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)

The physiopathological mechanisms resulting in increased left ventricular pressures in acute cardiac failure with normal systolic function are not well understood. Although coronary artery disease is commonly associated with acute episodes, the diagnostic value of troponin I measurement and the prevalence of ischaemia as the predisposing factor are not known. Twenty coronary patients (mean age 77 +/- 9 years) in acute cardiac failure with left ventricular ejection fractions of 50% or over and without angina, were studied retrospectively. The diagnostic value of troponin I (cTnI, AxSYM, method) was assessed by comparing with a control group of 16 acute cardiac failure patients without coronary disease. The frequency of hypertension and diabetes in the coronary group was 50 and 45% respectively. At the time of investigation, the pulmonary capillary and systemic arterial pressures were comparable in the coronary patients irrespective of the cTnl value. At threshold levels of 0.5 microgram/l, cTnl had a specificity of 100% and confirmed ischaemia in 60% of the coronary patients. Ischaemia was the commonest predisposing factor for increased cardiac pressures. Over a 268 +/- 101 days follow-up period, half the coronary patients were readmitted for acute cardiac failure and a third of them died. The authors conclude that silent ischaemia is a common predisposing factor for acute cardiac failure in coronary patients with normal systolic function and troponin I measurement is a useful diagnostic help.
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PMID:[Silent ischemia and acute cardiac insufficiency with normal systolic function: diagnostic value of troponin I measurement]. 1457 38

The aim of this study is to investigate the molecular events associated with the deleterious effects of acidosis on the contractile properties of cardiac muscle as in the ischemia of heart failure. We have conducted a study of the effects of increasing acidity on the Ca(2+) induced conformational changes of pyrene labelled cardiac troponin C (PIA-cTnC) in isolation and in complex with porcine cardiac or chicken pectoral skeletal muscle TnI and/or TnT. The pyrene label has been shown to serve as a useful fluorescence reporter group for conformational and interaction events of the N-terminal regulatory domain of TnC with only minimal fluorescence changes associated with C-terminal domain. Results obtained show that the significant decreases at pH 6.0 of site II Ca(2+) affinity of PIA-cTnC when complexed as a binary complex with either cTnI or cTnT are significantly reduced when cTnI is replaced with sTnI or cTnT with sTnT. However, this effect is appreciably diminished when the cTnI and cTnT in the ternary complex are replaced by sTnI and sTnT. The smaller effects in the ternary complex of replacing both cTnI and cTnT by their skeletal counterparts on depressing the Ca(2+) affinity from pH 7.0 to 6.0 arise from TnI replacement. Thus, changes in TnC conformation resulting from isoform-specific interactions with TnI and TnT could be an integral part of the effect of pH on myofilament Ca(2+)sensitivity.
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PMID:Differential pH effect on calcium-induced conformational changes of cardiac troponin C complexed with cardiac and fast skeletal isoforms of troponin I and troponin T. 1563 9

Cardiac failure is one of the leading causes of mortality in developed countries. As life expectancies of the populations of these countries grow, the number of patients suffering from cardiac insufficiency also increases. Effective treatments are being sought and recently a new class of drugs, the calcium sensitisers, was developed. These drugs cause a positive inotropic effect on cardio-myocytes by interacting directly with the contractile apparatus. Their mechanism of action is not accompanied by an increase in intracellular calcium concentration at therapeutic doses, as seen for the older generation of positive inotropic drugs, and thus does not induce calcium-related deleterious effects such as arrhythmias or apoptosis. Levosimendan is a novel calcium sensitiser which has been discovered by using cardiac troponin C (cTnC) as target protein. This drug has been proved to be a well-tolerated and effective treatment for patients with severe decompensated heart failure. This review describes the basic principles of muscle contraction, the main components of the contractile apparatus and their roles in the heart contraction. The regulatory proteins troponin C (cTnC), troponin I (cTnI), troponin T (cTnT), and tropomyosin (Tm) and their interactions are discussed in details. The concept of calcium sensitisation is thereafter explained and a few examples of calcium sensitisers and their putative mechanisms are discussed. Finally, the binding of levosimendan to cTnC and its mechanism of action are described and the results discussed under the light of the action of this drug in vitro and in vivo.
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PMID:The contractile apparatus as a target for drugs against heart failure: interaction of levosimendan, a calcium sensitiser, with cardiac troponin c. 1564 30

Cardiomyopathies are heart muscle diseases, which have been defined by their central hemodynamics and macropathology and divided in five major forms: dilated (DCM), hypertrophic (HCM), restrictive (RCM), right ventricular (RVCM), and nonclassifiable cardiomyopathies (NCCM). Furthermore, the most recent WHO/WHF definition also comprises, among the specific cardiomyopathies, inflammatory cardiomyopathy as a distinct entity, defined as myocarditis in association with cardiac dysfunction. Idiopathic, autoimmune, and infectious forms of inflammatory cardiomyopathy were recognized. Viral cardiomyopathy has been defined as viral persistence in a dilated heart. It may be accompanied by myocardial inflammation and then termed inflammatory viral cardiomyopathy (or viral myocarditis with cardiomegaly). If no inflammation is observed in the biopsy of a dilated heart (< 14 lymphocytes and macrophages/mm(2)), the term viral cardiomyopathy or viral persistence in DCM should be applied according to the WHF Task Force recommendations. Within the German heart failure net it is the authors' working hypothesis, that DCM shares genetic risk factors with other diseases of presumed autoimmune etiology and, therefore, the same multiple genes in combination with environmental factors lead to numerous different autoimmune diseases including DCM. Therefore, the authors' primary goal is to acquire epidemiologic data of patients with DCM regarding an infectious and inflammatory etiology of the disease. Circumstantial evidence points to a major role of viral myocarditis in the etiology of DCM. The common presence of viral genetic material in the myocardium of patients with DCM provides the most compelling evidence, but proof of causality is still lacking. In addition, autoimmune reactions have been described in many studies, indicating them as an important etiologic factor. Nevertheless, data on the proportion of patients, in whom both mechanisms play a role are still missing.A pivotal role for autoimmunity in a substantial proportion of patients with DCM is supported by the presence of organ-specific autoantibodies, inflammatory infiltrates and pro-inflammatory cytotoxic cytokines. Furthermore, familial occurrence of DCM has been described in about 20-30% of cases, with the presence of autoantibodies and abnormal cytokine profiles in first-degree relatives with asymptomatic left ventricular enlargement. This suggests the involvement of a disrupted humoral and cellular immunity early in the development of the disease. A similar pattern of humoral and cellular immune dysregulation has been described in other autoimmune diseases. There is considerable evidence that genetic factors play an important role in the pathogenesis of DCM, either as contributors to the susceptibility to environmental factors or as determinants of functional and structural changes that characterize the phenotypic expression of the disease.Yet, it is not known whether the susceptibility to immunologically mediated myocardial damage reflects the presence of genetic risk factors shared by other autoimmune diseases. Preliminary investigations suggest, that this is the case, because the frequency of autoimmune disorders other than DCM was higher in first-degree relatives of the subjects with DCM including juvenile diabetes, rheumatoid arthritis, thyroiditis, psoriasis, and asthma. The nature of the genetic risk is undetermined and probably involves genes in the major histocompatibility (MHC) locus as well as other susceptibility loci. Therefore, the authors started their investigation with the search for MHC class 2 DQ polymorphisms in the peripheral blood of patients with DCM in parallel to the search for new interesting susceptibility loci by the use of the microarray analysis regarding genes responsible for inflammatory and autoimmune diseases. By this approach a new insight in the familial clustering of other autoimmune diseases in patients with DCM and in genetic predisposition can be expected.
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PMID:Inflammatory dilated cardiomyopathy (DCMI). 1617 Jun 86

Acute heart failure syndromes (AHFS) are related to several diseases affecting not only the heart but also the kidneys and blood vessels. Emerging evidence indicates that myocardial injury may also play a role in the pathophysiology of AHFS, as suggested by increased levels of markers of injury, such as cardiac troponin (cTn). Although cTn is a known prognostic marker, the release of cTn during hospitalization has not been evaluated prospectively with serial measures. We prospectively evaluated patterns of cTn release by conducting serial measures of cTnI and cTnT in patients hospitalized for AHFS. This study enrolled 51 patients with AHFS who were admitted with worsening heart failure (HF) and a history of coronary artery disease (CAD) in whom an acute coronary event was not suspected. Levels of cTnI and cTnT were measured at 8, 32, 56, and 80 hours after study entry. At baseline, 73.9% of patients had detectable cTnI, and 43.5% had detectable cTnT levels. The median concentrations of cTnI and cTnT were unchanged from 0 to 32 hours, increased from 32 to 56 hours, then either plateaued (cTnT) or decreased to baseline (cTnI). Of the 26 patients who had no detectable cTn levels at baseline, 2 (7.7%) developed detectable cTnT and 5 (41.7%) developed detectable cTnI release during hospitalization. Detectable levels of cTn at baseline were related to short-term clinical events. In this study of patients with CAD in whom an acute coronary event was not suspected, most had detectable levels of cTn present at admission, and some patients developed cTn release during hospitalization. Because cTn release may be a marker for myocardial injury, this study raises the possibility that injury occurred in most patients admitted with AHFS. Therefore, the goal of therapy for AHFS should be not only to improve symptoms and hemodynamics but also to salvage myocardium. Accordingly, therapies for AHFS that are aimed at improving hemodynamics may affect long-term prognosis by either injuring or salvaging myocardium.
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PMID:The Pilot Randomized Study of Nesiritide Versus Dobutamine in Heart Failure (PRESERVD-HF). 1618 19

This review focuses on hypertrophic (HCM), restrictive (RCM) and arrhythmogenic right ventricular cardiomyopathies (ARVC). The clinical phenotype of HCM depends not only on the gene mutations involved, but also on "modifier genes". It is characterized by an asymmetrical hypertrophy. Investigations of endomyocardial biopsies (EMBs) typically reveal a disarray of the hypertrophied cardiomyocytes. Percutaneous septum ablation has gained relevance as the treatment of choice in hypertrophic obstructive cardiomyopathy. Myocardial and endomyocardial RCM-forms can be differentiated. Enlargement of the atria in concert with normal dimensions of the ventricles and almost normal systolic contractility as well as the dip-plateau phenomenon are characteristic findings in RCM. EMB diagnostics are pivotal to identify the causes underlying secondary RCM types. Treatment is directed at heart failure and specifically at the underlying disease. With ARVC, apoptosis, viral infection/inflammation and genetic dystrophy result in fibrofatty degeneration primarily of the right, and with further progression also of the left ventricle. The primary treatment goal in ARVC is prevention of sudden cardiac death. As for other cardiomyopathies, there is increasing evidence for the superiority of ICD compared with pharmacological approaches.
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PMID:[Cardiomyopathies II. Hypertrophic cardiomyopathy, restrictive cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy]. 1623 14

Cardiac troponin I (TnI) knockout mice exhibit a phenotype of sudden death at 17-18 days after birth due to a progressive loss of TnI. The objective of this study was to gain insight into the physiological consequences of TnI depletion and the cause of death in these mice. Cardiac function was monitored serially between 12 and 17 days of age by using high-resolution ultrasonic imaging and Doppler echocardiography. Two-dimensional B-mode and anatomical M-mode imaging and Doppler echocardiography were performed using a high-frequency ( approximately 20-45 MHz) ultrasound imaging system on homozygous cardiac TnI mutant mice (cTnI(-/-)) and wild-type littermates. On day 12, cTnI(-/-) mice were indistinguishable from wild-type mice in terms of heart rate, atrial and LV (LV) chamber dimensions, LV posterior wall thickness, and body weight. By days 16 through 17, wild-type mice showed up to a 40% increase in chamber dimensions due to normal growth, whereas cTnI(-/-) mice showed increases in atrial dimensions of up to 97% but decreases in ventricular dimensions of up to 70%. Mitral Doppler analysis revealed prolonged isovolumic relaxation time and pronounced inversion of the mitral E/A ratio (early ventricular filling wave-to-late atrial contraction filling wave) only in cTnI(-/-) mice indicative of impaired LV relaxation. cTnI(-/-) mouse hearts showed clear signs of failure on day 17, characterized by >50% declines in cardiac output, ejection fraction, and fractional shortening. B-mode echocardiography showed a profoundly narrowed tube-like LV and enlarged atria at this time. Our data are consistent with TnI deficiency causing impaired LV relaxation, which leads to diastolic heart failure in this model.
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PMID:Progressive troponin I loss impairs cardiac relaxation and causes heart failure in mice. 1752 46

Although beta-adrenergic stimuli are essential for myocardial contractility, beta-blockers have a proven beneficial effect on the treatment of heart failure, but the mechanism is not fully understood. The stimulatory G protein alpha-subunit (Gsalpha) couples the beta-adrenoreceptor to adenylyl cyclase and the intracellular cAMP response. In a mouse model of conditional Gsalpha deficiency in the cardiac muscle (Gsalpha-DF), we demonstrated heart failure phenotypes accompanied by increases in the level of a truncated cardiac troponin I (cTnI-ND) from restricted removal of the cTnI-specific N-terminal extension. To investigate the functional significance of the increase of cTnI-ND in Gsalpha-DF cardiac muscle, we generated double transgenic mice to overexpress cTnI-ND in Gsalpha-DF hearts. The overexpression of cTnI-ND in Gsalpha-DF failing hearts increased relaxation velocity and left ventricular end diastolic volume to produce higher left ventricle maximum pressure and stroke volume. Supporting the hypothesis that up-regulation of cTnI-ND is a compensatory rather than a destructive myocardial response to impaired beta-adrenergic signaling, the aberrant expression of beta-myosin heavy chain in adult Gsalpha-DF but not control mouse hearts was reversed by cTnI overexpression. These data indicate that the up-regulation of cTnI-ND may partially compensate for the cardiac inefficiency in impaired beta-adrenergic signaling.
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PMID:Removal of the N-terminal extension of cardiac troponin I as a functional compensation for impaired myocardial beta-adrenergic signaling. 1881 35

Transgenic models with pseudo phosphorylation mutants of troponin I, PKA sites at Ser 22 and 23 (cTnIDD(22,23) mice) or PKC sites at Ser 42 and 44 (cTnIAD(22,23)DD(42,44)) displayed differential force-frequency relationships and afterload relaxation delay in vivo. We hypothesized that cTnI PKA and PKC phosphomimics impact cardiac muscle rate-related developed twitch force and relaxation kinetics in opposite directions. cTnIDD(22,23) transgenic mice produce a force frequency relationship (FFR) equivalent to control NTG albeit at lower peak [Ca(2+)](i), while cTnIAD(22,23)DD(42,44) TG mice had a flat FFR with normal peak systolic [Ca(2+)](i), thus suggestive of diminished responsiveness to [Ca(2+)](i) at higher frequencies. Force-[Ca(2+)](i) hysteresis analysis revealed that cTnIDD(22,23) mice have a combined enhanced myofilament calcium peak response with an enhanced slope of force development and decline per unit of [Ca(2+)](i), whereas cTnIAD(22,23)DD(42,44) transgenic mice showed the opposite. The computational ECME model predicts that the TG lines may be distinct from each other due to different rate constants for association/dissociation of Ca(2+) at the regulatory site of cTnC. Our data indicate that cTnI phosphorylation at PKA sites plays a critical role in the FFR by increasing relative myofilament responsiveness, and results in a distinctive transition between activation and relaxation, as displayed by force-[Ca(2+)](i) hysteresis loops. These findings may have important implications for understanding the specific contribution of cTnI to beta-adrenergic inotropy and lusitropy and to adverse contractile effects of PKC activation, which is relevant during heart failure development.
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PMID:Calcium sensitivity, force frequency relationship and cardiac troponin I: critical role of PKA and PKC phosphorylation sites. 2008 17

The Ca(2+) dependent interaction between troponin I (cTnI) and troponin C (cTnC) triggers contraction in heart muscle. Heart failure is characterized by a decrease in cardiac output, and compounds that increase the sensitivity of cardiac muscle to Ca(2+) have therapeutic potential. The Ca(2+)-sensitizer, levosimendan, targets cTnC; however, detailed understanding of its mechanism has been obscured by its instability. In order to understand how this class of positive inotropes function, we investigated the mode of action of two fluorine containing novel analogs of levosimendan; 2',4'-difluoro(1,1'-biphenyl)-4-yloxy acetic acid (dfbp-o) and 2',4'-difluoro(1,1'-biphenyl)-4-yl acetic acid (dfbp). The affinities of dfbp and dfbp-o for the regulatory domain of cTnC were measured in the absence and presence of cTnI by NMR spectroscopy, and dfbp-o was found to bind more strongly than dfbp. Dfbp-o also increased the affinity of cTnI for cTnC. Dfbp-o increased the Ca(2+)-sensitivity of demembranated cardiac trabeculae in a manner similar to levosimendan. The high resolution NMR solution structure of the cTnC-cTnI-dfbp-o ternary complex showed that dfbp-o bound at the hydrophobic interface formed by cTnC and cTnI making critical interactions with residues such as Arg147 of cTnI. In the absence of cTnI, docking localized dfbp-o to the same position in the hydrophobic groove of cTnC. The structural and functional data reveal that the levosimendan class of Ca(2+)-sensitizers work by binding to the regulatory domain of cTnC and stabilizing the pivotal cTnC-cTnI regulatory unit via a network of hydrophobic and electrostatic interactions, in contrast to the destabilizing effects of antagonists such as W7 at the same interface.
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PMID:A structural and functional perspective into the mechanism of Ca2+-sensitizers that target the cardiac troponin complex. 2080 Nov 30

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