell line to test whether DFX induces the expression of HIF-1α and its target genes. Alveolarization and pulmonary vascular development were impaired in rats with BPD. However, DFX significantly ameliorated these effects. Immunohistochemical analysis showed that HIF-1α was significantly upregulated in the lungs of BPD rats treated with DFX. DFX was also found to induce HIF-1α in human small airway epithelial cells and to promote the expression of HIF-1α target genes. Our data suggest that DFX induces and activates HIF-1α, thereby improving alveolarization and vascular distribution in the lungs of rats with BPD.

[A Study on the Authenticity of Preoperative Pulmonary Bronchial Angiography by DeepInsight Software].

BACKGROUND: Precise segmentectomy has become the first choice of surgical treatment for pulmonary nodules and early lung cancer, and the key and difficult point of the surgery lies in the precise location and resection of the lesion. DeepInsight is an auxiliary software for precise lung surgery jointly developed by our center and Neusoft Company, which can determine the precise anatomy of the lung and locate the location of lung lesions before operation. This study is to verify the authenticity and reliability of DeepInsight lung bronchial angiography assisted surgery. METHODS: In this study, 1,020 patients with pulmonary nodules <2.0 cm in diameter were included in the Department of Thoracic Surgery Jiangsu Provincial People's Hospital from August 1, 2016 to December 31, 2019. Computed tomographic angiography (CTA) was performed on all the included patients before surgery. The DeepInsight software was used to perform preoperative bronchial angiography on the operative side of the lung to identify the affected pulmonary segments, pulmonary arteries and pulmonary veins. Two thoracic surgeons independently assessed the visibility of the affected pulmonary vessels using the 5-point method, and the χ² test assessed the consistency between observers. In addition, virtual imaging and real anatomy of pulmonary vessels on the operative side were performed during the operation, and the involved pulmonary vessels were finally determined by 2 chief physicians of thoracic surgery. RESULTS: There were no statistically significant differences between the number and spatial anatomy of the vessels involved in the pulmonary virtual imaging using DeepInsight software before operation and the number of vessels involved during operation in 1,020 patients. And the consistency among observers is quite satisfactory. CONCLUSIONS: The DeepInsight software virtual imaging of pulmonary bronchial vessels can accurately reconstruct the actual pulmonary vessels and assist the completion of pulmonary segmental resection.

[Translobar Phenomenon of Pulmonary Veins and Its Clinical Significance
in Lobectomy].

BACKGROUND: Lobectomy is the main treatment strategy for early lung cancer. However, there are many anatomical variations in the lungs, especially some pulmonary veins will deviate from the normal position, and even cross the border of lob to enter the adjacent lobes, which increases the difficulty and risk of lobectomy. This study aims to analyze the variation types and frequency of pulmonary translobar veins, and further investigate its clinical significance in lobectomy. METHODS: This study retrospectively included 916 patients who underwent lung resection in our center from December 2018 to November 2019, and selected 310 patients who underwent enhanced chest computed tomography (CT) examination before surgery. Enhanced chest CT and three-dimensional computed tomography bronchography and angiography (3D-CTBA) of these patients were applied to analyze the types and frequency of translobar veins. Further, 48 cases of lobectomy whose operation areas involved translobar veins were further screened out of 916 surgical cases (Among them, the translobar veins of 36 subjects were cut off and the other 12 patients were reserved). The effect of two different treatments on remaining lung was observed by surgical video. RESULTS: A total of 26 translobar veins patterns were identified with an overall incidence of 82.26%, much greater in the right than in the left lung (80.65% vs 11.94%). The major types (frequency >5%) in the right lung include: the VX2 (5.48%) that flows into the inferior pulmonary vein behind the intermediate bronchus, the V3b (58.39%) that converges the venous branches of the upper and middle lobe, the VX4 that flows into the V2 (13.23%) or V3 (12.58%) in the horizontal fissure, the VX4 (8.71%) or VX5 (7.42%) that flows into the left atrium beneath the middle lobe bronchus, and the VX6 that flows into V2 in the Oblique fissure. The major types in the left lung include the common trunk (9.36%) of the superior and inferior pulmonary vein, of which 4.84% are greater than 1 cm in length. Compared to the preserved group, circulatory function of the remaining lung was impaired in the severed group, with the impaired area failing to collapse long after ventilation is stopped, the incidence of postoperative hemoptysis (13.89% vs 0.00%) and pulmonary air leakage (19.44% vs 8.33%) increased, the postoperative hospital stay [(4.72±1.86) d vs (3.92±1.62) d] was longer, and the total drainage during 3 days after operation [(705.42±265.02) mL vs (604.92±229.64) mL] was more, but the difference is not statistically significant. CONCLUSIONS: There are a variety of types of translobar pulmonary veins and some of them have a high incidence; However, most of the translobar veins were neglected in surgery, which could adversely affect the safety of surgery and the recovery of patients after surgery.

Retinoic Acid: A Key Regulator of Lung Development.

Retinoic acid (RA) is a key molecular player in embryogenesis and adult tissue homeostasis. In embryo development, RA plays a crucial role in the formation of different organ systems, namely, the respiratory system. During lung development, there is a spatiotemporal regulation of RA levels that assures the formation of a fully functional organ. RA signaling influences lung specification, branching morphogenesis, and alveolarization by regulating the expression of particular target genes. Moreover, cooperation with other developmental pathways is essential to shape lung organogenesis. This review focuses on the events regulated by retinoic acid during lung developmental phases and pulmonary vascular development; also, it aims to provide a snapshot of RA interplay with other well-known regulators of lung development.

RESCUE-AF in Patients Undergoing Atrial Fibrillation Ablation: The RESCUE-AF Trial

BACKGROUND: Although contact force (CF)­sensing catheters improve procedural effectiveness and safety of atrial fibrillation ablation, recent reports documented a higher incidence of atrioesophageal fistula formation relative to ablation with non­CF-sensing catheters.The present study was to assess whether restricting CF to <20 g reduced risk for esophageal injury (EI) in patients with atrial fibrillation undergoing circumferential pulmonary vein isolation. METHODS: This prospective, single-center, randomized study enrolled 89 consecutive patients (mean age, 57.2±11.3 years; 57.3% men) with atrial fibrillation (68.5% paroxysmal and 31.5% persistent). Computed tomography angiography, transesophageal echocardiography, and esophageal endoscopy were conducted before the procedure, and a repeat esophageal endoscopy was performed after the procedure. Patients were randomized to restricted-CF group (n=44) or non-CF group (n=45), with circumferential pulmonary vein isolation using a CF-sensing (CF restricted to <20 g) or non­CF-sensing catheter, respectively. The primary end point was rate of EI post ablation. RESULTS: Baseline characteristics were evenly distributed between groups, without a case of preprocedural EI. With the same power setting, similar ablation time and average measured catheter tip temperature during posterior wall ablation just opposite to the esophagus in all patients in the restricted-CF group versus non-CF groups, there were no cases versus 9 (20%) cases of EI post ablation, respectively, with similar rate of freedom from atrial tachyarrhythmias at mean 31.3±6.5 months follow-up (68.2% versus 64.4%; P=0.3798). CONCLUSIONS: Risk for EI was minimized when CF was restricted to <20 g at the posterior left atrial wall, where the circumferential pulmonary vein isolation lesion set and the course of the esophagus overlapped in all subjects.

Development of the pulmonary vasculature in newborn lambs: structure-function relationships.

Our objectives were 1) to describe the quantitative light microscopy and ultrastructure of newborn lamb lungs and 2) to correlate hemodynamic changes during normoxia and hypoxia with the morphology. By light microscopy, we measured the percent muscle thickness (%MT) and peripheral muscularization of pulmonary arteries and veins from 25 lambs aged less than 24 h, 2-4 days, 2 wk, and 1 mo. At the same ages, lungs were isolated and perfused in situ and, after cyclooxygenase blockade with indomethacin, total, arterial (delta Pa), middle (delta Pm), and venous pressure gradients at inspired O2 fractions of 0.28 (mild hyperoxia) and 0.04 (hypoxia) were determined with inflow-outflow occlusion. During mild hyperoxia, delta Pa and delta Pm fell significantly between 2-4 days and 2 wk, whereas during hypoxia, only delta Pm fell. The %MT of all arteries (less than 50 to greater than 1,000 microns diam) decreased, and peripheral muscularization of less than 100-microns-diam arteries fell between less than 4 days and greater than 2 wk. Our data suggest that 1) the %MT of arteries determines normoxic pulmonary vascular resistance, because only arterial and middle segment resistance fell, 2) peripheral muscularization is a major determinant of hypoxic pulmonary vasoconstriction, because we observed a fall with age in peripheral muscularization of less than 100-micron-diam arteries and in delta Pm with hypoxia, and 3) the arterial limit of the middle segment defined by inflow-outflow occlusion lies in 100- to 1,000-microns-diam arteries.

Pulmonary venous flow from fetal to neonatal period.

There are few reports about the effect of fetal or transitional circulation on the pulmonary venous flow. The purposes of this study were to investigate flow patterns of the pulmonary vein serially from fetal to neonatal period and to determine the relationship between pulmonary venous flow and other parameters from aortic and mitral valve. Pulmonary venous flow velocity was analyzed in 21 normal term human fetuses. Postnatal follow-up studies were performed at 1, 6, 24 h, 3 days, 1 week and 1 month. In each time point, pulsed Doppler echocardiography was used to interrogate right upper pulmonary vein, mitral and aortic valve. The measured parameters of pulmonary vein were heart rate, velocity time integral (VTI), and velocities at systolic peak (S), at diastolic peak (D), at nadir between S and D (O), and at nadir between D and the next S (X). E/A ratio and VTI were measured for mitral valve and peak systolic velocity and VTI for aortic valve. Pulmonary venous flow in fetus was phasic and continuous with low velocity. One hour after birth, without a change of flow pattern, all velocities increased dramatically. These high velocities showed a significant decrease during 24 h after birth. Three days after birth, the velocity decreased slightly and flow pattern changed from continuous to interrupted pattern with or without atrial reversal. No Doppler parameters from aortic or mitral valve showed any correlation with parameters from pulmonary vein. In conclusion, the flow pattern of the pulmonary vein in fetus may result from low pulmonary flow and decreased capacitance of the pulmonary venous system. Sudden increase in the pulmonary flow after birth is likely to be responsible for the highest velocities recorded immediately after birth. Left to right shunt through the ductus arteriosus may also contribute to the flow pattern observed in the first several days, as do changes in reservoir function of the pulmonary vein.

[Histogenesis and structural organization of the walls of rat venae cavae and pulmonary veins]. / Gistogenez i strukturnaia organizatsiia stenki polykh i legochnykh ven krysy.

Using light and electron microscopic methods, the histogenesis and structural organization of the walls of rat venae cavae and pulmonary veins were studied in prenatal and postnatal periods of development. The special attention was paid to the appearance of the striated myocytes in the walls of these vessels during the process of ontogenesis. The time of initial divergent development of myoblastic differon was established, the stages of differentiation of striated myoblasts and the peculiarities of intercellular junctions were characterized, as well as the innervation and vascularization of the walls of venae cavae and pulmonary veins.

Normal and abnormal development of pulmonary veins: state of the art and correlation with clinical entities.

Interest for the pulmonary veins has increased in the past decade after the potential arrhythmogenicity of the myocardial sleeve surrounding these structures has been recognized. Furthermore, there are several clinical entities, such as anomalous connection pattern and pulmonary vein stenosis, that are related to abnormal pulmonary vein development. In this review, we will describe current literature and aim to elucidate and reorganize current opinions on normal and abnormal pulmonary vein development in relation to clinical (management of) diseases. Several unresolved questions will be addressed, as well as current conceptual controversies. First, a general overview of development of structures at the venous pole of the heart, including normal development of the pulmonary vein from a primitive Anlage, will be provided. Recent insights indicate an important contributory role of the mesoderm behind the heart, the so-called second heart field, to this area. Subsequently, the formation of a myocardial and smooth muscle vascular wall of the pulmonary veins and the left atrium is described, as well as current insights in the mechanisms involved in the differentiation of these different cell types in this area. Next, developmental concepts of normal pulmonary venous drainage patterns are reviewed, and an overview is provided of clinical entities related to abnormal development at several anatomical levels. Lastly, attention is paid to arrhythmogenesis in relation to pulmonary vein development, as well the consequences for clinical management.

[Evaluation of the development of pulmonary vessels with pulmonary venous index in congenital heart disease with decreased pulmonary blood flow].

OBJECTIVE: The development status of pulmonary artery is one of the most important criteria for decision-making strategy and predicting postoperative outcome in congenital heart disease with decreased pulmonary blood flow. Currently, Nakata index and McGoon index have been used as morphologic index in evaluating the development status of pulmonary artery. Those indices have some shortcoming. It was recently found that pulmonary veins index is a more precise morphological indicator of pulmonary blood flow and development status of pulmonary vessels. This study aimed to explore an index of evaluating pulmonary blood stream and the development of pulmonary vessels, as a criterion for surgical decision-making strategy. METHODS: The diameters of left and right pulmonary arteries and pulmonary veins were measured on DSA films in 74 patients with congenital heart disease with decreased pulmonary blood flow, The correlative analysis was done between Nakata index, McGoon index, pulmonary vein index (PVI) and postoperative outcome which were the length of stay in ICU, duration of mechanical ventilation and dose of inotropic drugs. RESULTS: Excellent correlations between the size of pulmonary veins and pulmonary arteries were found, the correlation between left pulmonary veins and distal portion of left pulmonary artery was 0.73, between left pulmonary veins and proximal portion of left pulmonary artery was 0.72, right pulmonary veins and distal portion of right pulmonary artery was 0.67, and right pulmonary veins and proximal portion of right pulmonary artery was 0.71. The length of stay in ICU, duration of mechanical ventilation and dose of inotropic drugs correlated well with PVI (r = -0.51, -0.478, and -0.693). Compared with Nakata index and McGoon index, PVI was a better criterion for evaluating the developmental status of the whole pulmonary vessels. In the right ventricular outlet reconstruction patients, the McGoon index for patients with low cardiac output syndrome (LCOS) was 1.36 +/- 0.51, and 1.97 +/- 0.58 for patients without LCOS (t = 2.347, P < 0.05), the Nakata index for patients with LCOS was 164 +/- 106 mm(2)/m(2) and 269 +/- 124 mm(2)/m(2) for patients without LCOS (t = 2.218, P < 0.05), the PVI for patients with LCOS was 152 +/- 77 mm(2)/m(2) and 273 +/- 125 mm(2)/m(2) for patients without LCOS (t = 2.936, P < 0.01), pulmonary vessel index of patients with LCOS was less than that of those without LCOS. When PVI was < or = 180 mm(2)/m(2), postoperative hemodynamics was unstable, the frequency of low cardiac output syndrome and mortality significantly increased. CONCLUSIONS: The development of pulmonary arteries and pulmonary veins correlated with each other. PVI is a precise morphological indicator of pulmonary blood flow and development of pulmonary vessels. It is a helpful indicator to decide surgical strategy.

Oxygen-induced alterations in lung vascular development in the newborn rat.

Newborn rats were exposed to air or hyperoxic conditions for the first 6 days of life. Resulting effects on the pulmonary vascular bed were determined by analysis of barium angiograms, scanning electron microscopy of methylmethacrylate corrosion casts and whole lung, morphometric estimations of pulmonary arteries/area and capillary number/area, and arterial blood gas measurements. Similar studies were also performed on the lungs of animals allowed to recover in air for 1 and 2 wk. Although the general pattern of the pulmonary arterial bed by barium angiograms appeared similar, diminished branching or underfilling of the distal arterial segments was more frequently encountered in hyperoxic-exposed animals. Morphometric examination and corrosion casts revealed differences in vascular pattern and density between hyperoxia and air-exposed animals. The number of capillaries/mm2 of lung tissue was less in hyperoxic-exposed pups than controls after 6 days of exposure to hyperoxia but markedly increased to slightly above control levels by 2 wk of air recovery. The number of 20--50 micrometers size vessels/mm2 followed a similar pattern of change. Corrosion casts of lung exposed to 6 days of hyperoxia revealed less microvascular density compared to air controls, but after 1 wk recovery in air, hyperoxic-exposed animal had a more extensive network of microvessels. Maximum PaO2 attained by animals in the various groups closely resembled the patterns of change in microvessel density. These findings support the thesis that a major alteration of lung vascular growth and development occurs subsequent to exposure of the newborn to hyperoxia.

Ultrastructural localization of nitric oxide synthase and endothelin in rat pulmonary artery and vein during postnatal development and ageing.

The ultrastructural distribution of nitric oxide synthase (neuronal isoform, type I) and endothelin immunoreactivity was examined in the developing and ageing male Wistar rat pulmonary artery and vein. This study demonstrates that from birth to old age (24 months) nitric oxide synthase and endothelin are localized within subpopulations of endothelial cells in the pulmonary vasculature. In the pulmonary artery and vein of newborn rats, and pulmonary vein of 24-month-old rats, positive labelling for nitric oxide synthase was also observed in the vascular smooth muscle. During development and ageing there were ultrastructural and immunocytochemical alterations in the intima of the pulmonary artery and vein. In older animals, damaged endothelial cells were seen alongside healthy-appearing cells, rich in cytoplasmic vesicles and endoplasmic reticulum. In contrast to damaged cells, the healthy-appearing endothelial cells displayed positive cytoplasmic labelling for nitric oxide synthase or endothelin. These immunopositive cells also appeared in the altered regions of the vessels where substantial enlargement of subendothelial extracellular matrix and the presence of various forms of degenerating macrophages and large bundles of collagen fibres were evident. Damage to the pulmonary artery was particularly evident at the ages of 12 and 24 months; various forms of macrophages, some of which displayed positive labelling for nitric oxide synthase and endothelin, were present in the altered intimal subendothelial zone. In conclusion, this study on the pulmonary vasculature suggests that endothelin and NOS in endothelial cells play a role in the local control of vascular tone throughout the lifespan of rats, even in older animals when there is intimal thickening and some endothelial damage. NOS and endothelin was also seen in smooth muscle and macrophages at certain stages in postnatal development and ageing.

Pattern of connective tissue development in swine pulmonary vasculature by immunolocalization.

Light microscopic immunolocalization studies were carried out on lung tissue from eight newborn and four adult pigs using antibodies to six extracellular matrix components. Antibodies to fibronectin, collagen type IV, and laminin localized on the same structures in adult and newborn lungs. By contrast, antibodies to the interstitial collagens (types I, III, and V) were less extensively localized in the newborn than in the adult, particularly those to type I because the fibres on which they localized in the newborn were thin and sparse. At all ages, antibodies to collagen types III and V co-localized on type I fibres and also on thin individual fibres which formed networks, more dense in the adult than in the newborn. At all ages, anti-type III collagen antibodies also localized on smooth muscle cells. In the adult, but not in the newborn, anti-type I and type V collagen antibodies localized on the connective tissue around the smooth muscle cells in the pulmonary arterial media and vein wall. The dominance of collagen type III suggests greater plasticity in the newborn pulmonary vasculature, which helps explain the recently described rapid changes in arterial wall structure which constitute adaptation to extrauterine life. The postnatal increase in collagen type I helps explain the documented postnatal increase in structural stiffness of the pulmonary arteries.

Development of the human pulmonary vein and its incorporation in the morphologically left atrium.

OBJECTIVE: Using a newly acquired archive of previously prepared material, we sought to re-examine the origin of the pulmonary vein in the human heart, aiming to determine whether it originates from the systemic venous sinus ("sinus venosus"), or appears as a new structure draining to the left atrium. In addition, we examined the temporal sequence of incorporation of the initially solitary pulmonary vein to the stage at which four venous orifices opened to the left atrium. METHODS: We studied 26 normal human embryos, ranging from 3.8 mm to 112 mm crown-rump length, and representing the period from the 12th Carnegie stage to 15 weeks of gestation. RESULTS: The pulmonary vein canalised as a solitary vessel within the mediastinal tissues so as to connect the intraparenchymal pulmonary venous networks to the heart, using the regressing dorsal mesocardium as its portal of cardiac entry. The vein was always distinct from the tributaries of the embryonic systemic venous sinus. The orifice of the solitary vein became committed to the left atrium by growth of the vestibular spine. During development, a marked disparity was seen between the temporal and morphological patterns of incorporation of the left-sided and right-sided veins into the left atrium. The pattern of the primary bifurcation was asymmetrical, a much longer tributary being formed on the left than on the right. Contact between the atrial wall and the venous tributary on the left initially produced a shelf, which became effaced with incorporation of the two left-sided veins into the atrium. CONCLUSIONS: The initial process of formation of the human pulmonary vein is very similar to that seen in animal models. The walls of the initially solitary vein in humans become incorporated by a morphologically asymmetric process so that four pulmonary veins eventually drain independently into the left atrium. Failure of incorporation on the left side may provide the substrate for congenital division of the left atrium.

Phosphodiesterase activity in intrapulmonary arteries and veins of perinatal lambs.

The transition from fetal to newborn life is marked by a reduction in pulmonary vascular tone mediated by the intracellular second messengers, cGMP and cAMP. We have compared the rates of phosphodiesterase (PDE)-catalyzed hydrolysis of cGMP and cAMP in intrapulmonary vessels of fetal (146 +/- 2 days gestation) and newborn (3-7-day-old) lambs, each n = 6. Lung vessels of second to sixth generations were dissected and cytosol was prepared by differential centrifugation. PDE activity in cytosol was determined by radiometric assay of the hydrolysis of exogenous nucleotides at 30 degrees C for 10 min. Rates of hydrolysis (pmol/min/mg protein) of cGMP were 225 +/- 38 in fetal arteries and different from 151 +/- 7 in veins. In newborn vessels, the rates were 155 +/- 49 and 63 +/- 13 in arteries and veins, respectively. Rates of cAMP hydrolysis by the fetus were 80 +/- 11 in arteries and 45 +/- 16 veins. In newborn lambs the rates were 69 +/- 10 in arteries and different from 18 +/- 4 in veins. Inhibition of PDE activity by zaprinast, a cGMP-specific PDE inhibitor, and rolipram, a cAMP-specific PDE inhibitor, was more in veins of fetal and newborn lambs. Our data show that rates of hydrolysis of the cyclic nucleotides were faster in fetal vessels than in the newborn. We speculate that this would result in a greater accumulation of the cyclic nucleotides in newborn vessels, particularly the veins, and therefore endow the veins with less vascular tone.

Postnatal growth and development of the lung.

The lung is qualitatively different at birth, compared to adult life, in many species. In the neonatal period, the peripheral part of the acinus is formed by primary saccules, and it is from the walls of these that alveoli develop postnatally in rats, mice, and rabbits. Alveolar development starts in utero in man and probably in several other species, including sheep, cat, and, probably, mammals with relatively advanced physical development at birth. A sequence of events is well established in rats and mice in the postnatal period. A phase of expansion first occurs, during which lung growth lags behind the increase in body weight and lungs enlarge primarily by expansion, but new tissue is laid down in the saccular wall. This is succeeded by a phase of tissue proliferation during which the saccule is subdivided by numerous secondary crests that develop in the saccular wall and result in the formation of alveoli. During this stage, the rate of lung growth exceeds the rate of body growth and there is a rapid increase in alveolar surface area. Elastic tissue plays a key role in the development of alveoli, and elastic fibers lie in the free margins of the secondary crests and around the mouths of the alveoli. At approximately 2 weeks of age, the rate of cellular multiplication and formation of alveoli is markedly diminished and the lung grows mainly by cellular enlargement, dilatation, and modification of pre-existing structures...

MRI and echocardiographic assessment of the diastolic dysfunction of normal aging: altered LV pressure decline or load?

Changes in diastolic indexes during normal aging, including reduced early filling velocity (E), lengthened E deceleration time (DT), augmented late filling (A), and prolonged isovolumic relaxation time (IVRT), have been attributed to slower left ventricular (LV) pressure (LVP) decay. Indeed, this constellation of findings is often referred to as the "abnormal relaxation" pattern. However, LV filling is determined by the atrioventricular pressure gradient, which depends on both LVP decline and left atrial (LA) pressure (LAP). To assess the relative influence of LVP decline and LAP, we studied 122 normal subjects aged 21-92 yr by Doppler echocardiography and MRI. LVP decline was assessed by color M-mode (V(p)) and the LV untwisting rate. Early diastolic LAP was evaluated using pulmonary vein flow systolic fraction, pulmonary vein flow diastolic DT, color M-mode (E/V(p)), and tissue Doppler (E/E(m)). Linear regression showed the expected reduction of E, increase in A, and prolongation of IVRT and DT with advancing age. There was no relation of age to parameters reflecting the rate of LVP decline. However, older age was associated with reduced E/V(p) (P = 0.008) and increased pulmonary vein systolic fraction (P < 0.001), pulmonary vein DT (P = 0.0026), and E/E(m) (P < 0.0001), all suggesting reduced early LAP. Therefore, reduced early filling in older adults may be more closely related to a reduced early diastolic LAP than to slower LVP decline. This effect also explains the prolonged IVRT. We postulate that changes in LA active or passive properties may contribute to development of the abnormal relaxation pattern during the aging process.