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PubMedDate not supplied

Gene expression of atrial natriuretic factor in ovine fetal heart during development.

OBJECTIVE: The present study quantified the abundance of atrial natriuretic factor (ANF) messenger RNA (mRNA) and determined the developmental pattern of ANF gene expression in the four cardiac chambers of the ovine fetus during the last two-thirds of gestation. METHODS: Twenty-one fetuses from 13 time-dated pregnant ewes at gestational ages of 60-145 days were used for this study. Total RNA from fetal atria and ventricles was extracted and ANF mRNA was analyzed by Northern blotting. The ANF mRNA signal was quantified by light densitometry. The abundance of ANF mRNA in the cardiac chambers across gestational ages was analyzed by linear regression analysis and one-way analysis of variance. RESULTS: Atrial natriuretic factor mRNA was much more abundant in the atria than in the ventricles of all fetuses at each gestational age studied. Atrial ANF mRNA levels were lowest in the younger fetuses at 60 days and increased with advancing gestation. Ventricular ANF mRNA levels were highest in fetuses at 60 days and decreased to almost nondetectable levels near term. No difference in ANF mRNA abundance was noted between the right and left atria or the right and left ventricles at each gestational age. CONCLUSION: A developmental pattern of ANF gene expression is demonstrated in the ovine fetal heart during the last two-thirds of gestation. This pattern shows that atrial ANF mRNA abundance increases while ventricular abundance decreases as the fetus matures. Expression of the ANF gene in the fetal period may be regulated developmentally or induced by cardiovascular changes in utero.

Animals↗
PubMed1999

Magnetic resonance imaging and invasive evaluation of development of heart failure in transgenic mice with myocardial expression of tumor necrosis factor-alpha.

BACKGROUND: Transgenic mice expressing tumor necrosis factor-alpha (TNF-alpha) in cardiac myocytes develop dilated cardiomyopathy, but the temporal progression to cardiac dysfunction is not well characterized. We asked (1) Does magnetic resonance imaging (MRI) provide a reproducible assessment of cardiac output in mice that correlates with invasive measurements obtained with thermodilution? (2) What is the time course of left ventricular (LV) remodeling in transgenic mice with myocardial expression of TNF-alpha? METHODS AND RESULTS: Transgenic mice from 2 different lineages with differing amounts of myocardial TNF-alpha expression [lineage 1 (L1) and lineage 2 (L2)] and littermate controls (LC) were studied. In protocol 1, cardiac output (CO) and stroke volume (SV) were measured by MRI and thermodilution (TD) in 15 mice (3 L1, 4 L2, 8 LC). In protocol 2, 23 mice (7 L1, 8 L2, 8 LC) were scanned at 1 month of life and every 4 weeks thereafter. In both protocols, cine-MRI was performed with the use of a 1.5-T clinical system (1.5-mm slices, 195x195 microm in-plane resolution). MRI CO and SV correlated well with TD [COTD (mL/min)=0.94*COMRI+0.72, r=0.84; SVTD( microL)=1. 01*SVMRI-1.07, r=0.94]. Serial MRI studies showed significant increase in LV mass and volumes over time and a significant decrease in ejection fraction in transgenic mice when compared with littermate controls. Compared with lineage 2, lineage 1 showed significantly larger LV mass and volumes and significantly lower ejection fraction. CONCLUSIONS: MRI assessment of cardiac function in mice correlates well with invasive measurements. Serial MRI studies in the TNF-alpha mouse model demonstrate that the rate of progression and severity of LV dysfunction are dependent on the degree of TNF-alpha overexpression.

Animals↗
PubMed1996

Endocardial cushion development and heart loop architecture in the trisomy 16 mouse.

Murine trisomy 16 (Ts16) is a model for Down's syndrome and has close to a 100% incidence of atrioventricular septal defects (AVSDs). These have been proposed to result from abnormal development of the endocardial cushions, but the mechanisms are unknown. We aim to identify the initial defects in Ts16 hearts, both to characterise the pathogenesis of AVSDs and as a first step in the search for molecular mechanisms. In 38 litters from an Rb(11.16)2H/Rb(16.17)7Bnr x C57BL/6J cross, which was examined on days 10 and 11 of gestation, 28.4% of embryos were trisomic. Trisomic embryos were uniformly retarded compared to their normal litter mates, having on average 3.3 fewer somite pairs. All further comparisons were made between embryos of the same somitic stage. Twenty-one trisomic and 21 normal embryos of between 15 and 43 somites were serially sectioned, and stereomorphometric methods were used to reconstruct the volumes of the endocardial cushions and to count their number of mesenchymal cells. There were fewer cells in Ts16 superior and inferior cushions. In contrast, the volumes of trisomic cushions were significantly greater than normal. Thus, cell density was markedly lower in trisomic cushions. Importantly, the volumes of the cushions in trisomic embryos were already greater than normal at the 18 somite stage, prior to the invasion of cushions by mesenchymal cells. The architecture of Ts16 heart tubes in 15-25 somite embryos was subtly abnormal. This was reflected in the angle between the axis of the atrioventricular canal and the first pharyngeal cleft, which was significantly larger in trisomic hearts and showed a different relationship to somite stage when compared to normal embryos. These observations suggest that the primary cardiac defect in Ts16 mice may be localised to the myocardium, thus influencing the shape of the heart tube, with changes in the mesenchymal population of the endocardial cushions being later events. Whether AVSDs arise from one or both of these abnormalities remains to be established.

Animals↗
PubMedDate not supplied

Heart check: the development and evolution of an organizational heart health assessment.

PURPOSE: The purpose of this article is to document the development, testing, and application of an organizational assessment tool used to measure employer support for heart health. Additional information is presented on its future research and applications plan. DESIGN: This article represents the pooling of results from multiple studies using a variety of designs, including pilot tests, cross-sectional analyses, and quasi-experiments. SETTING: Worksites covering the spectrum of employers across industry types and size, and throughout all of New York State. SUBJECTS: Over 10,000 New York employees and 1000 New York employers are represented in the multiple phases of this research. MEASURES: Heart Check is a 226-item inventory designed to measure such features in the worksite as organizational foundations, administrative supports, tobacco control, nutrition support, physical activity support, stress management, screening services, and company demographics. Additional side studies used professional judgments and behavioral surveys. RESULTS: As an assessment tool Heart Check shows evidence for reliability and validity. Applications of the instrument show characteristics that define high-scoring companies, quasi standards for New York employers, and, when applied during interventions, positive changes in organizational support levels. CONCLUSIONS: A relatively inexpensive, easy-to-use, and metrically tested instrument exists for measuring the construct of organizational support for employee heart health. The instrument shows promise as part of a system to enhance heart health through public health-based interventions in the workplace.

Cross-Sectional Studies↗
PubMed2000

Identification and genomic cloning of CMHC1. A unique myosin heavy chain expressed exclusively in the developing chicken heart.

We report the identification and cloning of a unique chick myosin heavy chain (CMHC1) that is expressed exclusively in the heart during embryogenesis. Using primers specific to myosin heavy chains, we used reverse transcriptase-polymerase chain reaction to clone and isolate CMHC1 from embryonic day 10 chicken heart RNA. Sequence analysis indicated that CMHC1 was a novel member of the myosin heavy chain family. Expression of the CMHC1 transcripts was detected in Hamburger Hamilton stage 10 chick embryos in the fusing myocardium. Expression of CMHC1 was maintained at high levels throughout the tubular heart of later stage embryos. Reverse transcriptase-polymerase chain reaction and in situ hybridizations failed to detect CMHC1 transcripts in the developing somites, limb buds, or skeletal musculature at any stage of chick development. Genomic CMHC1 clones have been isolated that contain sequences approximately 5.2 kilobase upstream of the presumptive CMHC1 transcription start site. Portions of the upstream regulatory region induced a 21-fold increase in reporter gene expression in primary cardiomyocytes. Because of its unique cardiac-restricted expression, CMHC1 will provide an excellent model system to study the molecular mechanisms required for the early developmental regulation of heart-specific genes.

3T3 Cells↗
PubMed1992

Effects of verapamil on ventricular tachycardia induced by ouabain in guinea pigs.

Calcium ions appear to play a central role in the development of ventricular arrhythmias associated with digitalis intoxication. Therefore, the effects of the calcium channel antagonist, verapamil, on ouabain-induced ventricular tachycardia were investigated. Ventricular tachycardia (three or more consecutive wide QRS complexes) was induced in guinea pigs by intravenous infusion of ouabain (1 microgram/min) and bursts of rapid ventricular stimulation. Of seven guinea pigs given the infusion of ouabain, all developed ventricular tachycardia at a dose of 82 +/- 17 micrograms/kg (mean +/- SD) and none developed heart block or asystole. Eight guinea pigs were treated with verapamil (2 micrograms/min for 30 minutes) prior to exposure to ouabain. Of those eight animals, only two developed ventricular tachycardia but six developed heart block or asystole at a significantly higher dose of ouabain (154 +/- 47 micrograms/kg). None of three control guinea pigs given an infusion of normal saline for 90 minutes developed ventricular tachycardia. These results show that pretreatment with verapamil inhibits ouabain-induced ventricular tachycardia in guinea pigs. Combined treatment with verapamil and ouabain is associated with a high incidence of heart block and asystole, which may limit the usefulness of verapamil.

Animals↗
PubMed1992

Persisting zones of slow impulse conduction in developing chicken hearts.

We performed a correlative electrophysiological and immunohistochemical study of embryonic chicken hearts during the septational period (Hamburger and Hamilton stages 13-31 [2-7 days of incubation]). The analyses yield conclusive evidence for slow conduction, up to 7 days of development, in the outflow tract, in the atrioventricular canal, and in the sinoatrial junction. The conduction velocity remains approximately 1 cm/sec in the outflow tract and increases in the ventricle 20-fold to approximately 20 cm/sec between 2 and 7 days of development. Transmembrane potentials of myocytes in the outflow tract and atrioventricular canal slowly rise (less than 5 V/sec), whereas in the atrium and ventricle, the upstroke velocity is eightfold to 13-fold higher. In the outflow tract, repolarization is completed only after the start of the next cycle. Because of the persistence of slow conduction, the myocardium flanking the developing atria and ventricle is thought to represent segments of persisting "primary" myocardium, whereas the more rapidly conducting "working" myocardium of the ventricle and atria is thought to represent more advanced stages of myocardial differentiation. The persisting primary myocardium was characterized by a continued coexpression of both the atrial and ventricular isoforms of myosin heavy chain. The developing atria and ventricle could be demarcated morphologically from the primary myocardium because the free walls of these segments only express their respective isoforms of myosin heavy chain. The slowly conducting myocardial zones appear to be essential for the function of the embryonic heart because 1) they provide the septating heart with alternating segments of slow and relatively fast conduction necessary for consecutive contraction of the atrial and ventricular segments and 2) their sphincterlike prolonged peristaltic contraction pattern can substitute for the adult type of one-way valves that start to develop at the end of septation.

Animals↗
PubMed2004

GATA4 is a dosage-sensitive regulator of cardiac morphogenesis.

Normal heart development is orchestrated by a set of highly conserved transcription factors that includes GATA4, Nkx2-5, and Tbx5. Heterozygous mutation of each of these genes causes congenital heart disease in humans. In mouse models, haploinsufficiency for Nkx2-5 or Tbx5 resulted in an increased incidence of structural heart disease, confirming that normal heart development is sensitive to small changes in expression levels of Nkx2-5 and Tbx5. However, mice haploinsufficient for GATA4 have not been reported to have cardiac abnormalities. We generated two new GATA4 alleles, GATA4(H) and GATA4(flox). GATA4(flox/flox) embryos expressed 50% less GATA4 protein in the heart and survived normally. In contrast, GATA4(H/H) embryos expressed 70% less GATA4 protein in the heart and died between days 13.5 and 16.5 of gestation. These embryos had common atrioventricular canal (CAVC), double outlet right ventricle (DORV), hypoplastic ventricular myocardium, and normal coronary vasculature. Myocardial hypoplasia was associated with diminished cardiomyocyte proliferation. Hemodynamic measurements demonstrated that these embryos had normal systolic function, severe diastolic dysfunction, and atrioventricular regurgitation. Surprisingly, expression levels of the putative GATA4 target genes ANF, BNP, MEF2C, Nkx2-5, cyclin D2, and BMP4 were unchanged in mutant hearts, suggesting that GATA4 is not a dose-limiting regulator of the expression of these genes during later stages of embryonic cardiac development. These data demonstrate that multiple aspects of embryonic cardiac morphogenesis and function are exquisitely sensitive to small changes in GATA4 expression levels.

Animals↗
PubMed2000

Using focus groups to develop a heart disease prevention program for ethnically diverse, low-income women.

Although low-income women have higher rates of cardiovascular disease (CVD) than higher-income women, health promotion and disease prevention are often low priorities due to financial, family, and health care constraints. In addition, most low-income women live in environments that tend to support and even promote high risk CVD behaviors. Low-income African-American, Hispanic, and White women constitute one of the largest groups at high risk for CVD but few heart disease prevention programs have effectively reached them. The purpose of this project was to use feedback from focus groups to generate ideas about how to best structure and implement future CVD intervention programs tailored to low-income populations. Seven focus groups were conducted with 51 low-income African-American, Hispanic, and White women from two urban and two agricultural communities in California. The women in the study shared many common experiences and barriers to healthy lifestyles, despite their ethnic diversity. Results of the focus groups showed that women preferred heart disease prevention programs that would address multiple CVD risk factors, emphasize staying healthy for themselves, teach specific skills about how to adopt heart-healthy behaviors, and offer them choices in effecting behavioral change. For health information, they preferred visual formats to written formats. They also expressed a desire to develop knowledge to help them separate health "myths" from health "facts" in order to reduce their misconceptions about CVD. Finally, they stressed that health care policies and programs need to address social and financial barriers that impede the adoption of heart-healthy behaviors.

Adult↗
PubMed1996

Apoptosis and DNA fragmentation in the bulbus cordis of the developing rat heart.

Histologic, ultrastructural and nick end labeling studies were made of the process of apoptosis in the bulbus cordis of rat embryos. Apoptosis was observed between the 14th and 16th days of gestational age, at which time the bulbus cordis undergoes extensive remodeling. Three types of mesenchymal cells were identified in this region: cells undergoing apoptosis, cells engaging in the phagocytic removal of apoptotic cells, and cells not involved in either of these two processes. Fragmentation of DNA, demonstrated by nick end labeling, was found only in the apoptotic cells. The combined use of morphologic and labeling techniques is extremely useful in the evaluation of the contribution of apoptosis to cardiac morphogenesis.

Animals↗
PubMed2005

ASD--lessons on genetic background from transgenic mice with inactive gene encoding metalloprotease, Tolloid-like 1 (TLL1).

Congenital heart defects still constitute serious medical problems. The background of such defects, however, is poorly understood. Little is also known about their pattern of inheritance. Lack of atrial and ventricular septum closures counts for a significant percentage of all congenital heart defects. Individuals harboring such defects always suffer poor quality of life. The only way to help those patients is cardiac surgery. Several genes have been implicated in the process of controlling heart development. Recent studies on transgenic mice null for tolloid-like 1 (tll1) gene revealed factors possibly involved in signaling pathways that, when absent, might affect heart development and cause problems mimicking those observed in atrial septal defects (ASDs). Lack of activity of this metalloprotease caused incomplete closure of the septum in murine fetal hearts and led to death in mid-gestation due to severe circulation problems. tll1 gene is located on the long arm of chromosome 4 (4q32-q33). The gene comprises of 6654 nucleotides and it encodes a protein 1013 amino acids long. Its human homologue tll1 is poorly investigated and until now no particular disorders have been linked to mutations in this gene.

Animals↗
PubMed1989

Preproenkephalin mRNA expression in developing rat heart and in cultured ventricular cardiac muscle cells.

Heart muscle tissue has previously been reported to have the highest content of preproenkephalin (ppEnk) mRNA of any tissue in the adult rat. We have determined that it is present in the ventricular cardiac muscle cells of the heart and is developmentally regulated. The expression of ppEnk mRNA was observed to be low throughout the first 2 weeks of postnatal development and decreases substantially during week 3. Expression was again low by week 4, but by adulthood (approx. 3 months), it reached a maximum. ppEnk mRNA was actively expressed in primary cardiac muscle cell cultures prepared from both neonatal and adult rats. Its steady-state content in cell cultures was observed to be increased by cyclic AMP and 3-isobutyl-1-methylxanthine. The phorbol ester phorbol 12-myristate 13-acetate elicited a transient effect (i.e. an increase was observed at 4 h and a return to control values by 24 h). We speculate that enkephalin may play a multi-functional role in the differentiation of neonatal cardiac muscle cells and in the terminally differentiated adult heart cell. We demonstrate that the primary culture systems employed in this study will be useful models with which to explore both transcriptional and translational regulation of ppEnk mRNA in the heart.

1-Methyl-3-isobutylxanthine↗
PubMed2005

Cell biology of cardiac cushion development.

The valves of the heart develop in the embryo from precursor structures called endocardial cushions. After cardiac looping, endocardial cushion swellings form and become populated by valve precursor cells formed by an epithelial-mesenchymal transition (EMT). Endocardial cushions subsequently undergo directed growth and remodeling to form the valvular structures and the membranous septa of the mature heart. The developmental processes that mediate cushion formation include many prototypic cellular actions including adhesion, signaling, migration, secretion, replication, differentiation, and apoptosis. Cushion morphogenesis is unique in that these cellular possesses occur in a functioning organ where the cushions act as valves even while developing into definitive valvular structures. Cardiovascular defects are the most common congenital defects, and one of the most common causes of death during infancy. Thus, there is significant interest in understanding the mechanisms that underlie this complex developmental process. In this regard, substantial progress has been made by incorporating an understanding of cardiac morphology and cell biology with the rapidly expanding repertoire of molecular mechanisms gained through human genetics and research using animal models. This article reviews cardiac morphogenesis as it relates to heart valve formation and highlights selected growth factors, intracellular signaling mediators, and extracellular matrix components involved in the creation and remodeling of endocardial cushions into mature cardiac structures.

Emigration and Immigration↗
PubMed1999

A murine model of hereditary hemorrhagic telangiectasia.

Endoglin (CD105), an accessory protein of the TGF-beta receptor superfamily, is highly expressed on endothelial cells. Hereditary hemorrhagic telangiectasia type 1 (HHT1) is associated with mutations in the Endoglin gene, leading to haploinsufficiency. To generate a disease model and ascertain the role of endoglin in development, we generated mice lacking 1 or both copies of the gene. Endoglin null embryos die at gestational day 10.0-10.5 due to defects in vessel and heart development. Vessel formation appears normal until hemorrhage occurs in yolk sacs and embryos. The primitive vascular plexus of the yolk sac fails to mature into defined vessels, and vascular channels dilate and rupture. Internal bleeding is seen in the peritoneal cavity, implying fragile vessels. Heart development is arrested at day 9.0, and the atrioventricular canal endocardium fails to undergo mesenchymal transformation and cushion-tissue formation. These data suggest that endoglin is critical for both angiogenesis and heart valve formation. Some heterozygotes, either with an inbred 129/Ola or mixed C57BL/6-129/Ola background, show signs of HHT, such as telangiectases or recurrent nosebleeds. In this murine model of HHT, it appears that epigenetic factors and modifier genes, some of which are present in 129/Ola, contribute to disease heterogeneity.

Abnormalities, Multiple↗
PubMed1998

Role of cardiac neural crest cells in cardiovascular development.

The discovery in the chick embryo that a specific region of the neural crest, termed the cardiac neural crest, is essential for septation of the cardiac outflow tract and for aortic arch artery development has led to the classification of a whole series of human cardiac defects as neural crest-associated. Recently, several mouse genetic models have been effectively employed to yield new insights into the relationship between cardiac neural crest and structural heart development. In all the animal models of neural crest-related heart defects, prenatal mortality is too high to be attributed to structural defects of the heart alone, and there are obvious signs of severe cardiac dysfunction. The evidence indicates that poor viability is from impaired cardiac excitation-contraction coupling and contractile function at the myocyte level. The continued study of experimental and genetically defined models with neural crest-associated heart defects will prove useful in identifying the common pathways by which the neural crest contributes to normal heart development.

Animals↗
PubMed2002

Propranolol prevents the development of heart failure by restoring FKBP12.6-mediated stabilization of ryanodine receptor.

BACKGROUND: In heart failure, protein kinase A-mediated hyperphosphorylation of ryanodine receptors (RyRs) in sarcoplasmic reticulum (SR) causes dissociation of FKBP12.6 from RyRs. This results in an abnormal Ca2+ leak through RyRs, possibly leading to cardiac dysfunction. In the present study, we assess whether beta-blockers can correct this defect in RyR in tachycardia-induced heart failure and thereby improve cardiac function. METHODS AND RESULTS: SRs were isolated from dog left ventricular muscles (normal group, 4 weeks of rapid right ventricular pacing with or without propranolol [P(+) or P(-)]). End-diastolic and end-systolic diameters both increased less in P(+) than P(-), associated with a smaller decrease in fractional shortening in P(+). In SR from P(-), a prominent Ca2+ leak was observed, and FK506 (which dissociates FKBP12.6 from RyR) did not induce an additional Ca2+ leak. However, there was no appreciable Ca2+ leak in SR from P(+), although FK506 induced a Ca2+ leak as in normal SRs. In SR from P(+), an FK506-induced conformational change in RyR, which was virtually absent in SR from P(-), was observed as in normal SRs. Both the stoichiometry of FKBP12.6 versus RyR, assessed by [3H]FK506 and [3H]ryanodine binding assays, and the protein expression of FKBP12.6, assessed by Western blot analysis, were restored by propranolol toward the levels seen in normal SRs. CONCLUSIONS: Low-dose propranolol corrects the defective interaction of FKBP12.6 with RyR (restoration of RyR conformational change and prevention of Ca2+ leak from RyR), apparently resulting in an attenuation of intracellular Ca2+ overload and hence preventing the development of left ventricular remodeling in heart failure.

Adrenergic beta-Antagonists↗