Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in several muscle structural proteins (the myosin heavy chain, alpha tropomyosin, cardiac troponin T and myosin binding protein C) result in a genetically dominant heart disease, hypertrophic cardiomyopathy. Biochemical data from studies of mutant myosin suggest a dominant-negative mechanism for inheritance of this disease. The most likely primary defect is sarcomere dysfunction, which is followed by the major clinical symptoms.
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PMID:Contractile protein mutations and heart disease. 879 11

ST-segment changes and biochemical signs of myocardial injury, and their relation to sympatho-adrenergic activation and cardiac function, were studied in a case series of 19 alcohol-dependent (DSM-III-R) men undergoing in-hospital treatment for alcohol withdrawal. No patient had any clinically apparent heart disease. Analyses of ST-segment depressions > or = 0.1 mV from 24 h ambulatory electrocardiographic recordings revealed horizontal or downsloping ST-segment depressions in seven of the patients. The serum concentration of creatine kinase (CKMB) the day after admission correlated with the urinary excretion of adrenaline (r = 0.74, P < 0.001) and noradrenaline (r = 0.71, P < 0.001). In the two patients with the highest adrenaline excretion and the highest serum concentrations of CKMB and cardiac troponin T, horizontal ST-segment depressions were detected as well. The left ventricular ejection fraction was > or = 0.65 (range 0.65-0.79) in all of the 17 alcoholic men who were examined by echocardiography. Our study shows that alcohol withdrawal is frequently associated with ST-segment abnormalities in men without impairment of heart function and that sympatho-adrenergic activation during withdrawal seems to influence the release of myocardial enzymes. Alcohol withdrawal should thus be considered a condition in which acute cardiac complications may be expected in susceptible individuals.
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PMID:ST-segment changes and catecholamine-related myocardial enzyme release during alcohol withdrawal. 910 13

We report on the evaluation of the second-generation assay for cardiac troponin T (cTnT) on the Enzymun system. This new assay is completely specific for the cardiac isoform of TnT, utilizing two cardiospecific monoclonal antibodies. The assay time is reduced to 45 min. The interassay precision shows a median CV of 5.5%; 20% interassay CV was found between 0.05 and 0.1 microg/L. The cardiosensitivity of the second-generation cTnT assay in patients with ischemic myocardial injury appears equivalent when compared with the first-generation assay. We found no falsely positive results in patients with skeletal muscle damage including multitraumas, surgery patients, and marathon runners who showed highly increased values with the unspecific first-generation assay. In Duchenne disease cTnT was still increased, but to a much lower extent. cTnT remains increased in renal failure, but to a lesser degree than with the first-generation assay. The cause of this increase remains unclear. Although a cross-reactivity of skeletal muscle TnT in the second-generation assay could be excluded by our findings, minor myocardial damage or expression of the cardiac isoform of TnT in regenerating muscles cannot be ruled out in those cases with apparently falsely increased cTnT values. The second-generation cTnT assay is a step forward in the combination of cardiosensitivity and cardiospecificity in biochemical markers for diagnosis of heart disease.
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PMID:Multicenter evaluation of a second-generation assay for cardiac troponin T. 934 7

Mutations in multiple cardiac sarcomeric proteins including myosin heavy chain (MyHC) and cardiac troponin T (cTnT) cause a dominant genetic heart disease, familial hypertrophic cardiomyopathy (FHC). Patients with mutations in these two genes have quite distinct clinical characteristics. Those with MyHC mutations demonstrate more significant and uniform cardiac hypertrophy and a variable frequency of sudden death. Patients with cTnT mutations generally exhibit mild or no hypertrophy, but a high frequency of sudden death at an early age. To understand the basis for these distinctions and to study the pathogenesis of the disease, we have created transgenic mice expressing a truncated mouse cTnT allele analogous to one found in FHC patients. Mice expressing truncated cTnT at low (< 5%) levels develop cardiomyopathy and their hearts are significantly smaller (18-27%) than wild type. These animals also exhibit significant diastolic dysfunction and milder systolic dysfunction. Animals that express higher levels of transgene protein die within 24 h of birth. Transgenic mouse hearts demonstrate myocellular disarray and have a reduced number of cardiac myocytes that are smaller in size. These studies suggest that multiple cellular mechanisms result in the human disease, which is generally characterized by mild hypertrophy, but, also, frequent sudden death.
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PMID:A truncated cardiac troponin T molecule in transgenic mice suggests multiple cellular mechanisms for familial hypertrophic cardiomyopathy. 963 14

The diagnosis of myocardial infarction (MI) is established in patients with chest pain and equivocal electrocardiogram changes by demonstrating a rise in blood levels of creatine kinase MB (CK-MB) and/or an increase in cardiac troponin I (cTnI) or cardiac troponin T (cTnT). Previous studies have shown that levels of CK-MB are increased in the left ventricle of individuals with heart disease; however, it has not been established whether there are differences in the ventricular myocardium concentrations of cTnI in diseased compared to healthy hearts. Using a simple extraction technique, concentrations of CK-MB and cTnI were measured in the left ventricle (LV) of six hearts obtained at autopsy from individuals ranging in age from 25 to 79 yr, with and without evidence of cardiac disease. The results show an 86-fold higher concentration of CK-MB and 7.7-fold lower concentration of cTnI in left ventricular myocardium of older men with and without cardiac disease, compared to that of younger men (< age 35 yr) without heart disease. These data suggest that age may need to be considered when setting cutoff limits for these markers for the diagnosis of myocardial infarction.
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PMID:Differences of creatine kinase MB and cardiac troponin I concentrations in normal and diseased human myocardium. 1184 17

Familial hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease characterized by varying degrees of ventricular hypertrophy and myofibrillar disarray. Mutations in cardiac contractile proteins cause HCM. However, there is an unexplained wide variability in the clinical phenotype, and it is likely that there are multiple contributing factors. Because mitochondrial dysfunction has been described in heart disease, we tested the hypothesis that mitochondrial dysfunction contributes to the varying HCM phenotypes. Mitochondrial function was assessed in two transgenic models of HCM: mice with a mutant myosin heavy chain gene (MyHC) or with a mutant cardiac troponin T (R92Q) gene. Despite mitochondrial ultrastructural abnormalities in both models, the rate of state 3 respiration was significantly decreased only in the mutant MyHC mice by approximately 23%. Notably, this decrease in state 3 respiration preceded hemodynamic dysfunction. The maximum activity of alpha-ketogutarate dehydrogenase as assayed in isolated disrupted mitochondria was decreased by 28% compared with isolated control mitochondria. In addition, complexes I and IV were decreased in mutant MyHC transgenic mice. Inhibition of beta-adrenergic receptor kinase, which is elevated in mutant MyHC mouse hearts, can prevent mitochondrial respiratory impairment in mutant MyHC mice. Thus our results suggest that mitochondria may contribute to the hemodynamic dysfunction seen in some forms of HCM and offer a plausible mechanism responsible for some of the heterogeneity of the disease phenotypes.
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PMID:Alterations in mitochondrial function in a mouse model of hypertrophic cardiomyopathy. 1241 46

Function of the heart begins long before its formation is complete. Analyses in mouse and zebrafish have shown that myocardial function is not required for early steps of organogenesis, such as formation of the heart tube or chamber specification. However, whether myocardial function is required for later steps of cardiac development, such as endocardial cushion (EC) formation, has not been established. Recent technical advances and approaches have provided novel inroads toward the study of organogenesis, allowing us to examine the effects of both genetic and pharmacological perturbations of myocardial function on EC formation in zebrafish. To address whether myocardial function is required for EC formation, we examined silent heart (sih(-/-)) embryos, which lack a heartbeat due to mutation of cardiac troponin T (tnnt2), and observed that atrioventricular (AV) ECs do not form. Likewise, we determined that cushion formation is blocked in cardiofunk (cfk(-/-)) embryos, which exhibit cardiac dilation and no early blood flow. In order to further analyze the heart defects in cfk(-/-) embryos, we positionally cloned cfk and show that it encodes a novel sarcomeric actin expressed in the embryonic myocardium. The Cfk(s11) variant exhibits a change in a universally conserved residue (R177H). We show that in yeast this mutation negatively affects actin polymerization. Because the lack of cushion formation in sih- and cfk-mutant embryos could be due to reduced myocardial function and/or lack of blood flow, we approached this question pharmacologically and provide evidence that reduction in myocardial function is primarily responsible for the defect in cushion development. Our data demonstrate that early myocardial function is required for later steps of organogenesis and suggest that myocardial function, not endothelial shear stress, is the major epigenetic factor controlling late heart development. Based on these observations, we postulate that defects in cardiac morphogenesis may be secondary to mutations affecting early myocardial function, and that, in humans, mutations affecting embryonic myocardial function may be responsible for structural congenital heart disease.
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PMID:Early myocardial function affects endocardial cushion development in zebrafish. 1513 99

Four isoforms of cardiac troponin T (cTnT), a protein essential for calcium-dependent myocardial force development, are expressed in the human; they differ in charge and length. Their expression is regulated developmentally and is affected by disease states. Human cTnT (hcTnT) isoform effects have been examined in reconstituted myofilaments. In this study, we evaluated the modulatory effects of overexpressing one cTnT isoform on in vitro and in vivo myocardial function. A hcTnT isoform, hcTnT(1), expressed during development and in heart disease but not in the normal adult heart, was expressed in transgenic (TG) mice (1-30% of total cTnT). Maximal active tension measured in skinned myocardium decreased as a function of relative hcTnT(1) expression. The pCa at half-maximal force development, Hill coefficient, and rate of redevelopment of force did not change significantly with hcTnT(1) expression. In vivo maximum rates of rise and fall of left ventricular pressure decreased, and the half-time of isovolumic relaxation increased, with hcTnT(1) expression. Substituting total cTnT charge for hcTnT(1) expression resulted in similar conclusions. Morphometric analysis and electron microscopy revealed no differences between wild-type (non-TG) and TG myocardium. No differences in isoform expression of tropomyosin, myosin heavy chain, essential and regulatory myosin light chains (MLC), TnI, or in posttranslational modifications of mouse cTnT, cTnI, or regulatory MLC were observed. These results support the hypothesis that cTnT isoform amino-terminal differences affect myofilament function and suggest that hcTnT(1) expression levels present during human development and in human heart disease can affect in vivo ventricular function.
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PMID:cTnT1, a cardiac troponin T isoform, decreases myofilament tension and affects the left ventricular pressure waveform. 1551 65

Familial hypertrophic cardiomyopathy is a genetic disease defined by cardiac hypertrophy in the absence of an increased external load. It is the most common inherited cardiac disorder occurring in 1 in 500 individuals. Ten genes exhibiting over 200 mutations have been identified. However, about 75% are due to mutations in just three genes: e-myosin heavy chain, cardiac troponin T, and myosin binding protein-C. Certain phenotypes are more common with certain genes, such as the myosin binding protein-C gene, which induces the disease predominantly in the fifth or sixth decade of life. Genetic animal models in the mouse and rabbit have helped to elucidate the pathophysiology. The primary defect imparted by the specific mutation alters contractile function, which stimulates release of various growth factors that induce secondary cardiac hypertrophy and fibrosis. Placebo single-blinded studies in the mouse indicate that losartan reverses the phenotype; in the rabbit, simvastatin essentially reversed the phenotype after 12 weeks of therapy. Clinical trials are ongoing in human familial hypertrophic cardiomyopathy.
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PMID:Genetic basis for hypertrophic cardiomyopathy: implications for diagnosis and treatment. 1581 32

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in the blood are clinical markers for the diagnosis of cardiac failure. This study was a comprehensive analysis of the postmortem pericardial levels of the natriuretic peptides in serial medico-legal autopsy cases (n=263, within 72 h postmortem) to assess their validity in investigating cardiac function. There was no significant relationship of pericardial ANP or BNP levels with postmortem time or the age of the subjects. The ANP and BNP levels showed negative correlations with the pericardial cardiac troponin T level. The ANP level was significantly elevated in drowning cases. Pericardial BNP and the BNP/ANP ratio were significantly higher for chronic congestive heart disease. However, asphyxiation, sharp instrument injury, hyperthermia, and fatal MA poisoning cases showed lower levels for both markers. These observations suggest that elevations in the postmortem pericardial ANP and BNP may mainly depend on acute atrial overload and subacute or chronic cardiac failure, respectively, and may be reduced by advanced myocardial damage.
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PMID:Postmortem pericardial natriuretic peptides as markers of cardiac function in medico-legal autopsies. 1674 45


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