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PubMedDate not supplied

[The pharmacokinetics and the concentration-and-effect relationship of prazosin in patients at the beginning of the subacute period of myocardial infarct complicated by the development of heart failure].

The pharmacokinetics of prazosin was studied in 16 patients in the early subacute period of myocardial infarction complicated with heart failure following a single and 10-day administration. The increase of the half-life of the drug (6.6 +/- 1.6 h) and the elevation of the blood plasma concentration 1-2.5 h after administration (87 +/- 33 ng/ml) were found. After 10-day administration the increase of the apparent total clearance of the drug was established. The blood plasma levels of prazosin significantly correlated with the change of the hemodynamic parameters measured invasively after a single administration of 2-5 mg of the drug. After 10 days of treatment the correlation weakened and the regression line angle reduced that reflected the development of tolerance to the drug. On the basis of the calculated effective concentrations, there were determined the optimal intervals of the drug dosage.

Aged↗
PubMed1996

An HF-1a/HF-1b/MEF-2 combinatorial element confers cardiac ventricular specificity and established an anterior-posterior gradient of expression.

The molecular determinants that direct gene expression to the ventricles of the heart are for the most part unknown. Additionally, little data is available on how the anterior/posterior axis of the heart tube is determined and whether the left and right atrial and ventricular chambers are assigned as part of this process. Utilizing myosin light chain-2 ventricular promoter/beta-galactosidase reporter transgenes, we have determined the minimal cis-acting sequences required for ventricular-specific gene expression. In multiple independent transgenic mouse lines, we found that both a 250 base pair myosin light chain-2 ventricular promoter fragment, as well as a dimerized 28 bp sub-element (HF-1) containing binding sites for HF1a and HF1b/MEF2 factors, directed ventricular-specific reporter expression from as early as the endogenous gene, at day 7.5-8.0 post coitum. While the endogenous gene is expressed uniformly throughout both ventricles, the transgenes were expressed in a right ventricular/conotruncal dominant fashion, suggesting that they contain only a subset of the elements which respond to positional information in the developing heart tube. Expression of the transgene was cell autonomous and its temporospatial characteristics not affected by mouse strain/methylation state of the genome. To determine whether ventricular-specific expression of the transgene was dependent upon regulatory genes required for correct ventricular differentiation, the 250 base pair transgene was bred into both retinoid X receptoralpha and Nkx2-5 null backgrounds. The transgene was expressed in both mutant backgrounds, despite the absence of endogenous myosin light chain-2 ventricular transcript in Nkx2-5 null embryos. Ventricular specification, as judged by transgene expression, appeared to occur normally in both mutants. Thus, the HF-1 element, directs chamber-specific transcription of a transgene reporter independently of retinoid X receptoralpha and Nkx2-5, and defines a minimal combinatorial pathway for ventricular chamber gene expression. The patterned expression of this transgene may provide a model system in which to investigate the cues that dictate anterior-posterior (right ventricle/left ventricle) gradients during mammalian heart development.

Animals↗
PubMed1999

Gata5 is required for the development of the heart and endoderm in zebrafish.

The mechanisms regulating vertebrate heart and endoderm development have recently become the focus of intense study. Here we present evidence from both loss- and gain-of-function experiments that the zinc finger transcription factor Gata5 is an essential regulator of multiple aspects of heart and endoderm development. We demonstrate that zebrafish Gata5 is encoded by the faust locus. Analysis of faust mutants indicates that early in embryogenesis Gata5 is required for the production of normal numbers of developing myocardial precursors and the expression of normal levels of several myocardial genes including nkx2.5. Later, Gata5 is necessary for the elaboration of ventricular tissue. We further demonstrate that Gata5 is required for the migration of the cardiac primordia to the embryonic midline and for endodermal morphogenesis. Significantly, overexpression of gata5 induces the ectopic expression of several myocardial genes including nkx2.5 and can produce ectopic foci of beating myocardial tissue. Together, these results implicate zebrafish Gata5 in controlling the growth, morphogenesis, and differentiation of the heart and endoderm and indicate that Gata5 regulates the expression of the early myocardial gene nkx2.5.

Amino Acid Sequence↗
PubMed1986

[Clinico-functional characteristics of pulmonary heart disease developing at high altitude as a result of chronic bronchitis].

It was shown that the high-altitude conditions of the Pamirs and Tien Shan (2800-3600 m above the sea-level) modified the clinicofunctional signs and a course of the cor pulmonale (CP) in chronic bronchitis. CP was detected in the examined patients with chronic bronchitis. As compared to the conditions of foothills (760 m) CP in mountain-dwellers was more noticeable in terms of the signs of pulmonary arterial hypertension, right ventricular hypertrophy developed in them 5 years earlier. The first obvious signs of cardiac decompensation developed in the presence of moderate (noticeable at the foothills) right ventricular hypertrophy and were often (51.5% of the patients against 21.6% under the foothills conditions) accompanied by disturbance of cardiac rhythm and conduction.

Adult↗
PubMed1987

[Analysis of the duration of the cell cycle periods of slowly proliferating myocytes of the conduction system in the developing mouse heart].

Cell cycle parameters of myocytes of the heart conduction system (CS) and working ventricular (WM) myocytes were determined using different autoradiographic methods. By the labeled mitoses technique, no significant difference in the mean durations of G2 + 1/2 M and S phases was found between myocytes from CS and WM. The double labeling method (with 14C- and 3H-thymidine) has given the mean durations of the S-phase of the same order as did labeled mitoses technique in both CS and WM. Label dilution experiment has shown that at each stage under investigation the mean values of cell cycle duration are rather similar in CS and WM myocytes and increase in both the compartments from the 15th day of embryonal development up to the 7th day post partum. These results suggest that the lower indices of labeled nuclei in CS, as compared with WM, may be explained mainly by the smaller fraction of proliferating cells among the total cell population.

Animals↗
PubMed2003

Antibody deposition in rat heart which develops transplant vasculopathy in (donor x recipient) F1 environment.

PURPOSE: We studied the gene expression in rat cardiac allografts retransplanted into (donor x recipient) F1 animals to identify unknown or unexpected genes whose expression might contribute to the progression of transplant vasculopathy. METHODS: Gene expression was first studied using a mRNA differential display, then it was further investigated using quantitative reverse transcription-polymerase chain reaction and immunohistochemistry. RESULTS: We found that the rat immunoglobulin kappa chain gene was preferentially induced in retransplanted cardiac allografts in which transplant vasculopathy was developing. The diseased vessels in the same allografts were heavily infiltrated with CD45R-positive B cells. The expression of two genes related to B-cell responses, B-lymphocyte chemoattractant, and CD40 ligand, showed a similar time course to that of the immunoglobulin kappa chain gene. We observed a heavy deposit of both IgM and IgG on the pathological neointima late in the development of transplant vasculopathy (i.e., 30 days after retransplantation) that was absent from the allografts immediately after retransplantation. CONCLUSION: During the development of transplant vasculopathy in a (donor x recipient) F1 environment, B cells were selectively recruited into the allografts and stimulated; meanwhile, antibodies against the pathological neointima were formed. These antibodies may be involved in the pathogenesis of transplant vasculopathy.

Animals↗
PubMed1998

Thyroid control of sarcolemmal Na+/Ca2+ exchanger and SR Ca2+-ATPase in developing rat heart.

Thyroid hormone (TH) levels increase in the postnatal life and are essential for maturation of myocardial Ca2+ handling. During this time, the sarcolemmal (SL) Na+/Ca2+ exchanger (NCX) function decreases and the sarcoendoplasmic reticulum (SR) Ca2+-ATPase (SERCA2) function increases. We examined the effects of postnatal hypo- or hyperthyroidism on NCX and SERCA2 in rat hearts. Animals were rendered hypothyroid by 0.05% 6-n-propyl-2-thiouracil in drinking water given to nursing mothers from days 2 to 21 postpartum. Hyperthyroidism was induced by daily injections of 10 microg/100 g body weight of 3,3',5-triiodo-L-thyronine during this period. Ventricular steady-state mRNA and protein levels of NCX and SERCA2 were analyzed by Northern and Western blotting. These were compared with SL Na+ gradient-induced and SR oxalate-supported Ca2+ transports in isolated membranes. In hypothyroidism, NCX mRNA and protein were elevated by 66 and 80%, respectively, and SERCA2 mRNA and protein were reduced to 55 and 70%, respectively (P < 0.05 vs. euthyroid). Corresponding differences were observed in the respective Ca2+ transports. Conversely, reduced NCX (by 50%) and elevated SERCA2 (by 150%) activities were found in hyperthyroidism (P < 0.05). The levels of NCX and SERCA2 mRNA and protein were, however, unchanged in hyperthyroidism, indicating that functional changes are not due to altered NCX and SERCA2 expression. In this case, a decline in noninhibitory phosphorylated phospholamban is a likely explanation for the elevated SR Ca2+ transport. In conclusion, physiological TH levels appear to be essential for normal reciprocal changes in the expression and function of myocardial NCX and SERCA2 during postnatal development.

Animals↗
PubMed2001

Bmp6 and Bmp7 are required for cushion formation and septation in the developing mouse heart.

The mature heart valves and septa are derived from the cardiac cushions which initially form as local outgrowths of mesenchymal cells within the outflow tract and atrioventricular regions. Endocardial cells respond to signals from the overlying myocardium and undergo an epithelial-to-mesenchymal transformation to invade the intervening extracellular matrix. The molecules that can induce and maintain these cell populations are not known, but many candidates, including several TGFbetas and BMPs, have been proposed based on their expression patterns and activities in other systems. In the present study, we describe the expression of Bmp6 and Bmp7 in overlapping and adjacent sites, including the cardiac cushions during mouse embryonic development. Previous analyses demonstrate that neither of these BMPs is required during cardiogenesis, but analysis of Bmp6;Bmp7 double mutants uncovers a marked delay in the formation of the outflow tract endocardial cushions. A proportion of Bmp6;Bmp7 mutants also display defects in valve morphogenesis and chamber septation, and the embryos die between 10.5 and 15.5 dpc due to cardiac insufficiency. These data provide the first genetic evidence that BMPs are involved in the formation of the cardiac cushions.

Animals↗
PubMed1998

Cell cycle-related changes in the voltage-gated Ca2+ currents in cultured newborn rat ventricular myocytes.

The expression of T-type Ca2+ current (ICa,T) has been reported to change during postnatal heart development and myocardial hypertrophy, which are characterized respectively by the arrest of the cell cycle soon after birth and a switching on of DNA synthesis in the terminally differentiated cardiac myocytes. The hypothesis that there are cell cycle-related changes in cardiac Ca2+ channel expression was tested by performing whole-cell voltage-clamp recording and BromodeoxyUridine (BrdU) immunolabeling to determine the S phase of the cell cycle in the same single cultured newborn rat ventricular cells. Myocytes were isolated from 1-day-old Wistar rats and cultured for 15 days. ICa,T was detected in 27% of the 5-day cultured myocytes. The progressive loss of ICa,T during the period of 15-day incubation, which resembles the developmental changes in vivo, paralleled the decrease in the percentage of cells showing BrdU labeling. At day 5 of cell culture, the fraction of myocytes expressing ICa,T was significantly higher in the BrdU-labeled population (95%) as compared with the non-labeled cells (19%). In addition, a 72-h treatment with 20 microM nickel, an ICa,T blocker, revealed no effect on the percentage of BrdU-positive cells. L-type Ca2+ current (ICa,L) was constantly expressed throughout the 15-day cell culture. The frequency of ICa,L expression was identical between the BrdU-labeled and the non-labeled myocytes, although the latter cell population demonstrated a relatively greater current density. No differences in the inactivating kinetics of ICa,L and their reaction to beta-adrenoceptor stimulation were observed between the two groups. These findings provide convincing evidence for the cell cycle-related expression of cardiac Ca2+ channel. Cardiomyocytes at the S phase of the cell cycle predominantly express ICa,T, while the major properties of ICa,L' are unchanged during the cell cycle. Such a cell cycle-related channel expression may play a critical role in regulating the cardiac electrophysiological properties during heart development and myocardial remodeling.

Animals↗
PubMed2005

Chlamydia pneumoniae seropositivity and risk of developing coronary heart disease in Western Saudi Arabia.

OBJECTIVES: To estimate the seroprevalence of IgG and IgA antibodies against Chlamydia pneumoniae (C. pneumoniae) among a sample of the Saudi population, and to evaluate whether there is a relationship between seropositivity to chronic infection with C. pneumoniae and the manifestation of symptomatic coronary heart disease (CHD). METHODS: We collected 273 sera samples from CHD patients and 273 sera samples from healthy matched controls from the Western region of Saudi Arabia during the period from November 2004 to May 2005. We tested anti-chlamydial IgG and IgA antibodies using enzyme-linked immunosorbent assay technique. RESULTS: We found 239 (87.5%) patients and 213 (78%) controls positive for C. pneumoniae IgG antibodies. However, 58 (21.2%) patients and 55 (23.9%) controls were positive for C. pneumoniae IgA antibodies. These results indicate a significant correlation between the presence of IgG antibodies and the development of CHD (p=0.003). Data of this study showed that the presence of IgG antibodies has a 2-fold increase risk in development of CHD. We found no significant correlation between the existence of IgA antibodies and CHD. CONCLUSION: Our study indicates that C. pneumoniae infection plays an important role in the development of CHD in the Saudi community, emphasizing the importance of developing strategies for prevention and control against this type of bacterial infection. However, we need further study throughout the Kingdom to approve these results in all regions.

Adult↗
PubMed2002

Requirement for AP-2alpha in cardiac outflow tract morphogenesis.

Most developing structures that express the transcription factor gene AP-2alpha are compromised in AP-2alpha mutant mouse embryos. Since the cardiac neural crest population is one prominent site of AP-2alpha expression, and because the neural crest is known to be required for normal cardiac morphogenesis, we have investigated the involvement of AP-2alpha in cardiac development. All AP-2alpha-deficient embryos examined had malformations of the outflow tract of the developing heart: most had double outlet right ventricle, and a small fraction had persistent truncus arteriosus. To visualize AP-2alpha-expressing cells during the period of cardiac morphogenesis, we established a new mutant germline allele in which an IRES-lacZ sequence was inserted by homologous recombination into the AP-2alpha locus. Positive expression was observed in the cardiac neural crest population during the E9.5-10.5 period (as well as in other known domains of AP-2alpha expression previously noted by in situ hybridization studies), and was mostly extinguished by E11.5 when the cardiac neural crest has migrated into the outflow tract of the developing heart. Importantly, the distribution of AP-2alpha-expressing cardiac neural crest appeared to be identical in normal and mutant embryos. From this analysis, we propose that the AP-2alpha gene functions within the neural crest lineage, that AP-2alpha is not required for neural crest cell migration, and that normal AP-2alpha gene function is required prior to E11.5. AP-2alpha may be involved in an interaction between neural crest and surrounding tissues in the subpharyngeal region, thereby promoting normal outflow tract morphogenesis.

Animals↗
PubMed1996

Nuclear and cellular size of myocytes in different segments of the developing rat heart.

BACKGROUND: In the embryonic heart, the individual cardiac segments show different growth rates. For the analysis of changing form in relation with changing function, data on number and shape of cardiomyocytes are necessary. Such data will give insight into the process of hypertrophy and/or hyperplasia as they may take place in the myocardium in the embryonic period. METHODS: We have measured the volumes of the nuclei and myocytes as well as the surface areas of the nuclear envelope and cellular membrane using stereological tools in rat embryos from 11 days postcoitum to 17 days postcoitum. From the data of the cellular volume of the myocytes and the myocardial volume of the individual segments, we have calculated the total number of myocytes during the developmental period. RESULTS: It is shown that the sinus venosus, sinu-atrial junction, and atrium increase their cellular volume during development, whereas the other cardiac segments show no difference in cellular volume. Similarly, the surface area of the cell membrane of the sinus venosus and sinu-atrial junction had increased during development. The nuclear volume and the surface area of the nuclear envelope did not differ during the period studied. The total number of myocytes showed a conspicuously smaller increase in the atrio-ventricular canal and distal outlet segment than in the other segments. CONCLUSIONS: The increase of the cellular volume in the segments sinus venosus and sinu-atrial junction seems to be due to a late differentiation process. In general, however, the increase of the myocardial volume in the individual cardiac segments is caused by hyperplasia of the cardiomyocytes in these segments and not by hypertrophy. The surface area of cells has a fixed relationship with cell volume, indicating that no important changes take place in the developmental period studied.

Age Factors↗
PubMed1987

Risk of developing complete heart block during bedside pulmonary artery catheterization in patients with left bundle-branch block.

We examined the incidence of complete heart block (CHB) as a complication of pulmonary artery catheterization with balloon-tipped, flow-directed catheters in patients with left bundle-branch block (LBBB). The study group included 47 consecutive critically ill patients with LBBB in the medical intensive care and coronary care units, who underwent a total of 82 pulmonary artery catheterizations. Twenty-six patients had an acute myocardial infarction, 34 patients had severe congestive heart failure (Killip class III or class IV), and 15 patients died during their hospitalization. Thirty patients had an old LBBB (more than one month in age), nine patients had a new LBBB, and the age of the LBBB was indeterminate in eight patients. There were five episodes of CHB in the group of patients with old LBBB. However, none of these episodes were related to the pulmonary artery catheterization, since CHB occurred either prior to catheterization (one case) or from one to 16 days after the pulmonary artery catheter had been removed (four cases). There were no episodes of CHB related to the pulmonary artery catheterization procedure in the patients with either old LBBB or indeterminate-aged LBBB. There were two episodes of CHB in patients with new LBBB. In both patients, the CHB occurred one day after the pulmonary artery catheter had been inserted. In both patients, CHB developed after episodes of ventricular tachycardia that eventually resulted in their deaths. Although it is unlikely, we could not rule out the possibility that the CHB was related to the presence of the pulmonary artery catheter. We conclude that the incidence of CHB complicating pulmonary artery catheterization with balloon-tipped, flow-directed catheters in critically ill patients with old or indeterminate-aged LBBB is extremely low. Therefore, we do not recommend the routine placement of a temporary transvenous pacemaker in all patients with LBBB prior to pulmonary artery catheterization.

Aged↗
PubMed2005

Common arterial trunk associated with a homeodomain mutation of NKX2.6.

Persistent truncus arteriosus (PTA) is a failure of septation of the cardiac outflow tract (OFT) into the pulmonary artery and the aorta. A common arterial trunk (CAT) is often diagnosed as PTA in the absence of evidence of embryological mechanism. We have used autozygosity mapping of a large consanguineous family segregating CAT to map the causative locus to chromosome 8p21. An F151L mutation was identified in the homeodomain of NKX2.6, a transcription factor expressed in murine pharyngeal endoderm and embryonic OFT myocardium. Although expression of Nkx2.6 during murine embryogenesis is strongly suggestive of a role for this gene in heart development, mice homozygous for a targeted mutation of Nkx2.6 are normal. However, in these mice, it has been shown that Nkx2.5 expression expands into regions lacking Nkx2.6, suggesting functional complementation. As transcriptional targets of NKX2.6 are unknown, we investigated functional effects of the mutation in transcriptional and protein interaction assays using NKX2.5 as a surrogate. Introduction of F157L into human NKX2.5 substantially reduced its transcription activating function, its synergism with partners at the atrial natriuretic factor (ANF) and connexin-40 (Cx40) promoters and its specific DNA binding. We tested NKX2.5 target promoters for NKX2.6 activity. NKX2.6 was inactive at ANF but weakly activated transcription of a Cx40 promoter, whereas the F151L mutant lacked this activity. These findings indicate a previously unsuspected role for NKX2.6 in heart development, which should be re-evaluated in more sophisticated model systems.

Amino Acid Sequence↗
PubMed2000

Transcriptional regulation of human cardiac homeobox gene CSX1.

Cardiac homeobox gene Csx/Nkx-2.5 is essential for normal heart development and morphogenesis and is the earliest marker for cardiogenesis. To elucidate the regulatory mechanisms of Csx/Nkx-2.5 expression, we have isolated and characterized the upstream regulatory region of human Csx/Nkx-2.5 (CSX1). Transfection of the reporter gene containing a 965-bp CSX1 5' flanking region indicated that this region confers cardiomyocyte-predominant expression of CSX1. Deletion and mutational analyses revealed two positive cis-regulatory elements in this region that are essential for CSX1 expression in cardiomyocytes. Electrophoretic mobility shift assay revealed that nuclear proteins prepared from cardiac myocytes bound to these elements in a sequence-specific manner. The identification of cis-regulatory sequences of the Csx/Nkx-2.5 gene will facilitate further analysis for the upstream regulatory factors that control the expression of Csx/Nkx-2.5 and the process of vertebrate heart development.

Animals↗
PubMedDate not supplied

[The immune and fibrinolytic systems in heart failure developing against a background of cardiac atherosclerosis].

A study made to gain insight into the bodily immune and fibrinolytic systems in 72 patients with cardiac insufficiency developed against the background of cardial atherosclerosis showed imbalance in the ratio of cellular to humoral links of immunity and enhancement of the autoimmune processed activity, inhibition of activity of the monocytomacrophagal link. Disturbances in the fibrinolytic system were manifested by blood and urine lowering of activity of the plasminogen activator, with the antiplasmin activity being on the decrease as well, which fact is regarded as formation of a new stationary state in the system of haemocoagulation maintaining hemostasis.

Adolescent↗
PubMed1989

Complete heart block developing during aortic valvuloplasty.

We report the occurrence of CHB consequent to ABV in an 80-year-old white woman with calcific aortic stenosis. The patient underwent ABV with a balloon 20 mm in diameter, resulting in only a modest increase in aortic valve area and a decrease in aortic valve gradient. The procedure was complicated by transient intermittent CHB which required temporary transvenous pacemaking and resolved within 72 hours. A second ABV was performed four weeks later with a balloon 23 mm in diameter. This was complicated by persistent CHB which required placement of a dual-chamber pacemaker.

Aged↗