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

Dilated cardiomyopathy is a disorder affecting heart muscle, characterized by ventricular dilation and reduced systolic function. It represents the most common cause of heart failure. Until recently, dilated cardiomyopathy was considered an exclusively sporadic and idiopathic disease. Now, as defined by the World Health Organization, cardiomyopathy includes not only the idiopathic form, but secondary ones such as ischemic or hypertensive. It is estimated that familial occurrence accounts for 30% of cases of idiopathic dilated cardiomyopathy. The most common mode of inheritance is the autosomal dominant type. The X-linked, autosomal recessive and mitochondrial forms are less common. Different genes or loci are responsible for the cardiac dilatation, and code for sarcomeric, cytoskeleton and nuclear lamina proteins. The molecular interactions of the mutated proteins with factors such as infectious agents or alcohol could explain the variety of presenting signs and symptoms of this type of cardiomyopathy. Recently the European Society of Cardiology published a definition and a protocol for the study of familial dilated cardiomyopathies. Genetic research in the field of dilated cardiomyopathy can increase our understanding of its pathogenesis and lead to new treatment modalities for the disease.
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PMID:Familial dilated cardiomyopathy. 1262 22

Heart failure, frequently the consequence of irreversible myocardial damage with subsequent formation of akinetic scar tissue, is a highly prevalent disease, and in its advanced stages associated with high mortality. The transplantation of exogenous cells with the inherent ability to contract has been put forward as one potential treatment strategy to increase contractility and cardiac performance. Besides skeletal myoblasts or stem cells from various sources, immature cardiomyocytes, such as fetal or neonatal cardiomyocytes, have been transplanted into normal, cryoinjured, infarcted myocardium, as well as into models of global heart failure. Survival of transplanted immature cardiomyocytes has been demonstrated up to 6-7 months, accompanied by vascularization of the grafted tissue. Transplants developed sarcomeric structures and other morphological features of differentiation. The principal possibility of cell-to-cell coupling between graft and host cells was demonstrated after cardiomyocyte transplantation into normal hearts and in some studies in damaged myocardium. But most long-term follow-up investigations in models of myocardial infarction reported that optimal integration of the engrafted cells appeared to be hindered by scar tissue, separating the transplant from the host. Nonetheless, in several studies, improved parameters of cardiac performance were demonstrated ex-vivo and in vivo. Potential mechanisms might involve beneficial effects on the remodeling process. In this review, we critically evaluate the potential value of cardiomyocyte transplantation as a new approach in the treatment of the syndrome of "heart failure".
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PMID:Cardiomyocyte transplantation into the failing heart-new therapeutic approach for heart failure? 1287 28

Dilated cardiomyopathy is now the leading cause of cardiovascular morbidity and mortality. While the molecular basis of this disease remains uncertain, evidence is emerging that gene expression profiles of left ventricular myocardium isolated from failing versus nonfailing patients differ dramatically. In this study, we use high-density oligonucleotide microarrays with approximately 22000 probes to characterize differences in the expression profiles further. To facilitate interpretation of experimental data, we evaluate algorithms for normalization of hybridization data and for computation of gene expression indices using a control spike-in data set. We then use these methods to identify statistically significant changes in the expression levels of genes not previously implicated in the molecular phenotype of heart failure. These regulated genes take part in diverse cellular processes, including transcription, apoptosis, sarcomeric and cytoskeletal function, remodeling of the extracellular matrix, membrane transport, and metabolism.
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PMID:Gene expression profiles in end-stage human idiopathic dilated cardiomyopathy: altered expression of apoptotic and cytoskeletal genes. 1470 57

Hypertrophic cardiomyopathy is a Mendelian disease characterized by cardiac hypertrophy. It has a prevalence of 1:500 individuals and is the most common cause of sudden death in the young. Other complications include heart failure and the need for heart transplantation. Hypertrophic cardiomyopathy is due to sarcomeric gene mutations, however, phenocopies with myocardial hypertrophy can be due to triplet-repeat syndromes (Friedreich ataxia and myotonic dystrophy), mitochondrial and metabolic diseases. In a peculiar form associated with Wolf-Parkinson-White syndrome, the disease is caused by mutations in the gamma2 regulatory subunit of the AMP-activated protein kinase gene, leading to a glycogen storage cardiomyopathy. In spite of the growing knowledge about the molecular basis of hypertrophic cardiomyopathy, very little is still known about the genotype-phenotype correlations and their clinical implications. In this review, the clinical and molecular genetics of hypertrophic cardiomyopathy are described.
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PMID:Familial hypertrophic cardiomyopathy: clinical features, molecular genetics and molecular genetic testing. 1471 53

Doxorubicin is an anti-tumor agent that represses cardiac-specific gene expression and induces myocardial cell apoptosis. Doxorubicin depletes cardiac p300, a transcriptional coactivator that is required for the maintenance of the differentiated phenotype of cardiac myocytes. However, the role of p300 in protection against doxorubicin-induced apoptosis is unknown. Transgenic mice overexpressing p300 in the heart and wild-type mice were subjected to doxorubicin treatment. Compared with wild-type mice, transgenic mice exhibited higher survival rate as well as more preserved left ventricular function and cardiac expression of alpha-sarcomeric actin. Doxorubicin induced myocardial cell apoptosis in wild-type mice but not in transgenic mice. Expression of p300 increased the cardiac level of bcl-2 and mdm-2, but not that of p53 or other members of the bcl-2 family. These findings demonstrate that overexpression of p300 protects cardiac myocytes from doxorubicin-induced apoptosis and reduces the extent of acute heart failure in adult mice in vivo.
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PMID:Expression of p300 protects cardiac myocytes from apoptosis in vivo. 1497 62

Idiopathic dilated cardiomyopathy is a common cause of heart failure. Half of cases are believed to be hereditary, and mutations in cardiac sarcomeric contractile protein genes have been reported with autosomal dominant inheritance. We used mutation analysis suitable for identification of both dominant and recessive mutations to investigate the sarcomeric gene for cardiac troponin I (TNNI3) in 235 patients with dilated cardiomyopathy. We identified a novel TNNI3 mutation in a family with recessive disease. Functional studies showed impairment of troponin interactions that could lead to diminished myocardial contractility. TNNI3 is the first recessive gene identified for this condition, and we suggest that other such genes could be pinpointed by mutation analyses designed to identify homozygous mutations.
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PMID:Novel mutation in cardiac troponin I in recessive idiopathic dilated cardiomyopathy. 1507 May 70

Sudden cardiac death is often due to a ventricular arrhythmia. When a patient presents with a malignant arrhythmia unrelated to a transient reversible cause, there is a high probability of recurrent arrhythmia and sudden death. Clinical trials have shown a uniform survival benefit from implantable cardioverter-defibrillator (ICD) therapy in survivors of a malignant arrhythmia when compared with drug therapy. However, only 1% to 5% of patients survive an out-of-hospital cardiac arrest, emphasizing the need for primary prevention of sudden death. Clinical trial data available in this regard are largely limited to patients with coronary artery disease (CAD). Mortality can be reduced by the ICD in patients with CAD and depressed left ventricular ejection fraction (LVEF) less than 30%. If left ventricular function is only moderately depressed (LVEF between 30% and 40%), the presence of nonsustained ventricular tachycardia with inducible ventricular arrhythmia at electrophysiologic testing identifies patients who benefit from an ICD. The role of the ICD in primary prevention of sudden death in patients with nonischemic dilated cardiomyopathy is less clear at this time. Preliminary data indicate that the presence of heart failure symptoms in this population increases risk of sudden death that can be prevented by an ICD. Antiarrhythmic drugs have little role in prevention of sudden death; however, drugs that block the effects of beta-adrenergic stimulation, angiotensin, and aldosterone reduce mortality partly through their salutary effects on sudden death. Finally, a number of inherited defects of genes coding for ion channels, contractile sarcomeric proteins, and cell-to-cell junction proteins can result in primary electrical abnormalities and sudden death. The ICD is effective for secondary prevention, but its role in primary prevention is controversial and should be based on individual risk factors.
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PMID:Sudden Cardiac Death. 1532 10

Mutations in sarcomeric proteins can lead to either hypertrophic or dilated cardiomyopathy depending on their effects on the structural and functional properties of the contractile unit of the heart. Mutations in cardiac troponin T, which binds the calcium-responsive troponin complex to alpha-tropomyosin, have been shown to result in cardiac hypertrophy or cardiac dilatation and heart failure, depending on the nature of the specific mutation. In this study, we report the identification of a novel cardiac troponin T mutation (A171S) leading to dilated cardiomyopathy and sudden cardiac death. In contrast to prior described mutations, the A171S mutation results in a significant gender difference in the severity of the observed phenotype with adult males (over 20 years of age) demonstrating more severe ventricular dilatation [left ventricular end diastolic dimension (LVEDD) 7.1 vs. 5.1cm; P=0.01, t test] and left ventricular dysfunction [left ventricular shortening fraction (LVSF) 21 vs. 34%; P=0.04, t test] than adult females. The described mutation substitutes a hydrophilic amino acid for a hydrophobic one in a highly conserved domain involved in the interaction between troponin T and alpha-tropomyosin. Interestingly, four previously described mutations within 12 amino acids of A171 lead to a hypertrophic phenotype, suggesting that further characterization of the functional consequences of the A171S mutation may lead to a better understanding of the pathophysiology of DCM and of the functional differences between HCM- and DCM-causing mutations in cardiac troponin T.
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PMID:Novel troponin T mutation in familial dilated cardiomyopathy with gender-dependant severity. 1546 34

Adverse left ventricular (LV) remodeling after myocardial infarction (MI) is a major cause for heart failure. Molecular modifiers of the remodeling process remain poorly defined. Patients with heart failure after MI have reduced LV expression levels of muscle LIM protein (MLP), a component of the sarcomeric Z-disk that is involved in the integration of stress signals in cardiomyocytes. By using heterozygous MLP mutant (MLP+/-) mice, we explored the role of MLP in post-MI remodeling. LV dimensions and function were similar in sham-operated WT and MLP+/- mice. After MI, however, MLP+/- mice displayed more pronounced LV dilatation and systolic dysfunction and decreased survival compared with WT mice, indicating that reduced MLP levels predispose to adverse LV remodeling. LV dilatation in MLP+/- mice was associated with reduced thickening but enhanced elongation of cardiomyocytes. Activation of the stress-responsive, prohypertrophic calcineurin-nuclear factor of activated T-cells (NFAT) signaling pathway was reduced in MLP+/- mice after MI, as shown by a blunted transcriptional activation of NFAT in cardiomyocytes isolated from MLP+/-/NFAT-luciferase reporter gene transgenic mice. Calcineurin was colocalized with MLP at the Z-disk in WT mice but was displaced from the Z-disk in MLP+/- mice, indicating that MLP is essential for calcineurin anchorage to the Z-disk. In vitro assays in cardiomyocytes with down-regulated MLP confirmed that MLP is required for stress-induced calcineurin-NFAT activation. Our study reveals a link between the stress sensor MLP and the calcineurin-NFAT pathway at the sarcomeric Z-disk in cardiomyocytes and indicates that reduced MLP-calcineurin signaling predisposes to adverse remodeling after MI.
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PMID:Attenuation of cardiac remodeling after myocardial infarction by muscle LIM protein-calcineurin signaling at the sarcomeric Z-disc. 1566 6

Ventricular hypertrophy develops in response to numerous forms of cardiac stress, including pressure or volume overload, loss of contractile mass from prior infarction, neuroendocrine activation, and mutations in genes encoding sarcomeric proteins. Hypertrophic growth is believed to have a compensatory role that diminishes wall stress and oxygen consumption, but Framingham and other studies established ventricular hypertrophy as a marker for increased risk of developing chronic heart failure, suggesting that hypertrophy may have maladaptive features. However, the relative contribution of comorbid disease to hypertrophy-associated systolic failure is unknown. For instance, coronary artery disease is induced by many of the same risk factors that cause hypertrophy and can itself lead to systolic dysfunction. It is uncertain, therefore, whether ventricular hypertrophy commonly progresses to systolic dysfunction without the contribution of intervening ischemia or infarction. In this review, we summarize findings from epidemiologic studies, preclinical experiments in animals, and clinical trials to lay out what is known-and not known-about this important question.
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PMID:Does load-induced ventricular hypertrophy progress to systolic heart failure? 1596 79


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