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Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

New developments in pediatric heart transplantation have influenced the nursing management of these patients. The patient population has changed over the past few years with an increase in patients with congenital heart disease and larger numbers of infants and young children. The management of patients prior to transplantation has become more complex, with new pharmacologic agents and the use of mechanical assist devices as a bridge to heart transplantation. The importance of accurate assessment and management of pulmonary hypertension both before and after transplantation have been recognized. FK506, a new immunosuppressant in clinical trial, appears promising as both a maintenance therapy and a rescue drug with fewer side effects than cyclosporine. The trend toward outpatient and home care for many transplant-related therapies reflects the wider trend in health care. The practice of the critical care nurse involved in pediatric heart transplantation has been influenced by these recent changes.
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PMID:New directions in pediatric heart transplantation. 159 42

In lymphocytes, the expression of early immune response genes is regulated by NF-AT transcription factors which translocate to the nucleus after dephosphorylation by the Ca2+-dependent phosphatase, calcineurin. We report here that mice bearing a disruption in the NF-ATc gene fail to develop normal cardiac valves and septa and die of circulatory failure before day 14.5 of development. NF-ATc is first expressed in the heart at day 7.5, and is restricted to the endocardium, a specialized endothelium that gives rise to the valves and septum. Within the endocardium, specific inductive events appear to activate NF-ATc: it is localized to the nucleus only in endocardial cells that are adjacent to the interface with the cardiac jelly and myocardium, which are thought to give the inductive stimulus to the valve primordia. Treatment of wild-type embryos with FK506, a specific calcineurin inhibitor, prevents nuclear localization of NF-ATc. These data indicate that the Ca2+/calcineurin/NF-ATc signalling pathway is essential for normal cardiac valve and septum morphogenesis; hence, NF-ATc and its regulatory pathways are candidates for genetic defects underlying congenital human heart disease.
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PMID:Role of the NF-ATc transcription factor in morphogenesis of cardiac valves and septum. 951 54

Hypertrophic cardiomyopathy (HCM) is an inherited form of heart disease that affects 1 in 500 individuals. Here it is shown that calcineurin, a calcium-regulated phosphatase, plays a critical role in the pathogenesis of HCM. Administration of the calcineurin inhibitors cyclosporin and FK506 prevented disease in mice that were genetically predisposed to develop HCM as a result of aberrant expression of tropomodulin, myosin light chain-2, or fetal beta-tropomyosin in the heart. Cyclosporin had a similar effect in a rat model of pressure-overload hypertrophy. These results suggest that calcineurin inhibitors merit investigation as potential therapeutics for certain forms of human heart disease.
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PMID:Prevention of cardiac hypertrophy in mice by calcineurin inhibition. 973 19

In the past 2 years, an emerging body of research has focused on a novel transcriptional pathway involved in the cardiac hypertrophic response. Ever since its introduction, the significance of the calcineurin-NFAT module has been subject of controversy. The aim of this review is to provide both an update on the current status of knowledge and discuss the remaining issues regarding the involvement of calcineurin in hypertrophic heart disease. To this end, the molecular biology of calcineurin and its direct downstream transcriptional effector NFAT are discussed in the context of the genetic studies that established the existence of this signaling paradigm in the heart. The pharmacological mode-of-action and specificity of the calcineurin inhibitors cyclosporine A (CsA) and FK506 is discussed, as well as their inherent limitations to study the biology of calcineurin. A critical interpretation is given on studies aimed at analyzing the role of calcineurin in cardiac hypertrophy using systemic immunosuppression. To eliminate the controversy surrounding CsA/FK506 usage, recent studies employed genetic inhibitory strategies for calcineurin, which confirm the pivotal role for this signal transduction pathway in the ventricular hypertrophy response. Finally, unresolved issues concerning the role of calcineurin in cardiac pathobiology are discussed based upon the information available, including its controversial role in cardiomyocyte viability, the reciprocal relationship between myocyte Ca(2+) homeostasis and calcineurin activity and the relative importance of calcineurin in relation to other hypertrophic signaling cascades.
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PMID:Calcineurin and hypertrophic heart disease: novel insights and remaining questions. 1192 91

During cardiogenesis, perturbation of a key transition at mid-gestation from cardiac patterning to cardiac growth and chamber maturation often leads to diverse types of congenital heart disease, such as ventricular septal defect (VSD), myocardium noncompaction, and ventricular hypertrabeculation. This transition, which occurs at embryonic day (E) 9.0-9.5 in murine embryos and E24-28 in human embryos, is crucial for the developing heart to maintain normal cardiac growth and function in response to an increasing hemodynamic load. Although, ventricular trabeculation and compaction are key morphogenetic events associated with this transition, the molecular and cellular mechanisms are currently unclear. Initially, cardiac restricted cytokine bone morphogenetic protein 10 (BMP10) was identified as being upregulated in hypertrabeculated hearts from mutant embryos deficient in FK506 binding protein 12 (FKBP12). To determine the biological function of BMP10 during cardiac development, we generated BMP10-deficient mice. Here we describe an essential role of BMP10 in regulating cardiac growth and chamber maturation. BMP10 null mice display ectopic and elevated expression of p57(kip2) and a dramatic reduction in proliferative activity in cardiomyocytes at E9.0-E9.5. BMP10 is also required for maintaining normal expression levels of several key cardiogenic factors (e.g. NKX2.5 and MEF2C) in the developing myocardium at mid-gestation. Furthermore, BMP10-conditioned medium is able to rescue BMP10-deficient hearts in culture. Our data suggest an important pathway that involves a genetic interaction between BMP10, cell cycle regulatory proteins and several major cardiac transcription factors in orchestrating this transition in cardiogenesis at mid-gestation. This may provide an underlying mechanism for understanding the pathogenesis of both structural and functional congenital heart defects.
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PMID:BMP10 is essential for maintaining cardiac growth during murine cardiogenesis. 1507 51

Cardiac hypertrophy is a leading predicator of progressive heart disease that often leads to heart failure and a loss of cardiac contractile performance associated with profound alterations in intracellular calcium handling. Recent investigation has centered on identifying the molecular signaling pathways that regulate cardiac myocyte hypertrophy, as well as the mechanisms whereby alterations in calcium handling are associated with progressive heart failure. One potential focal regulator of cardiomyocyte hypertrophy that also responds to altered calcium handling is the calmodulin-activated serine/threonine protein phosphatase calcineurin (PP2B). Once activated by increases in calcium, calcineurin mediates the hypertrophic response through its downstream transcriptional effector nuclear factor of activated T cells (NFAT), which is directly dephosphorylated by calcineurin resulting in nuclear translocation. While previous studies have convincingly demonstrated the sufficiency of calcineurin to mediate cardiac hypertrophy and progressive heart failure, its necessity remains an area of ongoing investigation. Here we weigh an increasing body of literature that suggests a causal link between calcineurin signaling and the cardiac hypertrophic response and heart failure through the use of pharmacologic inhibitors (cyclosporine A and FK506) and genetic approaches. We will also discuss the manner in which calcineurin-NFAT signaling is negatively regulated in the heart through a diverse array of kinases and inhibitory proteins. Finally, we will discuss emerging theories as to the mechanisms whereby alterations in intracellular calcium handling might stimulate calcineurin within the context of a contractile cell continually experiencing calcium flux.
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PMID:Calcium-calcineurin signaling in the regulation of cardiac hypertrophy. 1533 66

This review addresses the potential use of the intracellular ryanodine receptor (RyR) Ca(2+) release channel as a therapeutic target in heart disease. Heart disease encompasses a wide range of conditions with the major contributors to mortality and morbidity being ischaemic heart disease and heart failure (HF). In addition there are many rare, but devastating conditions, some of which are either genetically linked to the RyR and its regulatory proteins or involve drug-induced modification of the proteins. The defects in Ca(2+) signalling vary with the nature of the heart disease and the stage in its progress and therefore specific corrections require different modifications of Ca(2+) signalling. Compounds that activate the RyR are potential inotropic agents to increase the Ca(2+) transient and strength of contraction. Compounds that reduce RyR activity are potentially useful in conditions where excess RyR activity initiates arrhythmias, or depletes the Ca(2+) store, as in end stage HF. It has recently been discovered that the cardio-protective action of the drug JTV519 can be attributed partly to its ability to stabilise the interaction between the RyR and the 12.6 kDa binding protein for the commonly used immunosuppressive drug FK506 (FKBP12.6, known as tacrolimus). This has established the credibility of the RyR as a therapeutic target. We explore the possibility that mutations causing the rare RyR-linked arrhythmias will open the door to identification of novel RyR-based therapeutic agents. The use of regulatory binding sites within the RyR complex or on its associated proteins as templates for drug design is discussed.
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PMID:Agonists and antagonists of the cardiac ryanodine receptor: potential therapeutic agents? 1705 86