UMLS:C0018801 - FACTA Search

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Query: UMLS:C0018801 (heart failure)
72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Heart failure is an epidemic within the United States and, despite current medical therapy, carries a high mortality rate. Growth hormone and insulin-like growth factor-1 have known direct effects on the cardiovascular system. Improvement in contractility, reduction in wall stress, and increase in cardiac performance have been noted in animal experiments. Furthermore, preliminary data from human trials are encouraging. This report outlines the biology of growth hormone, the experimental and human data to support clinical trials of growth hormone treatment, and the outcome of trials reported to date.
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PMID:Exogenous growth hormone: a new therapy for dilated cardiomyopathy. 1111 52

Beneficial cardiac effects of growth hormone (GH) have been shown in heart failure in several settings, but studies are lacking on this and other forms of treatment in the cardiomyopathic (CM) mouse heart. In mice with dilated cardiomyopathy due to disruption of the muscle LIM protein (MLP) gene [MLP null mice (MLP-/-)], natural history was first assessed by an initial echocardiogram at 8 weeks and a later follow-up study (n = 31). In most mice, left ventricular (LV) dilation increased and/or function decreased by 5 months, and 3 of 12 mice followed for 9 months died. At the end of follow-up, 22 MLP-/- mice (average age 10.2 months) had both LV dilation and reduced LV function and were selected for studies of GH effects on cardiac function and gene expression; mice were randomized to vehicle (controls) or recombinant human (rh) GH and restudied after 2 weeks. In the GH-treated group compared to the control group, LV % fractional shortening and LV wall thickness (echocardiography) were increased, the LV dP/dtmax (catheter-tip micromanometry) was enhanced, and LV relaxation (tau) improved; however, the LV weight was not significantly increased. The LV expression of many genes was altered in MLP-/- mice, and several were influenced by GH. Thus, short-term RhGH treatment improved LV function in a setting of chronic cardiac deterioration and significantly reduced elevated LV mRNA expression of some (ANP, BNP) but not other members of the embryonic gene program. The MLP null cardiomyopathic mouse can be useful for exploring altered signaling and therapeutic interventions in heart failure.
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PMID:Effects of growth hormone on cardiac dysfunction and gene expression in genetic murine dilated cardiomyopathy. 1119 63

The increased availability of growth hormone (GH) in the mid-1980s, as a result of advances in recombinant DNA techniques, has allowed research into the use of this hormone at physiological dosage, as replacement therapy for adults with GH deficiency (GHD) and at pharmacological dosages as a possible therapeutic agent, for a number of disease states. GHD adults have increased body fat and reduced muscle mass and consequently, reduced strength and exercise tolerance. In addition, they are osteopenic, have unfavourable cardiac risk factors and impaired quality of life. In these individuals, replacing GH reverses these anomalies, although it may not alter the reduced insulin-sensitivity. A proportion of adults with GHD perceive a dramatic improvement in their well-being, energy levels and mood following replacement. GH has protein and osteoanabolic, lipolytic and antinatriuretic properties. GH has been considered for the therapeutic treatment of frailty associated with ageing, osteoporosis, morbid obesity, cardiac failure, major thermal injury and various acute and chronic catabolic conditions. Initial small, uncontrolled studies for many of these clinical problems suggested a beneficial effect of GH, although, later placebo-controlled studies have not observed such dramatic effects. Furthermore, with a recent publication demonstrating an approximate 2-fold increase in mortality in critically ill patients receiving large doses of GH, the use of GH should remain in the realms of replacement therapy and research, until there are significant advances in our understanding.
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PMID:Growth hormone: current and future therapeutic applications. 1124 3

Treatment with human recombinant growth hormone (GH) has yielded conflicting results in patients with congestive heart failure. We analyzed the baseline somatotrophic axis in 50 patients with dilated cardiomyopathy. Then, a double-blind, randomized, placebo-controlled study of GH was performed. We randomly allocated these patients to treatment with subcutaneous GH (2 IU daily) or placebo for a minimum of 12 weeks. The primary end-points were the effect on left ventricular (LV) mass and systolic wall stress. The secondary endpoint was LV ejection fraction. Severity of heart failure as determined by cardiac index, LV end-diastolic diameter, and plasma noradrenaline concentrations correlated markedly with baseline serum insulin-like growth factor-1 (IGF-1) levels. Patients in the GH group had an increase in LV mass compared with the placebo group (p = 0.0001). There was no significant difference in LV systolic wall stress, mean blood pressure, or systemic vascular resistance between the two groups. New York Heart Association (NYHA) functional classification and distance in 6-minute walk test remained unchanged. The change in IGF-1 concentrations between GH and placebo group was notably related (p = 0.0001) to the change in LV mass (p = 0.0001). The GH-induced increase of IGF-1 predicted the changes of ejection fraction (p < 0.05). A marked increase of ejection fraction of 7% was observed in patients whose IGF-1 increased by more than the median increase, in comparison to the patients with an increase below the median (p = 0.03). Serum levels of IGF-1 reflecting GH secretion are diminished in relation to severity of heart failure in patients with dilated cardiomyopathy. GH-induced increases of IGF-1 of more than 80 pg/mL caused notable improvement of ejection fraction. There is a marked increase in LV mass in patients with dilated cardiomyopathy given GH. Changes in LV mass are related to changes in serum IGF-1 concentrations.
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PMID:Growth hormone treatment in dilated cardiomyopathy. 1176 30

The wider availability of recombinant human growth hormone and insulin-like growth factor-I has resulted in an investigation into the potential benefits of the pharmacological administration of these anabolic peptides in a variety of clinical conditions, characterized by an increase in catabolic rate. The initial studies were small, often uncontrolled open investigations, but investigators have more recently concentrated on larger, controlled multi-centre trials. Studies to date have included patients with cardiac failure, sepsis, burns, cancer cachexia, end-stage renal failure, trauma and AIDS, and those prior to or following major surgery. The authors have in general cautiously interpreted positive effects of treatment with growth hormone and insulin-like growth factor-I, either alone or in combination, on net protein balance, body composition, well-being and performance. Two large, randomized, placebo-controlled European multi-centre studies have recently detailed the effects of growth hormone treatment in critically ill intensive care patients. Major increases in mortality and morbidity were associated with growth hormone treatment. The mechanism(s) accounting for the increased mortality remain poorly understood. These negative findings have led to a decrease in the clinical use of growth hormone and in research activity in the area of anabolic treatment in human illness.
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PMID:Treatment with growth hormone and insulin-like growth factor-I in critical illness. 1180 May 16

Chronic obstructive pulmonary disease, COPD is a highly prevalent disorder of increasing medical and socio-economical importance. It is characterized by irreversible airflow obstruction. Besides airflow obstruction also other features are present. One of these is respiratory muscle weakness. Inspiratory muscle weakness is caused by hyperinflation and by generalized muscle weakness causing both respiratory and peripheral muscle dysfunction. The expiratory muscles partake in this generalized muscle weakness. Hyperinflation shortens the inspiratory muscles although in chronic hyperinflation sarcomere adaptation occurs. Generalized muscle weakness is caused by deconditioning, malnutrition, electrolyte disturbances, cardiac failure, systemic inflammation and treatment with corticosteroids causing steroid-induced myopathy. The latter disease was studied intensively both in patients and in animal models of disease. The major findings were that microscopically a myopathic pattern was present associated with generalized fiber atrophy. This is in contrast to classical belief that the atrophy would be confined to type IIx fibers. We noted severe down-regulation of the IGF-I mRNA expression, without important changes in the expression of the binding proteins. This may be responsible for the observed muscle atrophy and the myopathy. The latter is likely to be caused by a simultaneous upregulation of the ubiquitin protease pathway attacking structural proteins. Presently, we study the relationship between local and systemic cytokine expression and respiratory and peripheral muscle dysfunction in COPD patients. Respiratory and peripheral muscle dysfunction have significant consequences for COPD patients. Both respiratory and peripheral muscle dysfunction are associated with reduced exercise tolerance and reduced quality of life. Both are independent determinants of survival, in addition to the degree of airflow obstruction as measured by FEV1. Finally, also the utilization of health care resources appeared to be related to respiratory and peripheral muscle weakness. Treatment of respiratory and peripheral muscle weakness in COPD patients is possible. Respiratory and peripheral muscle training have been shown to produce beneficial effects. Nutritional intervention and anabolic steroids are only useful in combination with muscle training. Systemic administration of growth hormone and IGF-I only produces small effects. In animal models, local administration of IGF-I and transfer of the IGF-I gene transfer appear more promising for the future. Lung volume reduction surgery, LVRS, improves the force-generating capacity of the inspiratory muscles, presumably because of the geometrical alterations it causes in these muscles. It does not appear to improve intrinsic inspiratory muscle function.
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PMID:Respiratory muscles in COPD: regulation of trophical status. 1181 11

Glycogen storage disease type II (GSD II), Pompe's disease, is caused by the deficiency of acid alpha-D-glucosidase (GAA) in lysosome and is the most common form of GSD in Taiwan. Most cases are the infantile form. The disease is relentless and most patients die of cardiac failure and respiratory tract infection in the first year of life. At present, no treatment has been proved effective for this fatal disease. The applicability of enzyme replacement therapy is under investigation. However, high price and transient efficiency are the major problems to be solved. Accordingly, gene therapy by viral method has been conducted. In this study we constructed a plasmid that contained 5'-shortened BglII-NotI fragment human GAA cDNA, downstream of CMV promoter and bovine growth hormone polyadenylation signal, as well as AAV ITR region. When fibroblasts obtained from GSD II patients were cultured and infected with rAAV-GAA, the GAA activity of the fibroblasts increased four- to five-fold. Using acid maltase deficient (AMD) Japanese quail as the animal model, rcAAV-GAA 0.1 ml per site (1 x 10(9)-10) particles), totally 10 different sites to make 1 ml (1 x 10(1)0-11) particles), was injected into unilateral deep pectoral muscle of AMD quails. Medium (hepes) was only injected in the same way into the contralateral deep pectoral muscle to serve as control. Four days after injection, PAS staining showed disappearance of the glycogenosomes with regeneration of myocytes surrounding the intramuscular injected area as compared with the contralateral muscle of the same birds. Using anti-GAA monoclonal antibody, GAA was demonstrated on the regenerated myocytes by immunohistochemical staining and absent on the contralateral muscle of the same birds. Nevertheless, T lymphocytes infiltration was noted in both the rcAAV-GAA and hepes (medium) injected muscles and more prominent in the rcAAV-GAA-injected site. Functional evaluation demonstrated that wing flapping movement improved with wide flapping in the rAAV-GAA injected side, but not in the counterpart. Unfortunately, these histochemical and functional improvements faded away in 14 days, probably due to destruction of rcAAV by cell-mediated immunity of infiltrated T cells. Taken together, the present study suggests that rAAV can enter either human or quail cells and express and effectively reduce the glycogen accumulation in the skeletal muscle of AMD quails. These preliminary results are similar to these of low-dose rGAA replacement therapy. The mechanisms underlying the induction of cell-mediated immunity are unknown. How to elevate the number of packaged AAV, enhance the infectivity of AAV and reduce cell-mediated immunity must be solved in the future.
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PMID:Adeno-associated virus-mediated transfer of human acid maltase gene results in a transient reduction of glycogen accumulation in muscle of Japanese quail with acid maltase deficiency. 1197 31

Cardiovascular disease is the major cause of morbidity and mortality in Westernised societies. It is well known that the aetiology of this devastating disorder involves both genetic and environmental factors. Sequence variants of the components of the renin-angiotensin-aldosterone system and the kallikrein-kinin system are suggested to have significant influences on cardiovascular homeostasis. Both gene targeting and transgenic studies in mice have clearly suggested a critical role of the angiotensin converting enzyme (ACE) gene in blood pressure regulation. Furthermore, an up-regulation of myocardial ACE gene expression has been observed in patients with heart failure. Thus, the ACE gene has been recognised as a top candidate gene for cardiovascular research. Over the past decade, the insertion/deletion (I/D) polymorphism of a 287-bp Alu element in intron 16 of the ACE gene has attracted significant attention and has been extensively investigated in a spectrum of cardiovascular phenotypes, because of its correlation with serum ACE activity. A large majority of previous studies have shown a positive association between the DD genotype and an increased risk of myocardial infarction, but results in hypertension, left ventricular hypertrophy, cardiomyopathy and restenosis after percutaneous transluminal coronary angioplasty remain quite controversial. Since ACE inhibitors are widely used in hypertension and congestive heart failure, we also review the literature on the relationship of ACE I/D polymorphism with ACE inhibitor response. It appears that this polymorphism has some moderate impact on the cardiovascular response to ACE inhibitors but there is no consensus as to which allele confers a more pronounced effect. In addition, previous data are suggestive of an association between the ACE I allele and a greater risk of increased occurrence of ACE inhibitor-induced cough, but such a relationship needs further confirmation. Overall, since ACE I/D is only an intronic marker, the true locus that controls the ACE enzyme activity remains to be identified, and could be located within either the ACE gene or another nearby gene such as the human growth hormone gene. We note that since associations tend to vary across different gender or ethnic groups, or across different socio-ecological settings, consideration of potential gene-gene and gene-environment interactions should be made. Furthermore, the dissection of the genetic underpinning of cardiovascular disease needs delineation of all molecular variants of the key physiological pathways that influence cardiovascular function.
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PMID:Angiotensin converting enzyme gene insertion/deletion polymorphism and cardiovascular disease: therapeutic implications. 1198 86

The pharmacotherapy currently recommended by the American College of Cardiology and the American Heart Association for heart failure (HF) is a diuretic, an angiotensin-converting enzyme inhibitor (ACEI), a beta-adrenoceptor antagonist and (usually) digitalis. This current treatment of HF may be improved by optimising the dose of ACEI used, as increasing the dose of lisinopril increases its benefits in HF. Selective angiotensin receptor-1 (AT(1)) antagonists are effective alternatives for those who cannot tolerate ACEIs. AT(1) antagonists may also be used in combination with ACEIs, as some studies have shown cumulative benefits for the combination. In addition to being used in Stage IV HF patients, in whom it has a marked benefit, spironolactone should be studied in less severe HF and in the presence of beta-blockers. The use of carvedilol, extended-release metoprolol and bisoprolol should be extended to severe HF patients as these agents have been shown to decrease mortality in this group. The ancillary properties of carvedilol, particularly antagonism at prejunctional beta -adrenoceptors, may give it additional benefits to selective beta(1)-adrenoceptor antagonists. Celiprolol and bucindolol are not the beta-blockers of choice in HF, as they do not decrease mortality. Although digitalis does not reduce mortality, it remains the only option for a long-term positive inotropic effect, as the long-term use of the phosphodiesterase inhibitors is associated with increased mortality. The calcium sensitising drug levosimendan may be useful in the hospital treatment of decompensated HF to increase cardiac output and improve dyspnoea and fatigue. The antiarrhythmic drug amiodarone should probably be used in patients at high risk of arrhythmic or sudden death, although this treatment may soon be superseded by the more expensive implanted cardioverter defibrillators, which are probably more effective and have fewer side effects. The natriuretic peptide nesiritide has recently been introduced for the hospital treatment of decompensated HF. Novel drugs that may be beneficial in the treatment of HF include the vasopeptidase inhibitors and the selective endothelin-A receptor antagonists but these require much more investigation. However, disappointing results have been obtained in a large clinical trial of the tumour necrosis factor alpha antagonist etanercept, where no likelihood of a difference between placebo and etanercept was observed. Small clinical trials with recombinant growth hormone to thicken ventricles in dilated cardiomyopathy have given variable results.
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PMID:Present and future pharmacotherapy for heart failure. 1208 91

Although the clinical picture of cardiac cachexia is well-known in patients with advanced chronic heart failure (CHF) the factors that determine who is at risk for this progressive catabolic syndrome and who is not remain unclear. Different endocrine systems have been accused of being involved in this process: an imbalance between catabolic and anabolic steroids with an elevated cortisol/dihydroepiandrosterone ratio, an increased resting metabolic rate due to high levels of circulating catecholamines, various cytokines are activated in CHF (i.e. TNF-alpha, IL-6, IL-1beta and others), and elevated levels of growth hormone (GH) with inappropriately normal or low serum levels of insulin-like growth factor-I (IGF-I) have been described in cardiac cachexia. These catabolic factors contribute to peripheral muscle atrophy, augment the expression of the inducible nitric oxide synthase (iNOS), which in turn inhibits the aerobic cellular metabolism. The present review examines whether the catabolic factors can be influenced by a classical anabolic intervention: regular physical exercise training. Long-term training programs increase skeletal muscle cytochrome c oxidase activity and are associated with reduced local expression of pro-inflammatory cytokines as well as iNOS, and augment local IGF-I production. In concert, these beneficial effects of exercise training may help to retard the catabolic process in CHF finally leading to cardiac cachexia and death.
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PMID:Chronic heart failure and skeletal muscle catabolism: effects of exercise training. 1216 19

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