Background-Circulating endothelial progenitor cells (EPCs) migrate to injured vascular endothelium and differentiate into mature endothelial cells. We investigated whether transplantation of vasodilator gene-transduced EPCs ameliorates monocrotaline (MCT)-induced pulmonary hypertension in rats. Methods and Results-We obtained EPCs from cultured human umbilical cord blood mononuclear cells and constructed plasmid DNA of adrenomedullin (AM), a potent vasodilator peptide. We used cationic gelatin to produce ionically linked DNA-gelatin complexes. Interestingly, EPCs phagocytosed plasmid DNA-gelatin complexes, which allowed nonviral, highly efficient gene transfer into EPCs. Intravenously administered EPCs were incorporated into the pulmonary vasculature of immunodeficient nude rats given MCT. Transplantation of EPCs alone modestly attenuated MCT-induced pulmonary hypertension (16% decrease in pulmonary vascular resistance). Furthermore, transplantation of AM DNA-transduced EPCs markedly ameliorated pulmonary hypertension in MCT rats (39% decrease in pulmonary vascular resistance). MCT rats transplanted with AM-expressing EPCs had a significantly higher survival rate than those given culture medium or EPCs alone. Conclusions-Umbilical cord blood-derived EPCs had a phagocytosing action that allowed nonviral, highly efficient gene transfer into EPCs. Transplantation of AM gene-transduced EPCs caused significantly greater improvement in pulmonary hypertension in MCT rats than transplantation of EPCs alone. Thus, a novel hybrid cell-gene therapy based on the phagocytosing action of EPCs may be a new therapeutic strategy for the treatment of pulmonary hypertension. Key Words: pulmonary heart disease Ⅲ natriuretic peptides Ⅲ gene therapy Ⅲ endothelium T he pulmonary endothelium plays an important role in the regulation of pulmonary vascular tone through the release of vasoactive substances such as nitric oxide, prostacyclin, and adrenomedullin (AM). 1 Dysfunction of the endothelium may play a role in the pathogenesis of pulmonary hypertension, including primary pulmonary hypertension. 2 Thus, pulmonary endothelial cells may be a therapeutic target for the treatment of pulmonary hypertension. Recently, endothelial progenitor cells (EPCs) have been discovered in adult peripheral blood. 3 EPCs are mobilized from bone marrow into the peripheral blood in response to tissue ischemia or traumatic injury, migrate to sites of injured endothelium, and differentiate into mature endothelial cells in situ. 4 -6 These findings raise the possibility that transplanted EPCs may serve not only as a tissue-engineering tool to reconstruct the pulmonary vasculature but also as a vehicle for gene delivery to injured pulmonary endothelium.We prepared biodegradable gelatin that could hold negatively charged protein or plasmid DNA in its positively charged lattice structure. 7,8 We have shown that the gelatin is promptly phagocytosed and then gradually degraded by phagocytes, including macrophages. 9 However, whether EPCs phagocytose ionically l...

For evaluation of lung hypoplasia in congenital diaphragmatic hernia rCDHl, we measured lung-thorax transverse area ratio rLT ratio), which was defined as the area of bilateral lung profiles divided by the profile area of thorax ai the level of the four-chamber view of the heart, using fetal ultrasonography. LT ratio in cases with CDH was lower than that in the control group and related well to the postnatal respiratory condition. Measurement of LT ratio using fetal ultrasonography may be useful in predicting the degree of lung hypoplasia in fetuses with CDH. Indexing Words: Congenital diaphragmatic hernia · Fetal diagnosis · Fetal ultrasonography · Fetal surgery · Lung hypoplasia · Antenatal evaluation A newborn infant with a congenital diaphragmatic hernia (CDHl often suffers from severe res-Piratory failure after birth. The causes of respiratory failure are thought to be lung hypoplasia due to compression by herniated viscera before birth and the associated persistent fetal circulation. 1 Due to the recent development of fetal ultrasonographic diagnosis, early operation has been performed after cesarean section. However, the prognosis of fetuses with CDH is still poor in spite of maximum treatment with conventional respiratory and pharmacological methods. 2 In cases with severe hypoplastic lung, high-frequency oscillatory ventilation (HFOVl, extracorporeal membrane oxygenation iECMOl, and fetal surgery may be recommended.:! To decide whether these treatments are indicated, the severity of lung hypoplasia should be properly evaluated. While Polyhydramnios has been reported to be predicrom the ''tive of poor outcome in cases with CDH, 2 no study has assessed the ultrasonographic evaluation of lung hypoplasia.For evaluation of lung hypoplasia in CDH, lung-thorax transverse area ratio (LT ratio) was measured using fetal ultrasonography in normal control fetuses and 8 cases with CDH. PATIENTS AND METHODSFetal examination was made by using a dynamic image ultrasound scanner, the Hitachi EUB 25-M (linear probe, 3.5 MHzl and YHP 77020 (sector probe, 3.5 MHz). The section chosen for determining the LT ratio was a transverse section of the chest, which included four chambers of the heart and two ribs on both sides of the same level. The image obtained enddiastole of the heart, which was visualized by slow-motion replay of the recorded videotape used for measurement. Figure 1 shows ultrasonograms of a control fetus and a case with CDH. The area of the thorax, bounded by the inner border of bilateral ribs, the posterior edge of sternum, and the center of the vertebra, was measured by using digigrammer Casio BX-1. The area of the lungs was 705

Using pulsed Doppler ultrasound, blood flow in the inferior vena cava (IVC) was studied in 47 normal fetuses from 24 to 40 weeks of gestation and 35 abnormal fetuses, with the exception of those with arrhythmias. The abnormal fetuses were divided into 4 groups according to diagnosis, i.e., 6 cases of heart disease with hydrops (group 1), 9 cases of heart disease without hydrops (group 2), 11 cases of hydrops without heart disease (group 3), and 9 cases of other fetal diseases (group 4). By measuring the velocity of IVC blood flow, we defined a new index, the change in parallel with reverse flow velocity, and called it the preload index (PLI). In normal fetuses, PLI values ranged from 0 to 0.37 and had no relation with gestational age. The PLI was significantly higher in groups 1–3 than in normal fetuses. In group 1, the PLI was also higher than in group 2. In group 3, the PLI values in 4 cases of chylothorax, 1 of chyloascites and 1 of cytomegalovirus infection were significantly lower than in the remaining 5 cases where the cause of hydrops was undetermined. The PLI was normal in 9 fetuses with other diseases and no hydrops. The PLI was increased in conditions in which excessive preload, tricuspid regurgitation, or some kind of structural heart disease were present.

We have summarized the care management of pregnant women with complete atrioventricular block (CAVB) by reviewing data from the published literature as well as our own experience in 32 pregnancies. Obstetrical management of women with a permanent pacemaker implanted prior to conception has been sufficiently reported thus far, and the management of such patients is considered to be of low risk. Since CAVB usually does not cause any specific obstetrical problems during pregnancy, prepregnancy prophylactic placement of a permanent pacemaker is not indicated in all asymptomatic patients. However, when asymptomatic women without pacemakers become pregnant, there is a subset that ultimately develops heart failure during pregnancy. Therefore, close surveillance of pregnant patients with CAVB is warranted. The current increase in the use of permanent pacemakers in young women with symptomatic CAVB will certainly limit the need for intrapartum temporary pacing in patients who do not require a pacemaker before pregnancy. In fact, most women with CAVB, who do not require a permanent pacemaker before delivery, can be safely managed during labor without temporary pacing. However, the clinical symptoms and cardiac function of patients should be carefully followed after delivery, even when pregnancy and delivery are uneventful.