Normal cardiovascular development in mice deficient for 16 genes in 550 kb of the velocardiofacial/DiGeorge syndrome region. (9/190)

Hemizygous interstitial deletions in human chromosome 22q11 are associated with velocardiofacial syndrome and DiGeorge syndrome and lead to multiple congenital abnormalities, including cardiovascular defects. The gene(s) responsible for these disorders is thought to reside in a 1.5-Mb region of 22q11 in which 27 genes have been identified. We have used Cre-mediated recombination of LoxP sites in embryonic stem cells and mice to generate a 550-kb deletion encompassing 16 of these genes in the corresponding region on mouse chromosome 16. Mice heterozygous for this deletion are normal and do not exhibit cardiovascular abnormalities. Because mice with a larger deletion on mouse chromosome 16 do have heart defects, the results allow us to exclude these 16 genes as being solely, or in combination among themselves, responsible for the cardiovascular abnormalities in velocardiofacial/DiGeorge syndrome. We also generated mice with a duplication of the 16 genes that may help dissect the genetic basis of "cat eye" and derivative 22 syndromes that are characterized by extra copies of portions of 22q11, including these 16 genes. We also describe a strategy for selecting cell lines with defined chromosomal rearrangements. The method is based on reconstitution of a dominant selection marker after Cre-mediated recombination of LoxP sites. Therefore it should be widely applicable to many cell lines.  (+info)

Cardiac findings in 31 patients with Noonan's syndrome. (10/190)

OBJECTIVE: To evaluate cardiac findings in 31 Noonan syndrome patients. METHODS: Thirty-one (18 males and 13 females)patients from 26 families affected with Noonan's syndrome were evaluated from the cardiac point of view with electrocardiography and Doppler echocardiography. RESULTS: Twenty patients had some type of cardiac abnormality. The most frequent was pulmonary valve stenosis followed by hypertrophic myocardiopathy, commonly associated with valve defects. Upper deviation of the QRS axis was observed in 80% of these patients. CONCLUSION: In view of the high frequency and diversity of cardiac abnormalities present in Noonan syndrome, cardiac evaluation with electrocardiography and echocardiography should be performed in all patients diagnostically suspected of having this disease.  (+info)

Cardiovascular abnormalities with normal blood pressure in tissue kallikrein-deficient mice. (11/190)

Tissue kallikrein is a serine protease thought to be involved in the generation of bioactive peptide kinins in many organs like the kidneys, colon, salivary glands, pancreas, and blood vessels. Low renal synthesis and urinary excretion of tissue kallikrein have been repeatedly linked to hypertension in animals and humans, but the exact role of the protease in cardiovascular function has not been established largely because of the lack of specific inhibitors. This study demonstrates that mice lacking tissue kallikrein are unable to generate significant levels of kinins in most tissues and develop cardiovascular abnormalities early in adulthood despite normal blood pressure. The heart exhibits septum and posterior wall thinning and a tendency to dilatation resulting in reduced left ventricular mass. Cardiac function estimated in vivo and in vitro is decreased both under basal conditions and in response to beta-adrenergic stimulation. Furthermore, flow-induced vasodilatation is impaired in isolated perfused carotid arteries, which express, like the heart, low levels of the protease. These data show that tissue kallikrein is the main kinin-generating enzyme in vivo and that a functional kallikrein-kinin system is necessary for normal cardiac and arterial function in the mouse. They suggest that the kallikrein-kinin system could be involved in the development or progression of cardiovascular diseases.  (+info)

Cell lineages and tissue boundaries in cardiac arterial and venous poles: developmental patterns, animal models, and implications for congenital vascular diseases. (12/190)

Multiple cell populations with different embryological histories are involved in the morphogenesis of the cardiac arterial and venous poles as well as in the correct alignment and connection of the developing vessels with the cardiac chambers. Formation of the aorta and the pulmonary trunk is a complicated process orchestrated via a specific sequence of highly integrated spatiotemporal events of cell proliferation, migration, differentiation, and apoptosis. The peculiar susceptibility of this intricate cell network to be altered explains the frequency of congenital cardiovascular diseases of the arterial and venous poles. We review this topic from the "vascular point of view," putting major emphasis on (1) the existence of different cell lineages from which smooth muscle cells of the aorticopulmonary trunk can be derived, (2) the establishment of cell/tissue boundaries in the cardiovascular connecting regions, and (3) the animal models that can mimic human congenital defects of the arterial and venous poles of the heart.  (+info)

TBX1 is responsible for cardiovascular defects in velo-cardio-facial/DiGeorge syndrome. (13/190)

Velo-cardio-facial syndrome (VCFS)/DiGeorge syndrome (DGS) is a human disorder characterized by a number of phenotypic features including cardiovascular defects. Most VCFS/DGS patients are hemizygous for a 1.5-3.0 Mb region of 22q11. To investigate the etiology of this disorder, we used a cre-loxP strategy to generate mice that are hemizygous for a 1.5 Mb deletion corresponding to that on 22q11. These mice exhibit significant perinatal lethality and have conotruncal and parathyroid defects. The conotruncal defects can be partially rescued by a human BAC containing the TBX1 gene. Mice heterozygous for a null mutation in Tbx1 develop conotruncal defects. These results together with the expression patterns of Tbx1 suggest a major role for this gene in the molecular etiology of VCFS/DGS.  (+info)

Cardiopulmonary malformations in the inv/inv mouse. (14/190)

The inv/inv mouse carries an insertional mutation in the inversin gene, (inv, for inversion of embryonic turning). Previously it had been reported that almost 100% of the homozygous offspring (inv/inv) were characterized by situs inversus totalis. In this report we identify the spectrum of cardiopulmonary anatomical abnormalities in inv/inv mice surviving to birth to determine whether the abnormalities seen are of the categories classically associated with human situs abnormalities. Stillborn mice, offspring that died unexpectedly (within 48 hr after birth), and neonates with phenotypic characteristics of situs inversus (right-sided stomachs, growth failure or jaundice) were processed for standard histological examination. Of 173 offspring, 34 (20%) neonates (11 stillborn, 9 unexpected deaths, and 14 mice with situs inversus phenotype) were examined, 27 of which were genotyped to be inv/inv. Interestingly, three inv/inv mice (11%) were found to have situs solitus. Twenty-four had situs inversus with normal, mirror-image cardiac anatomy (dextrocardia with atrioventricular concordance, ventriculoarterial concordance and a right aortic arch). The overall incidence of cardiovascular anomalies observed was 10 out of 27 (37%). The most frequent severe malformation, identified in 3 out of 27 animals, was a complex consisting of pulmonary infundibular stenosis/atresia with absence of pulmonary valve tissue and a ventricular septal defect. The pulmonary phenotype in inv/inv mice was situs inversus with occasional minor lobar abnormalities. We conclude that 1) cardiopulmonary malformations in inv/inv mice are not rare (37%), 2) the cardiopulmonary malformations observed in inv/inv specimens are not of the spectrum typically associated with human heterotaxia. In particular, inv/inv mice have a propensity for defects in the development of the right ventricular outflow tract and the interventricular septum, and 3) approximately one out of ten inv/inv mice is born with situs solitus and shows cardiac anomalies that correspond to those observed in inv/inv specimens with situs inversus. Our data therefore suggest that inversin, the product of the inv locus, may have specific roles in cardiac morphogenesis independent of its role in situs determination.  (+info)

Sex differences of body fat distribution and cardiovascular dysmetabolic factors in old age. (15/190)

BACKGROUND: The relationship between sexual differences of body fat distribution and cardiovascular dysmetabolic factors in old people is controversial. OBJECTIVES: To use centrality index-derived body fat distribution to clarify its relationship with glucose tolerance status, blood pressure and lipid profile. DESIGN: Cross-sectional survey in a tertiary-care medical centre in Tainan, Taiwan. SUBJECTS: 114 men and 101 women, aged > or = 60 years. METHODS: We measured total % body fat and body fat distribution (reflected as centrality index) by dual energy x-ray absorptiometry, and plasma glucose, glycosylated haemoglobin, blood pressure, total cholesterol, triglyceride, high-density lipoprotein (HDL) cholesterol and atherogenic index (total cholesterol/HDL cholesterol). RESULTS: Centrality index showed better linear correlation with cardiovascular dysmetabolic factors than body mass index, total % body fat and waist-to-hip ratio, except in systolic blood pressure. Women had higher total % body fat, but the % abdominal fat and centrality index were both higher in men. Subjects with diabetes mellitus had the highest centrality index compared with those with impaired or normal glucose tolerance. After adjustment for age and total % body fat, men still had higher diastolic blood pressure, triglyceride levels and atherogenic indices, but lower HDL cholesterol levels than women. However, when further adjusted for centrality index, the sex differences in cardiovascular dysmetabolic factors were statistically insignificant. CONCLUSIONS: Centrality index is a useful method for assessing body fat distribution in older people. Body fat distribution is an important factor in sex differences of cardiovascular dysmetabolic factors in old people.  (+info)

Unstable angina and elevated c-reactive protein levels predict enhanced vasoreactivity of the culprit lesion. (16/190)

BACKGROUND: Because plaque inflammation may modulate coronary vasomotion, the association between systemic levels of C-reactive protein (CRP) and coronary vasoreactivity was assessed in patients with stable or unstable angina. METHODS AND RESULTS: In 31 patients with stable angina and 23 patients with unstable angina undergoing coronary angiography, minimal luminal diameter (MLD) of the culprit lesion was measured by quantitative coronary angiography at baseline, during the cold pressor test (CPT), and after intracoronary administration of nitroglycerin (NTG) and expressed as percent change from baseline. MLD of patients with unstable angina exhibited a greater reduction during CPT and a greater increase after NTG than did patients with stable angina (-17+/-14% versus -5+/-12%, P=0.0013, and 34+/-25% versus 8+/-20%, P<0.001, respectively). According to preprocedural serum levels of CRP, 36 patients had normal (+info)