Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A protein has been isolated from the venom of the western diamondback rattlesnake (Crotalus atrox) which induces acute myocardial depression when administered to experimental animals. Purification was achieved by gel filtration on Sephadex G-100, DEAE- and CM-cellulose ion-exchange chromatography, ultra-filtration, and adsorption chromatography on hydroxyapatite. Amino acid analysis of the highly purified protein indicated N-terminal isoleucine and C-terminal tyrosine residues, and the absence of free sulfhydryl groups. Rabbits were immunized against the myocardial depressor protein (MDP) and a highly specific antiserum prepared which made it possible to study other snake venoms for the presence or absence of MDP. All of the North American Crotalid species of snakes contain MDP in varying degrees of concentration, but none of the Asiatic snake venoms tested reacted with the antiserum to the myocardial depressor protein. Intravenous administration of MDP to experimental animals (dogs, cats) produces an immediate and profound decrease in the cardiac output, the left ventricular systolic and mean pressures, the velocity of shortening of the contractile element, the systemic arterial pressure and an elevation in the left ventricular end-diastolic and pulmonary wedge pressures. These hemodynamic changes indicate that MDP administration induces an acute myocardial failure which is does dependent. The potential use of this protein for the reproducible causation of left ventricular failure, obviating the need for the more commonly used surgical ligation of the coronary arteries, warrants a full investigation into its structure, active site and its mechanism of action on the myocardial cell.
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PMID:Comparative biochemistry and pharmacology of salivary gland secretions. III. Chromatographic isolation of a myocardial depressor protein (MDP) from the venom of Crotalus atrox. 96 63

A patient with mitochondrial encephalomyopathy who died from progressive intractable cardiac failure at the age of 18 is reported. At the age of 4, he presented with short stature, but multiorgan disorders including deafness, focal glomerulosclerosis, epilepsy and dilated cardiomyopathy appeared later in his clinical course. Laboratory tests showed hyperlactatemia and hyperpyruvatemia. Histopathological findings demonstrated mitochondrial myopathy with ragged red fibers and focal cytochrome C oxidase-deficient fibers in skeletal and cardiac muscles. The activity of cytochrome C oxidase was 30% less than the control level in skeletal muscle. Sequencing of the entire mitochondrial tRNA genome revealed a novel point mutation in the tRNA(Ile) region (nt 4269). This A-to-G substitution was found in none of the 30 controls by screening using mispairing PCR and Ssp I digestion methods, suggesting that this new mutation was pathogenic in our case.
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PMID:Mitochondrial tRNA(Ile) mutation in fatal cardiomyopathy. 163 86

Amyloid fibril material was extracted from autopsy material of a patient who died from progressive cardiac failure at age 64. He had enlarged heart on routine X-ray at age 47 and the first symptoms of cardiac failure at age 62. Fractionation of the fibril material resolved peptide fragments immunoreactive with anti-human transthyretin (TTR). One of the peptides was further purified by high-performance liquid chromatography (HPLC) and subjected to tryptic peptide mapping along with TTR isolated from the patient's serum. In both instances, sequencing procedures revealed, in addition to the normal peptide 12 (residues 105-126), an abnormal peptide with an isoleucine for valine substitution at position 122. This substitution has been described previously in a patient with systemic senile amyloidosis (SSA) homozygous for this variant. The results question whether SSA is a clinical entity related to TTR Ile 122 with phenotypic expression in the homozygous condition.
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PMID:Cardiac amyloidosis: report of a patient heterozygous for the transthyretin isoleucine 122 variant. 223 88

A prospective study of congestive cardiac failure in 221 elderly Nigerians seen at Ahmadu Bello University Hospital, Zaria, and Ife University Teaching Hospitals Complex, Ile-Ife from 1974 to 1979 is reported. Hypertension, iodopathic cardiomegaly and pulmonary heart disease were major causes of cardiac failure. No case of coronary atherosclerotic heart disease was seen. Ventricular conduction defect was the commonest E.C.G. abnormality recorded. In over half of the patients, there was coexisting disease, mild to moderate anaemia being the most common.
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PMID:Congestive cardiac failure in elderly Nigerians: a prospective clinical study. 645 36

Cardiac amyloidosis is caused by amyloid deposits derived from different human plasma proteins. It can lead to cardiac conduction disturbances, restrictive cardiomyopathy, and low output heart failure. The heart is variably involved during the development of systemic amyloidosis and seems to be more frequently affected in immunoglobulin (primary) than in reactive (secondary) amyloidosis. Amyloid is common in the elderly. Isolated atrial amyloid, for which a major subunit is the atrial natriuretic peptide, seems to be three times more frequent than senile cardiac amyloid, which is derived from normal prealbumin (transthyretin). Like polyneuropathy, cardiac amyloidosis is a prominent clinical feature of hereditary amyloidosis, namely of the autosomal dominant transthyretin (TTR) type. All 28 cases of TTR amyloidoses reported so far were heterozygotes for a single nucleotide change in the gene for TTR that resulted in amino acid substitutions in the mature protein. A new TTR genetic variant is reported in a German family where the index patient presented at the age of 63 with anginal pain and arrhythmia. Electrocardiography was suggestive of a pseudoinfarction pattern, and echocardiography and cardiac catheterisation showed signs of hypertrophic nonobstructive cardiomyopathy with increased ventricular filling pressures and a prominent "a" wave. Amyloid of the TTR type was identified by immunohistochemistry in the endomyocardial biopsy specimen. Hybrid isoelectric focusing established heterozygosity by showing normal TTR protein and an electrically neutral TTR variant differing from all known TTR variants so far. The patient died in an accident before investigations were complete. Electrophoretic analysis of the plasma from his first degree relatives (son, daughter, brother, and mother) identified the asymptomatic 22 year old son as an apparently heterozygous carrier of the mutant TTR protein. Comparative tryptic peptide mapping and sequencing showed that isoleucine at position 68 of the amino acid sequence was replaced by leucine.
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PMID:Cardiac amyloidosis: a review and report of a new transthyretin (prealbumin) variant. 803 17

A threonine to isoleucine polymorphism at amino acid 164 in the fourth transmembrane spanning domain of the beta 2-adrenergic receptor (beta 2AR) is known to occur in the human population. The functional consequences of this polymorphism to catecholamine signaling in relevant cells or to end-organ responsiveness, however, are not known. To explore potential differences between the two receptors, site-directed mutagenesis was carried out to mimic the polymorphism. Transgenic FVB/N mice were then created overexpressing wild-type (wt) beta 2AR or the mutant Ile-164 receptor in a targeted manner in the heart using a murine alpha myosin heavy chain promoter. The functional properties of the two receptors were then assessed at the level of in vitro cardiac myocyte signaling and in vivo cardiac responses in intact animals. The expression levels of these receptors in the two lines chosen for study were approximately 1200 fmol/mg protein in cardiac membranes, which represents a approximately 45-fold increase in expression over endogenous beta AR. Myocyte membrane adenylyl cyclase activity in the basal state was significantly lower in the Ile-164 mice (19.5 +/- 2.7 pmol/min/mg) compared with wt beta 2AR mice (35.0 +/- 4.1 pmol/min/mg), as was the maximal isoproterenol-stimulated activity (49.8 +/- 7.8 versus 77.1 +/ 7.3 pmol/min/mg). In intact animals, resting heart rate (441 +/- 21 versus 534 +/- 17 bpm) and dP/dtmax (10,923 +/- 730 versus 15,308 +/- 471 mmHg/sec) were less in the Ile-164 mice as compared with wt beta 2AR mice. Similarly, the physiologic responses to infused isoproterenol were notably less in the mutant expressing mice. Indeed, these values, as well as other contractile parameters, were indistinguishable between Ile-164 mice and nontransgenic littermates. Taken together, these results demonstrate that the Ile-164 polymorphism is substantially dysfunctional in a relevant target tissue, as indicated by depressed receptor coupling to adenylyl cyclase in myocardial membranes and impaired receptor mediated cardiac function in vivo. Under normal homeostatic conditions or in circumstances where sympathetic responses are compromised due to diseased states, such as heart failure, this impairment may have important pathophysiologic consequences.
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PMID:Myocardial signaling defects and impaired cardiac function of a human beta 2-adrenergic receptor polymorphism expressed in transgenic mice. 881 27

A national epidemiological study undertaken in November 1995 recensed the data of 2563 patients admitted to 373 Intensive Care Units for acute myocardial infarction. There were 1827 men and 736 women with an average age of 67 years. Seventeen per cent of patients had left ventricular ejection fration (LVEF) < or = 35%. The mortality rate at 5 days was 7.7%. Clinical heart failure (Killip > 1) was observed in 34.4% of patients. 63% of patients were admitted before the 6th hour. Forty-six per cent of patients underwent early revascularisation by thrombolysis and/or angioplasty. The most widely used drugs in the first 5 days were heparin (96%), aspirin (89%), betablockers (65%), and angiotension converting enzyme inhibitors (46%). The influence of region on the demographical features, morbidity, mortality and therapeutic practice was studied. France was divided into 6 regions. In the Centre, the patients were older, with increased morbidity and mortality compared with the national average. Patients in the North East were similar and had a higher incidence of obesity. In the Ile de France, patients were generally younger with a higher incidence of tobacco consumption and their infarcts were generally less severe. Finally, in the South East, the mortality was particularly low. In multivariate analysis living in this region was good prognostic factor whereas low LVEF (< or = 35%) and age > or = 65 years were poor prognostic factors. This study, for the first time in France, describes the clinical features of myocardial infarction admitted to the Intensive Care Unit with respect to criteria of severity (LVEF, Killip) and region of origin of the patients. Its confirms large regional variations in the severity of acute myocardial infarction.
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PMID:[Epidemiology of myocardial infarction in France. Regional specificities]. 953 25

We report an autopsy case of a pedigree of familial amyloidotic polyneuropathy (FAP) with a mutation of isoleucine-50 transthyretin (ATTR Ser50Ile). A 47-year-old man started developing severe diarrhea and weight loss at age 41 years, followed by urinary incontinence, autonomic-nervous-system abnormalities and serious heart failure; the diagnosis of FAP (ATTR Ser50Ile) was made on the basis of genetic, histochemical and immunohistochemical analysis. Six years after the initial symptoms, he died of septic shock. Autopsy revealed suppurative peritonitis, perforation of the sigmoid colon and marked systemic amyloid deposition. The total amount of amyloid deposited in the heart was greatly increased and was much lower in the thyroid gland and kidneys compared with amyloid deposits in ordinary FAP (ATTR Val30Met). Amyloid deposition in peripheral vessel walls was prominent, particularly in lymphatics and veins. His elder sister, 54 years old, started to develop orthostatic hypotension at age 49 years, followed by dysesthesia, diarrhea and severe congestive heart failure. Endomyocardial biopsy revealed severe TTR-amyloid deposition; ultrastructural examination demonstrated that amyloid fibrils were deposited disproportionately and extended radially around microvessels.
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PMID:Familial amyloidotic polyneuropathy (ATTR Ser50Ile): the first autopsy case report. 1083 37

Defective calcium (Ca(2+)) signaling, manifest as a loss of excitation-contraction (EC) coupling gain in cardiac muscle, likely plays an important role in the pathophysiology of human heart failure. The mechanism underlying this loss of cardiac EC coupling gain involves altered regulation of the cardiac ryanodine receptor (RyR2), the major sarcoplasmic reticulum Ca(2+) release channel in the heart. This altered regulation of RyR2 is due, in part, to hyperphosphorylation of the channel by cyclic adenosine monophosphate-dependent protein kinase A (PKA). PKA phosphorylation of RyR2 is controlled by a macromolecular signaling complex that targets PKA and two phosphatases (PP1 and PP2A) to the channel. The targeting of PKA, PP1, and PP2A to RyR2 is dependent on the binding of targeting proteins to the channel via highly conserved leucine/isoleucine zippers (LIZs). Formation of an ion channel macromolecular signaling complex is a novel role of LIZs. Recognition of this new function for LIZ motifs has provided a road map for rapidly identifying components of the RyR2 macromolecular signaling complex that play a key role in regulating normal cardiac physiology as part of the "fight or flight" response. The components of the RyR2 macromolecular signaling complex are also novel targets for heart failure and cardiac arrhythmia therapeutics.
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PMID:Regulation of ryanodine receptors via macromolecular complexes: a novel role for leucine/isoleucine zippers. 1206 56

The Val122Ile mutant transthyretin (TTR Ile122) is an amyloidogenic protein which has been described as the major protein component of amyloid fibrils isolated from patients with familial amyloidotic cardiomyopathy (FAC), a disease characterized by cardiac failure and amyloid deposits in the heart. The reasons for the deposition of TTR are still unknown and it is conceivable that a conformational alteration, resulting from the mutation, is fundamental for amyloid formation. The three-dimensional structure of TTR Ile122 was determined and refined to a crystallographic R factor of 15.8% at 1.9 A resolution. The r.m.s. deviation from ideality in bond distances is 0.019 A and in angle-bonded distances is 0.027 A. The presence of two crystallographically independent monomers in the asymmetric unit allowed additional means of estimation of atomic coordinate error. The structure of the mutant is essentially identical to that of the wild-type transthyretin (TTR). The largest deviations occur in surface loops and in the region of the substitution. The protein is a tetramer composed of identical subunits; each monomer has two four-stranded beta-sheets which are extended to eight-stranded beta-sheets when two monomers associate through hydrogen bonds forming a dimer, which is the crystallographic asymmetric unit. The replacement of valine for isoleucine introduces very small alterations in relation to the wild-type protein; nevertheless they seem to confirm a tendency for a less stable tetrameric structure. This would support the idea that the tetrameric structure might be disrupted in amyloid fibrils.
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PMID:Structure of the Val122Ile variant transthyretin - a cardiomyopathic mutant. 1529 6


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