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)

Certain forms of cardiac failure appear to be associated with a decrease in the Ca++ sensitivity of the contractile structures, possibly due to troponin I phosphorylation. Interference of cardiotonic drugs with myofibrillar Ca++ activation instead of enhancement of Ca++ influx may therefore provide a more causal therapeutic concept in the treatment of cardiac insufficiency. APP 201-533 (3-Amino-6-methyl-5-phenyl-2(1H)-pyridinone) (the structure of which is shown below) is a novel cardiotonic agent acting neither via beta adrenoceptor stimulation nor inhibition of Na+/K+ ATPase. In the 100 microM concentration range, it increases the Ca++ sensitivity and the Ca++ affinity of functionally isolated cardiac contractile structures. This coincides with an inhibitory effect on the cAMP-dependent protein kinase from rat liver. A possible relation with the regulation of troponin I phosphorylation is discussed.
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PMID:Myofibrillar Ca++ activation and heart failure--Ca++ sensitization by the cardiotonic agent APP 201-533. 281 53

We have examined four models of experimental cardiac hypertrophy and heart failure for alterations in troponin isoform expression, particularly in the re-expression of the fetal isoforms. Cardiac protein extracts from experimental and sham-operated control rats were analyzed using one dimensional gel electrophoresis, followed by Western blotting and detection with antibodies specific for troponin I and T. No alteration in protein profile was observed for these proteins between control, hypertrophied and failing heart samples. The data demonstrate that reversion to the fetal pattern of troponin expression is not a feature of experimental cardiac hypertrophy and heart failure in the rat.
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PMID:Troponin I and T protein expression in experimental cardiac hypertrophy. 760 98

Recent reports have demonstrated the presence of two isoforms of troponin I in the human fetal heart, namely, cardiac troponin I and slow skeletal muscle troponin I. Structural and physiological considerations indicate that these isoforms would confer differing contractile properties on the myocardium, particularly on the phosphorylation-mediated regulation of contractility by adrenergic agonists. We have investigated the developmental expression of these isoforms in the human heart from 9 weeks of gestation to 9 months of postnatal life, using Western blots revealed with troponin I antibodies to detect troponin protein isoforms and Northern blots to detect the corresponding mRNAs. The results show the following: 1) Slow skeletal muscle troponin I is the predominant isoform throughout fetal life. 2) After birth, the slow skeletal isoform is lost, with cardiac troponin I being the only isoform detectable by 9 months of postnatal development. 3) The protein isoforms and their corresponding mRNAs follow the same pattern of accumulation, suggesting that the transition in troponin expression is regulated at the level of gene transcription. The developmental transition in troponin I isoform content has implications for contractility of the fetal and postnatal myocardium. We further analyzed right and left ventricular muscle samples from 17 hearts in end-stage heart failure resulting from pulmonary hypertension, ischemic heart disease, or dilated cardiomyopathy. Cardiac troponin I mRNA remained abundant in each case, and slow skeletal muscle troponin I mRNA was not detectable in any of sample. We conclude that alterations in troponin I isoform content do not therefore contribute to the altered contractile characteristics of the adult failing ventricle.
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PMID:Troponin I gene expression during human cardiac development and in end-stage heart failure. 847 26

Evidence from ventricular preparations of cat, sheep, rat and dog suggests that both beta 1-adrenoceptors (beta 1AR) and beta 2-adrenoceptors (beta 2AR) mediate positive inotropic effects but that only beta 1AR do it through activation of a cAMP pathway. On the other hand, our evidence has shown that both beta 1AR and beta 2AR hasten relaxation of isolated human myocardium consistent with a common cAMP pathway. We have now investigated in the isolated human right atrial appendage, a tissue whose beta-AR comprise around 2/3 of beta 1AR and 1/3 of beta 2AR, whether or not beta 2AR-mediated effects occur via activation of a cAMP pathway. We carried out experiments on atria obtained from patients without advanced heart failure undergoing open heart surgery. To activate beta 2AR, we used the beta 2AR-selective ligand zinterol. Experiments were carried out on paced atrial strips (1 Hz) and tissue homogenates and membrane particles. Zinterol caused positive inotropic and lusitropic (i.e. reduction of t1/2 of relaxation) effects with EC50 values of 3 and 2 nM, respectively. The zinterol-evoked effects were unaffected by the beta 1AR-selective antagonist CGP 20712A (300 nM) but blocked surmountably by the beta 2AR-selective antagonist ICI 118551 (50 nM) which reduced both EC50 values to 1 microM. Zinterol stimulated adenylyl cyclase activity with an EC50 of 30 nM and intrinsic activity of 0.75 with respect to (-)-isoprenaline (600 microM); the effects were resistant to blockade by CGP 20712A (300 nM) but antagonised surmountably by ICI 118551 (50 nM). Zinterol bound to membrane beta AR labelled with (-)-[125I] cyanopindolol with higher affinity for beta 2AR than for beta 1AR; the binding to beta 2AR but not to beta 1AR was reduced by GTP gamma S (10 microM). In the presence of CGP 20712A (300 nM) (-)-isoprenaline (400 microM) (to activate both beta 1AR and beta 2AR maximally) and zinterol (10 microM) increased contractile force 3.4-fold and 2.5-fold respectively and reduced relaxation t1/2 by 32% and 18% respectively. These effects of (-)-isoprenaline and zinterol were associated (5 min incubation) with phosphorylation (pmol P/mg supernatant protein) of troponin I and C-protein to values of 8.4 +/- 2.0 vs 12.4 +/- 2.3 and 10.1 +/- 2.5 vs 8.6 +/- 1.6 respectively. (-)-Isoprenaline and zinterol also caused phosphorylation of phospholamban (1.8 +/- 0.3 vs 0.4 +/- 0.1 pmol P/mg respectively) specifically at serine residues. We conclude that in human atrial myocardium activation of both beta 1AR and beta 2AR leads to cAMP-dependent phosphorylation of proteins involved in augmenting both contractility and relaxation.
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PMID:Beta 2-adrenoceptor activation by zinterol causes protein phosphorylation, contractile effects and relaxant effects through a cAMP pathway in human atrium. 897 46

Cardiac troponin T (cTnT) and troponin I (cTnI) have been suggested as new, more specific markers of myocardial cellular damage. The objective of this study was to examine how the distributions of cTnI and cTnT were affected in postinfarction left ventricular remodeled (LVR) myocardium. At 2 months postinfarct in a porcine heart failure model, both Western blot and biochemical assay analyses were performed on left ventricular myocardium remote from the infarct zone in ligation animals (n = 8). Results were compared with data from the left ventricular myocardium from similar sized healthy (control) pigs (n = 7). Autoradiograms from Western blot analysis showed that the protein mass for cTnI and cTnT in LVR hearts decreased 80% (P < 0.001) and 40% (P < 0.02), respectively, when compared with nondiseased tissue. Similarly, the concentrations for cTnI and cTnT in LVR hearts decreased 42% (P < 0.05) and 70% (P < 0.001), respectively, compared with nondiseased normal tissue. The clinical assumption is that the appearance of cTnI and cTnT in the blood is proportional to chronic loss of cTnI and cTnT from injured myocardium associated with left ventricular remodeling.
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PMID:Cardiac troponin I and T alterations in hearts with severe left ventricular remodeling. 919 51

Cardiac troponin I, a specific and sensitive marker of myocardial damage, was detected in the blood of 6 of 26 patients studied in our Heart Failure Clinic. In these patients functional class, ventricular function, and prognosis were significantly worse than in those without detectable troponin I. This study suggests that troponin I may represent the biochemical marker of myocardial damage occurring in severe heart failure.
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PMID:Detectable serum troponin I in patients with heart failure of nonmyocardial ischemic origin. 920 29

We describe an improved procedure using a standard microplate immunoassay reader to measure the concentration of troponin T in human serum. We also describe an immunoassay for troponin I in serum. Only 160 microliters of serum are needed for a single analysis of each troponin. For comparison, creatine kinase MB mass analysis in serum was performed with a commercial luminometric method. From 95 apparently healthy people the following values were obtained: creatine kinase MB mass 2.6 +/- 1.2 micrograms/l, troponin T 0.027 +/- 0.025 microgram/l and troponin I 0.03 +/- 0.031 microgram/l. We compared the results of troponin T and troponin I methods with each other, as well as with those of creatine kinase MB mass measured in 48 patients with verified acute myocardial infarction and in 60 control patients with non-cardiac chest pain. The correlation between troponin T and troponin I values was 0.91 for the total material and 0.94 for 48 patients with acute myocardial infarction. Troponin I showed better earlier sensitivity than troponin T (p = 0.043). In nine patients in the control group, creatine kinase MB mass exceeded the reference limit of 5.0 micrograms/l, while in two patients the cut-off limit of 10.0 micrograms/l was also surpassed, pointing to non-specificity. In the group of infarct patients, the highest serum creatinine value was 193 mumol/l, whereas in the control group it was 406 mumol/l. The sera of patients with impaired renal function without any cardiac failure showed no increase in troponin T and troponin I values. In conclusion, serum creatine kinase MB mass and troponin I seem to confirm an acute myocardial infarction more rapidly than does troponin T; troponin I has the highest cardiac specificity.
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PMID:Comparison of the troponin T and troponin I ELISA tests, as measured by microplate immunoassay techniques, in diagnosing acute myocardial infarction. 936 95

Recently, it has been reported that the protein kinase C (PKC) beta isoform plays a critical role in the development of hypertrophy and heart failure. The purpose of the present study was to clarify the mechanism by which activation of PKCbeta led to depressed cardiac function. Thus, we used a PKCbeta2 overexpressing mouse, an animal model of heart failure, to examine mechanical properties and Ca2+ signals of isolated left ventricular cardiomyocytes. The percentage of shortening, rate of shortening, and rate of relengthening of cardiomyocytes were markedly reduced in PKCbeta2 overexpression mice compared to wild-type control mice, although the baseline level and amplitude of Ca2+ signals were similar. These findings suggested a decreased myofilament responsiveness to Ca2+ in transgenic hearts. Therefore, the incorporation of [32P] inorganic phosphate into cardiac myofibrillar proteins was studied in Langendorff-perfused hearts. There was a significant increase in the degree of phosphorylation of troponin I in PKCbeta2-overexpressing transgenic mice. The depressed cardiomyocyte function improved after the superfusion of a PKCbeta selective inhibitor. These findings indicate that in vivo PKCbeta2-mediated phosphorylation of troponin I may decrease myofilament Ca2+ responsiveness, and thus causes cardiomyocyte dysfunction. Since chronic and excess activation of PKCbeta2 plays a direct and contributory role in the progression of cardiac dysfunction, the PKCbeta selective inhibitor may provide a new therapeutic modality in the setting of heart failure.
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PMID:In vivo phosphorylation of cardiac troponin I by protein kinase Cbeta2 decreases cardiomyocyte calcium responsiveness and contractility in transgenic mouse hearts. 964 59

A number of molecular and cellular alterations have been identified in the failing human heart that help to understand contraction and relaxation abnormalities. Cyclic AMP dependent pathways are desensitized due to quantitative changes in beta-adrenoceptors, beta-adrenoceptor kinase, and inhibitory G-proteins. Calcium homeostasis is impaired, characterized by a decreased calcium reuptake rate of the sarcoplasmic reticulum, an increased threshold of the calcium release channel, and an increased Na+/Ca2+ exchanger expression. Myofibrillar function may be affected by a decrease in Mg2(+)-ATPase activity and in troponin I phosphorylation, and by changes in TnT isoform expression. These alterations seem to occur independently of the underlying etiology of heart failure and are most likely consequences rather than primary causes of the disease. Most likely, chronic neurohumoral activation and abnormal mechanical load initiate the majority of the hitherto known changes in the myocardium and promote the further progression of cardiac failure as part of a vicious circle. Further extension of knowledge of pathophysiological mechanisms should improve therapeutical strategies which aim at slowing the progression of heart failure and at reversing secondary alterations by interrupting the deleterious influence of neurohumoral activation. Future progress will depend on answers to current gaps in our knowledge of heart failure, including the unknown primary cause of idiopathic dilated cardiomyopathy, factors underlying the greatly variable progression of pump failure, as well as the exact pathophysiological role of the molecular alterations as described in this review.
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PMID:Cellular and molecular aspects of contractile dysfunction in heart failure. 979 11

The progression of cardiac failure is related to the loss of functional myocytes. The aim of these studies was to describe the structural degradation of the myocardium by the use of cardiac troponins as specific and sensitive markers of cardiac cell necrosis. The cardiac isoforms of troponin I and troponin T were measured in patients with NYHA class III-IV heart failure using second generation immunoassays without cross-reactivity with the skeletal isoforms of the two proteins. The results showed that the cardiac troponin I (72.1 +/- 15.8 vs 20.4 +/- 3.2 pg/mL; p < 0.01) and troponin T (0.21 +/- 0.6 vs 0.0005 +/- 0.002 ng/mL; p < 0.001) concentrations were significantly higher in patients with cardiac failure compared to a control population of healthy volunteers. These results suggest that troponin I and troponin T may have valuable clinical applications in the biological monitoring of cardiac failure and the appreciation of its progression.
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PMID:[The troponin complex: a new biochemical approach to cardiac insufficiency]. 989 19


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