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[Modern development of cardiac pacing].

In the submitted review the author presents after a historical introduction the contemporary possibilities of permanent pacing. He mentions the main reasons why a fixed rate pacing without atrioventricular synchronization is unphysiological and led to the development of dual chamber DDD pacemakers and ventricular pacemakers with a variable frequency of pacing. The main contribution of this so-called physiological pacing is an increase of the cardiac output and the work capacity of patients, as compared with fixed rate pacing. The author present also examples of diagnostic and antitachycardiac stimulation and discusses possibilities of their combination with an implantable cardioverter-defibrillator in ventricular tachyarrhythmias.

Cardiac Pacing, Artificial↗

[Cardiotoxicity due to prolonged administration of THP (2"R-4'-O-tetrahydropyranyl-adriamycin)].

The effect of the anthracycline analogue, pirarubicin, on cardiac function was examined. One hundred and four patients with gynecologic malignancies were treated with 40-50 mg/body THP ADM every 3 to 4 weeks by iv bolus injection. Three out of 104 cases that had developed cardiac failure received more than 1,500 mg. One case receiving 1,340 mg developed cardiac failure and expired 3 years after completion of treatment for malignancy. From the above experience, it is concluded that the MTD of pirarubicin seems to be 1,500 mg/body or 1,100 mg/m2.

Adult↗

Beneficial effect of perindopril, an angiotensin-converting enzyme inhibitor, on left ventricular performance and noradrenaline myocardial content during cardiac failure development in the rat.

The left coronary artery in rats was ligated for a period of 15 days to induce hypertrophy of the non-infarcted myocardium. Left ventricular performances were evaluated in the working heart model. In addition, cardiac hypertrophic indices and noradrenaline content were measured. Variables were determined in the absence or presence of the angiotensin-converting enzyme inhibitor, perindopril. A 35 and 60% decrease in the coronary and cardiac output, respectively, and a 57% decrease in the noradrenaline content of the non-infarcted left ventricular free wall were seen. Furthermore, a 15% increase in the heart/body weight ratio was observed in the infarcted group. After chronic treatment of the animals with perindopril (2 mg.kg-1 body weight, per os), coronary and cardiac output were impaired to a lesser extent: 8 and 35% respectively, with only a 15% decrease in the noradrenaline content of the non-infarcted left ventricular free wall. Furthermore, the increase in heart/body weight ratio was significantly less than in the nontreated infarct group (7%). We conclude that the beneficial effects of converting enzyme inhibition, during the development of myocardial infarction, on left ventricular performances are associated with a decrease in the hypertrophic indices and a normalization of sympathetic activity.

Angiotensin-Converting Enzyme Inhibitors↗

Atrial natriuretic peptide accelerates proliferation of chick embryonic cardiomyocytes in vitro.

The developing embryonic heart has been reported to contain significant levels of atrial natriuretic peptide (ANP). In this study, the role of ANP in cardiac development was evaluated using cultured cardiomyocytes isolated from chick embryos. We analyzed the effect of ANP on cell number, DNA synthesis, total RNA level, the expression of cell-cycle-specific and sarcomeric proteins, and levels of lactate dehydrogenase and creatine phosphokinase. ANP increased overall DNA synthesis (measured by BrdU incorporation, P < 0.01) and enhanced cell proliferation. Morphologically, the development of the cardiomyocyte network was distinctly enhanced in the ANP-treated cells. Cellular RNA content was elevated; likewise, myosin and tropomyosin biosynthesis was significantly greater in ANP-treated cells. In addition, expression of G1/S-specific protein increased, whereas G2/M-specific protein remained unchanged by ANP treatment. An antibody against ANP and a specific ANP receptor antagonist, HS-142-1, antagonized and/or attenuated the action of ANP on both cell proliferation and protein biosynthesis. These results indicate that ANP accelerates myocardial cell proliferation by enhancing entry into S phase and by increasing DNA synthesis during S phase specifically through receptor mediated pathway. The in vitro effects of ANP on myocardial cell proliferation, together with the elevated levels of ANP seen in vivo during normal heart formation, suggest a possible autocrine function of ANP in embryonic cardiac development.

Animals↗

Hairy-related transcription factors inhibit GATA-dependent cardiac gene expression through a signal-responsive mechanism.

Combinatorial actions of transcription factors in multiprotein complexes dictate gene expression profiles in cardiac development and disease. The Hairy-related transcription factor (HRT) family of basic helix-loop-helix proteins is composed of transcriptional repressors highly expressed in the cardiovascular system. However, it has remained unclear whether HRT proteins modulate gene expression driven by cardiac transcriptional activators. Here, we have shown that HRT proteins inhibit cardiac gene transcription by interfering with GATA transcription factors that are implicated in cardiac development and hypertrophy. HRT proteins inhibited GATA-dependent transcriptional activation of cardiac gene promoters such as the atrial natriuretic factor (ANF) promoter. Adenovirus-mediated expression of Hrt2 suppressed mRNA expression of ANF and other cardiac-specific genes in cultured cardiomyocytes. Among various signaling molecules implicated in cardiomyocyte growth, constitutively active Akt1/protein kinase B alpha relieved Hrt2-mediated inhibition of GATA-dependent transcription. HRT proteins physically interacted with GATA proteins, and the basic domain of HRT was critical for physical association as well as transcriptional inhibition. These results suggest that HRT proteins may regulate specific sets of cardiac genes by modulating the function of GATA proteins and other cardiac transcriptional activators in a signal-dependent manner.

Animals↗

Indirect recognition of allopeptides promotes the development of cardiac allograft vasculopathy.

Graft loss from chronic rejection has become the major obstacle to the long-term success of whole organ transplantation. In cardiac allografts, chronic rejection is manifested as a diffuse and accelerated form of arteriosclerosis, termed cardiac allograft vasculopathy. It has been suggested that T-cell recognition of processed alloantigens (allopeptides) presented by recipient antigen-presenting cells through the indirect pathway of allorecognition plays a critical role in the development and progression of chronic rejection. However, definitive preclinical evidence to support this hypothesis is lacking. To examine the role of indirect allorecognition in a clinically relevant large animal model of cardiac allograft vasculopathy, we immunized MHC inbred miniature swine with synthetic polymorphic peptides spanning the alpha(1) domain of an allogeneic donor-derived swine leukocyte antigen class I gene. Pigs immunized with swine leukocyte antigen class I allopeptides showed in vitro proliferative responses and in vivo delayed-type hypersensitivity responses to the allogeneic peptides. Donor MHC class I disparate hearts transplanted into peptide-immunized cyclosporine-treated pigs not only rejected faster than unimmunized cyclosporine-treated controls (mean survival time = 5.5 +/-1.7 vs. 54.7 +/-3.8 days, P < 0.001), but they also developed obstructive fibroproliferative coronary artery lesions much earlier than unimmunized controls (<9 vs. >30 days). These results definitively link indirect allorecognition and cardiac allograft vasculopathy.

Animals↗

Neurotrophin-3 and TrkC are expressed in the outflow tract of the developing chicken heart.

Transcripts encoding trkC and full-length (catalytic) TrkC receptors were detected in the outflow tract of the chicken heart during early development (stage 17; embryonic day [E] 2.5) before the start of septation. Expression of trkC mRNA persisted through early septation (stage 25, E4.5-E5) but was no longer evident by the end of septation (stage 34, E8). Neurotrophin-3 (NT-3) mRNA was also shown to be present in the outflow tract throughout cardiac development. Quail-chick chimeras were used to confirm that cardiac neural crest cells were not present in the outflow tract at stage 17 (E2.5). Our results show that NT-3 interacts with cells in the outflow tract that are not of neural crest origin. This finding indicates that, in addition to effects on neural crest cells, NT-3 may be important for cardiac development due to its interaction with cells in the outflow tract such as those arising from the secondary heart field.

Animals↗

[Differentiation of cardiomyocyte].

In the recent decade, remarkable progress has been made in the field of cardiac development through the use of molecular, biological and genetic techniques. Several genes that regulate this process have been cloned, and their functions have been analyzed in vivo and in vitro. Cardiac-specific transcription factors, including Csx/Nkx-2.5, GATA4, MEF2 and dHAND/eHAND, play central roles in cardiac development. Loss-of-function of gain-of-function studies have revealed that these factors regulate heart morphogenesis and cardiac-specific gene expressions. Cardiac-specific genes, including MLC2v, cardiac alpha-actin and ANP, have specific binding sequences for transcription factors in their promoter regions and expressions of these genes are regulated by binding of transcription factors. In addition to the transcription factors, growth factors secreted from ectoderm and endoderm play important roles in induction of cardiomyocytes. Decapentaplegic and bone morphogenetic proteins, members of the transforming growth factor-beta superfamily, induce the expression of cardiac-specific transcription factors in the precardiac mesodrem and are indispensable to cardiomyocyte differentiation. We think that understanding the genetic cascade of cardiomyocyte differentiation will open the gate for cardiomyogenesis from non-cardiac cells.

Animals↗

Ultrastructural analysis of development of myocardium in calreticulin-deficient mice.

BACKGROUND: Calreticulin is a Ca2+ binding chaperone of the endoplasmic reticulum which influences gene expression and cell adhesion. The levels of both vinculin and N-cadherin are induced by calreticulin expression, which play important roles in cell adhesiveness. Cardiac development is strictly dependent upon the ability of cells to adhere to their substratum and to communicate with their neighbours. RESULTS: We show here that the levels of N-cadherin are downregulated in calreticulin-deficient mouse embryonic hearts, which may lead to the disarray and wavy appearance of myofibrils in these mice, which we detected at all investigated stages of cardiac development. Calreticulin wild type mice exhibited straight, thick and abundant myofibrils, which were in stark contrast to the thin, less numerous, disorganized myofibrils of the calreticulin-deficient hearts. Interestingly, these major differences were only detected in the developing ventricles while the atria of both calreticulin phenotypes were similar in appearance at all developmental stages. Glycogen also accumulated in the ventricles of calreticulin-deficient mice, indicating an abnormality in cardiomyocyte metabolism. CONCLUSION: Calreticulin is temporarily expressed during heart development where it is required for proper myofibrillogenesis. We postulate that calreticulin be considered as a novel cardiac fetal gene.

Animals↗

Microtubules in cardiac toxicity and disease.

Microtubules (MTs) are dynamic, cytoskeletal fibers that are found in every eukaryotic cell type. MTs serve a wide range of functions, including cell division, membrane and vesicle transport, and motility. As such, MTs play pivotal roles in cardiac development and function. Agents that disrupt normal MT function, including such therapeutic agents as vincristine and paclitaxel, have also been shown to affect essential cardiac activities such as sarcomere mechanics, beat rate, and the secretion of important molecules (e.g., atrial natriuretic factor). Disease states that lead to either ischemia- or pressure overload- induced cardiac hypertrophy also alter the microtubule cytoskeleton in several ways. A fuller understanding of the contributions of MTs to cardiac development and function will be necessary to minimize the deleterious side effects of the therapeutic application of MT-disrupting drugs. This review summarizes current hypotheses and experimental results that demonstrate the central role of MTs in heart cell function and disease.

Growth↗

Calreticulin in the heart.

Calreticulin is a Ca2+ binding/storage chaperone resident protein of the endoplasmic reticulum. This protein plays a key role in the calreticulin/calnexin cycle and the quality control pathways in the endoplasmic reticulum. Calreticulin deficiency is lethal due to impaired cardiac development. However, over-expression of the protein in developing and postnatal heart leads to bradycardia, complete heart block and sudden death. Ultrastructural evidence indicates that the deficiency associated with the absence of calreticulin in the heart may be due to a defect in the development of the contractile apparatus and/or a defect in development of the conductive system as well as a metabolic abnormality. Collectively, we postulate that calreticulin and endoplasmic reticulum plays an important role in cardiac development and postnatal pathologies.

Animals↗

How congenital heart disease originates in fetal life.

Knowledge of the early development of the heart has increased rapidly in recent years as microscopic techniques, experimental models using animal, avian and insect species, and various genetic techniques have been brought to bear on the mysteries of human fetal cardiac development. The development of the heart occurs rapidly from embryonic day 18 in humans to the twelfth week of fetal life. The stages include gastrulation and formation of the primitive heart tube with rhythmic contractions appearing at day 21, segmentation of the primitive heart tube, looping, realignment of inflow and outflow segments, septation of the atria, ventricles and outflow segments, formation of atrio-ventricular valves, and development of aortic and pulmonary trunks and aortic arches. The genes and factors currently known to be involved in cardiac development are reviewed, but much is still to be determined as the field is evolving with extraordinary rapidity.

Aorta↗

Molecular cloning and developmental expression of rat glycogenin in cardiac tissue.

Glycogenin is a self-glycosylating protein required to initiate glycogen biosynthesis. Utilizing the differential display technique to analyze changes in gene expression during early postnatal cardiac development, we have isolated and cloned a 484 bp cDNA fragment that corresponds to the 3' end of rat glycogenin. Northern blot analysis on neonatal cardiac tissues demonstrated hybridization to a 1.7-1.8 kb transcript, which was highly expressed at 3 days and at progressively reduced levels at 1, 2, 3 and 4 weeks of age. A 1624 bp fragment of rat glycogenin was cloned by RT-PCR that includes a 1002 bp open reading frame encoding a 333 amino acid protein. At the nucleotide level, rat glycogenin exhibited 87.2 and 83.6% identity with human and rabbit glycogenin over the open reading frame. The deduced amino acid sequence showed 86.7 and 83.4% identity with human and rabbit sequences, respectively. Given the significance of glycogenin in glycogen biosynthesis, the results of this study suggest a possible molecular basis for the regulation of glycogen during early postnatal cardiac development. In addition, the nucleotide and amino acid sequences of rat glycogenin may be used to investigate the physiological and pathophysiological roles of glycogenin in rat tissues.

Amino Acid Sequence↗

Detection of myosin gene expression in the developing heart using probes derived by polymerase chain reaction.

The polymerase chain reaction provides a rapid method for the molecular cloning of DNA probes suitable for the detection of specific messenger RNA. We have used this approach to prepare probes specific for human cardiac myosin messenger RNA and demonstrate here the use of such probes in the analysis of human cardiac development by hybridization in situ to sections of fetal tissue. This combination of techniques is suitable for the detection of any messenger RNA for which sequence data are available, and offers a powerful new approach to the analysis of cardiac development.

Fetal Heart↗

Anthracycline induced myocardial damage. An analysis of 16 autopsy cases.

The hearts of 16 autopsy cases with a past history of administration of anthracycline antitumor drugs (DNR, ADR and ACM) and a sign of cardiac failure were investigated morphologically. In macroscopic observation, both ventricles were more or less dilated with thinning of the ventricular wall. Mural thrombi were recognized in the left ventricle of 2 cases. Histologically, the myocardial lesions could be roughly classified into two groups, a) myocardial changes in cases with rapidly developed cardiac failure (acute form), and b) myocardial changes in cases with relatively slowly developed cardiac failure. In acute form, myocardial cells showed marked swelling with dilatation of central sarcoplasmic core, marked reduction of myofibrils, vacuolization of cytoplasm and enlargement of nucleus accompanied by distinct large nucleolus. Necrotic myocardial cells were scattered among these degenerative cells. These degenerative and necrotic cells were distributed diffusely in both ventricular walls, but were more frequent in the left ventricular wall than in the right one. Inflammatory cell infiltration was also recognized not only in the myocardium, but also in the endocardium and epicardium. In chronic form, on the other hand, atrophy and attenuation of myocardial cells with a hypereosinophilic change of the cytoplasm and an increase in number of brown pigments, and marked reduction of myocardial cells were most common findings. These changes of chronic form, however, could not be identified as the specific changes of anthracycline cardiotoxicity. Fibrosis was hardly seen in the myocardium of both acute and chronic forms.

Aclarubicin↗

Differentiation of pluripotent embryonic stem cells into cardiomyocytes.

Embryonic stem (ES) cells have been established as permanent lines of undifferentiated pluripotent cells from early mouse embryos. ES cells provide a unique system for the genetic manipulation and the creation of knockout strains of mice through gene targeting. By cultivation in vitro as 3D aggregates called embryoid bodies, ES cells can differentiate into derivatives of all 3 primary germ layers, including cardiomyocytes. Protocols for the in vitro differentiation of ES cells into cardiomyocytes representing all specialized cell types of the heart, such as atrial-like, ventricular-like, sinus nodal-like, and Purkinje-like cells, have been established. During differentiation, cardiac-specific genes as well as proteins, receptors, and ion channels are expressed in a developmental continuum, which closely recapitulates the developmental pattern of early cardiogenesis. Exploitation of ES cell-derived cardiomyocytes has facilitated the analysis of early cardiac development and has permitted in vitro "gain-of-function" or "loss-of-function" genetic studies. Recently, human ES cell lines have been established that can be used to investigate cardiac development and the function of human heart cells and to determine the basic strategies of regenerative cell therapy. This review summarizes the current state of ES cell-derived cardiogenesis and provides an overview of how genomic strategies coupled with this in vitro differentiation system can be applied to cardiac research.

Animals↗