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NF-kappaB signaling blockade by Bay 11-7085 during early cardiac morphogenesis induces alterations of the outflow tract in chicken heart.

UNLABELLED: Nuclear factor kappaB (NF-kappaB) is a pleiotropic transcription factor implicated in the regulation of diverse morphologic cardiac alterations, for which the p50 and p65 subunits form the most prevalent dimeric form in the heart. NF-kappaB is inactivated by proteins of the IkappaB family, which trap it in the cytoplasm. It is not known whether NF-kappaB influences cardiac development. OBJECTIVE: Here we investigated the role of NF-kappaB in regulating transcription in chicken heart morphogenesis. Specifically, we tested whether NF-kappaB activation is required for normal formation of the outflow tract (OFT) during a critical stage of heart development. METHODS AND RESULTS: We designed a reporter vector with kappaB binding sites for Rel family members in the promoter, upstream from the cDNA of Green Fluorescent Protein (GFP). This construct was injected directly into the developing heart of chicken embryos. NF-kappaB activation was subsequently inhibited by administration of the specific pharmacological agent Bay 11-7085. We found that forced NF-kappaB expression was associated with multiple congenital cardiac alterations of the OFT (mainly IVC, DORV and great arteries stenosis). CONCLUSION: These findings indicate that blockade of NF-kappaB induces apoptosis and is an important factor in the development of OFT during cardiogenesis. However, it remains unknown which members of the Rel family are relevant in this process.

Animals↗

Limb growth and cardiac complications of fistulas in children.

To assess the long term effects of arteriovenous (AV) fistulas placed in children for hemodialysis, we retrospectively evaluated 26 patients, ages 4 to 20 years, for: limb growth, evidence of excessive flow through the fistula, limb function and patient acceptance of the limb's appearance. The fistulas were created an average of 31 months prior to the study. Fourteen patients had wrist fistulas. Twelve patients had PTFE grafts; 5 in the upper thigh and 7 in the upper arm. Of the 5 patients with thigh PTFE fistulas, 3 developed ipsilateral limb hypertrophy, another developed cardiac failure and the other had excessive flow through the fistula without cardiac failure. One of the 7 children with an upper arm PTFE graft developed arm edema without hypertrophy. Two of the 14 children with wrist fistulas developed evidence of excessive flow through the fistula. Six of 26 patients (23%) required fistula ligation because of a complication.

Adolescent↗

Persistent cardiac and urinary tract infections with Borrelia burgdorferi in experimentally infected Syrian hamsters.

The heart can be severely affected in humans with Lyme disease, causing conduction defects and, rarely, heart failure. Although immunodeficient and young mice may develop cardiac lesions, cultivation of Borrelia burgdorferi from cardiac tissues of experimentally infected animals has not been reported previously. We infected Syrian hamsters with B. burgdorferi 297 and found a marked tropism of the spirochete for myocardial and urinary tract tissues. Fifty-six of 57 hearts (98%) and 52 of 58 bladders (90%) were culture positive. The cardiac infection was persistent and could be documented in 21 of 22 hearts (96%) cultured from days 28 to 84 postinfection. The urinary tract was also a site of persistent infection in most animals, with 18 of 23 bladders (78%) being culture positive from days 28 to 84. The persistence of spirochetes was specific for the heart and bladder, as indicated by negative cultures of specimens from the liver and spleen, in which only 1 of 23 cultures was positive from days 28 to 84. Because of the high isolation rates, tropism, and persistence that we found for B. burgdorferi in the hamster heart and bladder, these sites will be useful and important for the cultivation of spirochetes in experimental studies that evaluate the efficacies both of candidate vaccines in preventing infection and of antibiotics in eradicating organisms from privileged sites. In addition, the clear demonstration of persistent cardiac infection with B. burgdorferi may provide a useful model for studying the pathogenesis of cardiac Lyme disease.

Animals↗

Functional analysis and chromosomal mapping of Gata5, a gene encoding a zinc finger DNA-binding protein.

The GATA family of zinc finger proteins are transcriptional regulators with critical functions in lineage differentiation and embryonic development. Based on structural and expression pattern comparisons, the GATA proteins have been subdivided into two groups. The first subgroup consists of GATA-1, -2, and -3, which are all highly expressed in the hematopoietic system, whereas GATA-4, -5, and -6 are present essentially in the heart and gut. We have isolated and functionally characterized the rat GATA-5 cDNA, which encodes a 45-kDa protein with 71%, 73%, and 97% homology to its amphibian, avian, and murine homologs, respectively. Northern blot analysis showed that rat GATA-5 is expressed in a dynamic pattern during embryonic and postnatal development. In the midgestation embryo, GATA-5 transcripts are most abundant in the heart and decrease dramatically in the postnatal heart; in contrast, GATA-5 expression is upregulated in the lung and gut during postnatal development. Functional studies with recombinant GATA-4, -5, and -6 proteins show that GATA-5 has preferential affinity for a subset of GATA elements found on cardiac promoters and differentially activate cardiac gene transcription. Structure-function analysis revealed the presence of an activation domain within the carboxy terminal region of GATA-5 that is essential for transcriptional regulation of target promoters. Linkage analysis localized Gata5 to distal mouse Chromosome (Chr) 2 in a conserved linkage group with genes localized to rat Chr 3q43 and human Chr 20q13.2-q13.3. The results suggest that GATA-5 may have specific downstream targets and that GATA-4, -5, and -6 can only partially substitute for each other in cardiogenesis. Thus, Gata5 probably plays a specialized evolutionary conserved role in cardiac development.

Amino Acid Sequence↗

The resuscitation greats. Cemil Topuzlu Pasha: one of the forgotten pioneers in the history of open chest cardiac massage.

One of the pioneers of open chest cardiac massage was Cemil Topuzlu Pasha, in Turkey. He presented his experience in open heart cardiac massage in several papers published in Ottoman and French and German. On 27 August 1903 one of his patients undergoing external urethrotomy under chloroform anaesthesia developed cardiac arrest and he performed open chest cardiac massage. He reported his approach to this event and discussed the literature regarding resuscitation available at the beginning of 20th century. Meanwhile he had defined "Do Not Resuscitate" code in cases involving serious heart disease and other diseases where life expectancy is very short. The Ottoman version of his report is translated in this paper.

Anesthesia↗

Transient erythroblastopenia in a child with Kawasaki syndrome: a case report.

PURPOSE: We describe for the first time the case of a child with Kawasaki syndrome and associated transient erythroblastopenia. PATIENTS AND METHODS: A 5 1/2-month-old infant with Kawasaki syndrome as evidenced by lymphadenopathy, fever, rash conjunctival injection, and extremity changes had associated anemia and reticulocytopenia requiring transfusion and thrombocytopenia. Bone marrow aspiration was consistent with a transient erythroblastopenia. She developed cardiac aneurysms despite therapy with i.v. immunoglobulin and aspirin. RESULTS: The anemia and reticulocytopenia resolved with normalization of her hemoglobin. The platelet count increased and she developed a thrombocytosis characteristic of this clinical entity. She completely recovered without recurrence of either the anemia or reticulocytopenia. CONCLUSIONS: We speculate that the cause of the erythroblastopenia and thrombocytopenia is an inflammatory insult of Kawasaki syndrome on the bone marrow and its various lineages causing the myriad hematological abnormalities now associated with Kawasaki syndrome. It is possible that the i.v. immunoglobulin aids in neutralizing the triggering agent and therefore shortening the duration of the marrow insult.

Female↗

Disruption of COX-2 modulates gene expression and the cardiac injury response to doxorubicin.

To determine the role of cyclooxygenase (COX)-2 in anthracycline-induced cardiac toxicity, we administered doxorubicin (Dox) to mice with genetic disruption of COX-2 (COX-2-/-). After treatment with Dox, COX-2-/- mice had increased cardiac dysfunction and cardiac cell apoptosis compared with Dox-treated wild-type mice. The expression of the death-associated protein kinase-related apoptosis-inducing protein kinase-2 was also increased in Dox-treated COX-2-/- animals. The altered gene expression, cardiac injury, and dysfunction after Dox treatment in COX-2-/- mice was attenuated by a stable prostacyclin analog, iloprost. Wild-type mice treated with Dox developed cardiac fibrosis that was absent in COX-2-/- mice and unaffected by iloprost. These results suggest that genetic disruption of COX-2 increases the cardiac dysfunction after treatment with Dox by an increase in cardiac cell apoptosis. This Dox-induced cardiotoxicity in COX-2-/- mice was attenuated by a prostacyclin analog, suggesting a protective role for prostaglandins in this setting.

Animals↗

Cardiac toxicity related to cancer treatment.

Cardiac toxicity is a dose-limiting toxicity that may occur during cancer treatment or several years after therapy ends. Cardiac toxicity may be caused by chemotherapy, biotherapy, and radiation therapy and may result in cardiomyopathy, congestive heart failure, dysrhythmias, and myocardial ischemia. The risk for developing cardiac toxicity varies based on type of treatment, patient age, presence of preexisting or concurrent heart disease, and concomitant treatment. Patients at high risk require careful evaluation and monitoring during and in the years following therapy to detect cardiac changes. Fortunately, cardioprotective agents and newer radiation therapy techniques decrease the risk for treatment-related cardiac toxicity. Oncology nurses can become more informed in the assessment of cardiac toxicity and can arm themselves with knowledge about early identification of symptoms as well as specific agents and treatments that increase risk for cardiac toxicity.

Adolescent↗

Pericardial effusion as a cause of morbidity in patients on maintenance hemodialysis: is it preventable?

OBJECTIVE: Cardiovascular diseases are the cause for 45% mortality and 20% morbidity in hemodialysis (HD) patients. Pericardial effusion (PE) accounts for 03-04% of all deaths in HD patients as a result of tamponade, arrhythmias or heart failure. This study aims to find out the prevailance and precipitating factors for PE in hemodialysis patients. PATIENTS AND METHODS: Fifty-five patients were identified for echo-cardiographic assessment on the basis of signs and symptoms suggestive of PE i.e., hypotension during dialysis, dyspnea, globular heart in chest x-ray, raised JVP, soft heart sounds and low voltage ECG. A matched controlled group of 55 patients for age, sex, dialysis schedule, cause of ESRD and dialysis bath, was also studied echocardiographically. RESULTS: Pericardial Effusion was detected in 12 patients (10.9%), 10 (83.3%) were on 2/week and only two on 3/week dialysis. Of these 75% were non-compliant in fluid intake and 58.3% were irregular in treatment. The morbidity of PE in study group (18.2%) is significantly higher as compared to controls (3.6%) (P = < 0.05). No correlation was found between development of PE and high iPTH and low albumin levels. Ten patients with mild PE responded to vigorous dialysis. Two patients developed cardiac tamponade needing pericardiocentesis. CONCLUSION: We have identified 2/week dialysis (inadequate dialysis dose), acetate bath and fluid and dialysis non-compliance as factors contributing to development of PE in HD patients.

Adult↗

[Acute pulmonary edema following airway obstruction and cardiac tamponade related to mediastinal tumor].

A case is reported of acute airway obstruction and pulmonary oedema of mixed origin (cardiogenic and non cardiogenic), occurring in a patient after surgical treatment for pericardial tamponade due to a mediastinal tumour. This 45 year old female patient had a non-Hodgkin lymphoma, mostly located within the anterior and middle mediastinum. When she developed cardiac tamponade, emergency cardiac decompression was carried out. The surgical procedure went well, despite an episode of severe hypotension. Immediately after extubation, she developed paradoxical breathing with retraction and cyanosis. She was reintubated and ventilated. The chest X-ray showed bilateral alveolar infiltrates, mostly around the hilar. Two hours later, she was again extubated and developed again the same respiratory failure. This time, she was intubated and ventilated for 48 h. She was then extubated with no problem. It seemed most probable that transmission to the interstitial space of a negative intrapleural pressure due to the inspiratory efforts made against an occluded airway was the principal mechanism responsible for the accumulation of fluid to this space.

Airway Obstruction↗

Wnt signal transduction and the formation of the myocardium.

Soon after fertilization, vertebrate embryos grow very rapidly. Thus, early in gestation, a sizeable yet underdeveloped organism requires circulating blood. This need dictates the early appearance of a contractile heart, which is the first functional organ in both the avian and mammalian embryo. The heart arises from paired mesodermal regions within the anterior half of the embryo. As development proceeds, these bilateral precardiac fields merge at the midline to give rise to the primary heart tube. How specific areas of nondifferentiated mesoderm organize into myocardial tissue has been a question that has long intrigued developmental biologists. In recent years, the regulation of Wnt signal transduction has been implicated as an important event that initiates cardiac development. While initial reports in Drosophila and the bird had implicated Wnt proteins as promoters of cardiac tissue formation, subsequent findings that the WNT inhibitors Dkk1 and crescent possess cardiac-inducing activities led to the contrary hypothesis that WNTs actively inhibit cardiogenesis. This seeming contradiction has been resolved, in part, by more recent information indicating that Wnts stimulate multiple signal transduction pathways. In this review, we will examine what is presently known about the importance of regulated Wnt activity for the formation of the heart and the development of the myocardium and discuss this information in context of the emerging complexity of Wnt signal transduction.

Animals↗

GDNF family receptors in the embryonic and postnatal rat heart and reduced cholinergic innervation in mice hearts lacking ret or GFRalpha2.

Members of the GDNF family, which are important during peripheral nervous system development and kidney organogenesis, signal via Ret and GFRalpha receptors. Here we have studied their possible role in heart development. Gfra1 was expressed in the endocardial cushion mesenchyme at E12 and later, in the developing and mature valves, and in the walls of the aorta and the pulmonary trunk. Gfra2 was expressed in the outer layers of the aorta and pulmonary trunk and in the valves at E18-P60. Endocardial cells showed moderate Gfra2 mRNA and protein expression between E12 and E15. Gfra3 mRNA was detected, mainly postnatally, in scattered cells of the atria and the great vessels. In embryonic and postnatal rat cardiac ganglia, Ret and Gfra2 transcripts were seen in the neurons, whereas Gfra1 and Gfra3 mRNA were preferentially found in non-neuronal cells within the ganglia. GFRalpha2 immunoreactivity was seen in both cardiac ganglion neurons and their nerve fibers. There were no obvious non-neuronal defects in hearts of Ret-, GFRalpha1-, or GFRalpha2-deficient mice, suggesting that these receptors are not essential for gross cardiac development. However, E18 Ret-deficient mice exhibited a reduced volume of cardiac ganglia and cholinergic innervation of the ventricular conduction system. Moreover, adult Gfra2(-/-) mice showed reduced cholinergic innervation by 40% in their ventricles and by 60% in the ventricular conduction system. These findings indicate that GFRalpha2/Ret signaling is required for normal cholinergic innervation of heart.

Animals↗

Role of FK506-binding protein 12 in development of the chick embryonic heart.

A cDNA encoding chicken FK506-binding protein 12 (FKBP12) was isolated and sequenced. The predicted amino acid sequence of the chicken protein shows high homology to those of FKBP12 proteins of other species ranging from human to frog. The possible role of FKBP12 in chick embryonic cardiac development was examined. Northern blot analysis revealed that FKBP12 mRNA is distributed widely in chick embryos, being especially abundant in the heart; the amount of FKBP12 mRNA in the embryonic heart decreased with time. Administration of FK506 to chick embryos at 7 to 9 days resulted in marked cardiac enlargement. FK506 also reduced the expression of myosin, induced a more elongated cell morphology, and impaired network formation in cultured chick embryonic cardiomyocytes. These results suggest that FKBP12 is important in the regulation of contractile function and phenotypic expression in chick cardiomyocytes during embryonic development.

Amino Acid Sequence↗

Clinical usefulness of the cardiac multi-detector-row CT.

Along with improvement of the temporal and special resolution, multi-detector-row CT has become able to generate artifact-less heart images. We discuss the potential benefits of the newly developed cardiac application, demonstrating informative cases.Two- and three-dimensional (2D and 3D) cardiac images were produced throughout one cardiac cycle. By paging 2D and 3D images in cardiac cycle order, animated movies were generated. Cardiac imaging with multi-detector-row CT, acquired during a single breath hold, provides information about: (1) clear morphology of heart chambers and myocardium, (2) wall motion and systolic thickening, (3) myocardial perfusion, (4) volume assessment, and (5) coronary anatomy and pathophysiology.

Female↗

Cardiac perforation associated with continuous infusional chemotherapy.

The case history is reported of a 51-year-old man with metastatic colonic carcinoma who was receiving a continuous 5-fluorouracil infusion via a central venous catheter and who developed cardiac perforation and pericardial effusion. This complication has not previously been reported in association with continuous chemotherapy infusion.

Antineoplastic Agents↗

Examination of the in vivo cardiac electrophysiological effects of nesiritide (human brain natriuretic peptide) in conscious dogs.

BACKGROUND: Human brain natriuretic peptide (hBNP) is a new therapeutic agent, nesiritide, indicated in patients with decompensated congestive heart failure, a group at significant risk of developing cardiac arrhythmias. Whether hBNP has cardiac electrophysiologic effects has not been reported. METHODS AND RESULTS: In 9 healthy, chronically instrumented, conscious dogs, hemodynamic and electrophysiologic parameters were assessed at baseline and during recombinant hBNP (nesiritide) infusion at 0.03 and 0.09 microg/kg/min after 1 hour at each dose. Infusion of hBNP produced dose-related increases (P <.001) in hBNP and cyclic GMP plasma levels and reductions (P <.05) in mean arterial pressure. Mean central venous pressure and sinus cycle length did not change significantly. Infusion of hBNP produced no significant changes in any of the electrophysiologic parameters including no change in surface ECG variables (P wave duration, PR interval, QRS duration, and QTc interval), corrected sinus node recovery time, atrioventricular nodal Wenckebach cycle length, and atrial and ventricular effective refractory periods measured at a 400 ms cycle length. Spontaneous or induced arrhythmias were not observed during hBNP infusion. CONCLUSIONS: In conscious, healthy dogs, short-term infusion of recombinant hBNP has no significant effects on atrial or ventricular electrophysiologic parameters.

Animals↗

A rational screening and treatment strategy based on the electrocardiogram alone for suspected cardiac contusion.

The charts of 71 patients admitted to one teaching institution over a 4-year period with a primary or secondary diagnosis of "rule out cardiac contusion" and of another 62 admitted to a second institution with more severe injuries and suspicion of cardiac contusion were reviewed to determine if mortality or morbidity would have occurred if all patients with normal electrocardiograms (EKGs) in the emergency department (ED) were discharged (or admitted to unmonitored beds for other injuries). Only 13 patients developed cardiac problems: two elderly patients died in the ED, while the others experienced arrhythmias or, less commonly, pump failure requiring treatment or observation. All 13 had EKG changes present while still undergoing evaluation in the ED: 11 had a specific problem on arrival, 1 developed a problem while still being evaluated in the ED, and the 13th had what was probably an iatrogenic problem. Importantly, 5 of 12 patients had normal creatine phosphokinase-MB fractions, and 5 of 9 had normal echocardiograms. No patient with a normal EKG had subsequent cardiac problems. Operative intervention for other injuries was necessary in 26 patients overall, and there was no cardiac morbidity. We conclude that had the EKG been used as the sole screening tool, approximately 25% of these patients could have been discharged from the ED without missing problems. In addition, management would have been greatly simplified, and the hospital would have realized substantial savings, both in terms of direct costs and in the freeing of valuable and scarce resources.

Adult↗

A national programme for on-site defibrillation by lay people in selected high risk areas: initial results.

OBJECTIVE: To report on the effectiveness of an initiative to reduce deaths from sudden cardiac arrest occurring in busy public places. SETTING: 110 such places identified from ambulance service data as high risk sites. PATIENTS: 172 members of the public who developed cardiac arrest at these sites between April 2000 and March 2004. 20,592 defibrillator months' use is reported, representing one automated external defibrillator (AED) use every 120 months. INTERVENTION: 681 AEDs were installed; staff present at the sites were trained in basic life support and to use AEDs. MAIN OUTCOME MEASURES: Initial rhythm detected by AED, restoration of spontaneous circulation, survival to hospital discharge. RESULTS: 172 cases of cardiac arrest were treated by trained lay staff working at the site before the arrival of the emergency services during the period. A shockable rhythm was detected in 135 (78%), shocks being administered in 134 an estimated 3-5 minutes after collapse; 38 (28.3%) patients subsequently survived to hospital discharge. Spontaneous circulation was restored in five additional patients who received shocks but died later in hospital. In 37 cases no shock was initially indicated; one patient survived after subsequent treatment by paramedics, cardiopulmonary resuscitation having been given soon after collapse. Overall, irrespective of the initial rhythm, 39 patients (22.7%), were discharged alive from hospital. For witnessed arrests of presumed cardiac cause in ventricular fibrillation (an international Utstein comparator) survival was 37 of 124 (29.8%). CONCLUSIONS: The use of AEDs by lay people at sites where cardiac arrest commonly occurs is an effective strategy to reduce deaths at these sites.

Aged↗