Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Cardiomyocyte apoptosis is present in many cardiac disease states, including heart failure and ischemic heart disease. Apoptosis is associated with the activation of caspases that mediate the cleavage of vital and structural proteins. However, the functional contribution of apoptosis to these conditions is not known. Furthermore, in cardiac myocytes, apoptosis may not be complete, allowing the cells to persist for a prolonged period within the myocardium. Therefore, we examined whether caspase-3 cleaved cardiac myofibrillar proteins and, if so, whether it affects contractile function. The effects of caspase-3 were studied in vitro on individual components of the cardiac myofilament including alpha-actin, alpha-actinin, myosin heavy chain, myosin light chain 1/2, tropomyosin, cardiac troponins (T, I, C), and the trimeric troponin complex. Exposure of the myofibrillar protein (listed above) to caspase-3 for 4 h resulted in the cleavage of alpha-actin and alpha-actinin, but not myosin heavy chain, myosin light chain 1/2, and tropomyosin, into three fragments (30, 20, and 15 kDa) and one major fragment (45 kDa), respectively. When cTnT, cTnI, and cTnC were incubated individually with caspase-3, there was no detectable cleavage. However, when the recombinant troponin complex was exposed to caspase-3, cTnT was cleaved, resulting in fragments of 25 kDa. Furthermore, rat cardiac myofilaments exposed to caspase-3 exhibited similar patterns of myofibrillar protein cleavage. Treatment with the caspase inhibitor DEVD-CHO or z-VAD-fmk abolished the cleavage. Myofilaments, isolated from adult rat ventricular myocytes after induction of apoptotic pathway by using beta-adrenergic stimulation, displayed a similar pattern of actin and TnT cleavage. Exposure of skinned fiber to caspase-3 decreased maximal Ca(2+)-activated force and myofibrillar ATPase activity. Our results indicate that caspase-3 cleaved myofibrillar proteins, resulting in an impaired force/Ca(2+) relationship and myofibrillar ATPase activity. Induction of apoptosis in cardiac cells was associated with similar cleavage of myofilaments. Therefore, activation of apoptotic pathways may lead to contractile dysfunction before cell death.
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PMID:Functional consequences of caspase activation in cardiac myocytes. 1197 44

Cardiac troponin(cTn) is a sensitive marker for acute myocardial infarction(AMI). However, some cases of renal failure have been reported to show false positive results for cardiac troponin T(cTnT). Recently, it has been reported that heart-type fatty acid-binding protein(H-FABP) is a sensitive marker for AMI in the early phase. We evaluated the usefulness of cardiac troponin I(cTNI) using serum samples from patients(age 57-96) confirmed to have AMI with chest pain(n = 48), unstable angina pectoris(n = 11), cardiac failure(n = 5), others with high creatine phosphokinase(CK) activity(n = 81) and renal failure(n = 28), by comparing among cTnT(qualitative and quantitative), H-FABP, CK and creatine phosphokinase isoenzyme MB(CK-MB) activity. The diagnostic validity of cTn was assessed by receiver operating characteristic(ROC) curve analysis. The cut off value for AMI of cTnI was 0.8 ng/ml, cTnT was 0.16 ng/ml and H-FABP was 19.0 ng/ml. The overall diagnostic sensitivity of cTnI was 83.1%, and 84.8% for cTnT (quantitative), 72.3% for cTnT(qualitative), 64.8% for H-FABP, 81.8% for CK and 59.3% for CK-MB. The overall diagnostic specificity of cTnI was 90.9%, and 81.3% for cTnT(quantitative), 60.5% for cTnT (qualitative), 53.2% for H-FABP, 52.9% for CK and 87.7% for CK-MB. The overall diagnostic efficiency of cTnI was 86.5%, and 82.7% for cTnT(quantitative), 63.6% for cTnT(qualitative), 59.8% for H-FABP, 69.0% for CK and 71.9% for CK-MB. False positive results for cTnI were found in a few cases with renal failure. cTnT(qualitative) showed false positive results in 22/28 with serum creatinine over 2.1 mg/dl due to renal failure. In conclusion, cTnI detection is considered a useful and sufficiently sensitive marker for AMI.
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PMID:[Usefulness of cardiac troponin I in patients with acute myocardial infarction]. 1245 79

Endomyocardial biopsy (EMB) is currently the standard method to diagnose acute graft rejection. However, considering the potential complications of this procedure, a noninvasive marker of rejection would be an ideal alternative or at least a helpful adjunct to posttransplant management. We measured myoglobin (Myo), creatine kinase MB mass (CK-MBm), troponin T (cTnT), serum amyloid A (SAA), and C-reactive protein (CRP) in 57 patients (mean age 37.5 years) who underwent orthotopic heart transplantation for end-stage cardiac failure between January and December 2001.Endomyocardial biopsies were performed routinely after surgery and histologically diagnosed rejection was graded according to the criteria of the International Society of Heart and Lung Transplantation. Concomittant with the biopsies, blood samples were drawn from the coronary sinus (central blood samples) and from a peripheral vein (peripheral blood samples) to assay biochemical markers. Among 149 EMB evaluated, 87 were negative (grade 0); 28 showed grade 1a rejection; 26 showed grade 1b; and 8 showed grade > 1b (2 were grade 2, 6 were grade 3a). Grades 0 and 1a were considered to be negative, while grades 1b and >1b were considered positive indicating potential acute graft rejection. cTnT, Myo, CK-MBm, SAA, and CRP levels were measured in 149 central blood samples and 149 peripheral blood samples. Myo and CK-MBm did not show significant changes. cTnT seems to be a potentially useful addition to the EMB results, while SAA and CRP showed variations with respect to EMB grade both in central and peripheral samples.
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PMID:Utility of biochemical markers in the follow-up of heart transplant recipients. 1469 83

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

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

Over the forty years since its discovery, there has been a profound transition in thinking with regard to the role of troponin in the control of cardiac function. This transition involved a change in perception oftroponin as a passive molecular switch responding to membrane controlled fluctuations in cytoplasmic Ca2+ to a perception of troponin as a critical element in signaling cascades that actively engage in control of cardiac function. Evidence demonstrating functionally significant developmental and mutant isoform switches and post-translational modifications of cardiac troponin complex proteins, troponin I (cTnI) and troponin T (cTnT) provided convincing evidence for a more complicated role of troponin in control of cardiac function and dynamics. The physiological role of these modifications of troponin is reviewed in this monograph and has also been reviewed elsewhere (Solaro and Rarick, 1998; Gordon et al., 2000; Solaro et al., 2002a; Kobayashi and Solaro, 2005). Our focus here is on studies related to modifications in troponin that appear important in the processes leading from compensated hypertrophy to heart failure. These studies reveal the potentially significant role of post-translational modifications of troponin in these processes. Another focus is on troponin as a target for inotropic agents. Pharmacological manipulation of troponin by small molecules remains an important avenue of approach for the treatment of acute and chronic heart failure (Kass and Solaro, 2006).
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PMID:Heart failure, ischemia/reperfusion injury and cardiac troponin. 1727 66

Appropriate evaluation of short- and medium-term cardiovascular risk in acute coronary syndromes (ACS) patients should allow to individualize and improve treatment in the future. Natriuretic peptides can be measured in plasma using reliable and fast methods. B-type natriuretic peptide (BNP) is released into the circulation by the cardiac ventricle in response to increases in wall stress. Both BNP and NT-proBNP have been shown to aid in the diagnosis of heart failure. In addition, these peptides correlate with left ventricular dilatation, remodelling and dysfunction, and have the capacity of improving significantly the early risk stratification in patients with ST- or non-ST-elevation ACS. BNP determinations can be associated to cardiac troponins (for example, cTnT) and C-reactive protein (CRP). Plasma concentrations of these biomarkers are related to different physiopathological mechanisms: tissue necrosis (cTnT), neuro-hormonal activation (BNP, NT-proBNP) or inflammatory process and plaque instability (CRP). Combining two or three of these biomarkers for better risk stratification has the potential to improve substantially the outcomes in patients with ACS.
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PMID:[Multiparametric evaluation of cardiac risk in acute coronary syndromes: value of biological blood markers]. 1807 51

The N-terminal variable region of cardiac troponin T (TnT) is a regulatory structure that can be selectively removed during myocardial ischaemia reperfusion by mu-calpain proteolysis. Here we investigated the pathophysiological significance of this post-translational modification that removes amino acids 1-71 of cardiac TnT. Working heart preparations were employed to study rat acute myocardial infarction and transgenic mouse hearts over-expressing the N-terminal truncated cardiac TnT (cTnT-ND). Ex vivo myocardial infarction by ligation of the left anterior descending coronary artery induced heart failure and produced cTnT-ND not only in the infarct but also in remote zones, including the right ventricular free wall, indicating a whole organ response in the absence of systemic neurohumoral mechanisms. Left ventricular pressure overload in mouse working hearts produced increased cTnT-ND in both ventricles, suggesting a role of haemodynamic stress in triggering an acute whole organ proteolytic regulation. Transgenic mouse hearts in which the endogenous intact cardiac TnT was partially replaced by cTnT-ND showed lowered contractile velocity. When afterload increased from 55 mmHg to 90 mmHg, stroke volume decreased in the wild type but not in the transgenic mouse hearts. Correspondingly, the left ventricular rapid-ejection time of the transgenic mouse hearts was significantly longer than that of wild type hearts, especially at high afterload. The restricted deletion of the N-terminal variable region of cardiac troponin T demonstrates a novel mechanism by which the thin filament regulation adapts to sustain cardiac function under stress conditions.
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PMID:Restricted N-terminal truncation of cardiac troponin T: a novel mechanism for functional adaptation to energetic crisis. 1855 68

Patients with End-Stage Renal Disease (ESRD) are at high risk of death as a result of the cardiovascular disease (CVD), which cannot be explained by the conventional risk factors only. Haemodialysis patients frequently have elevated serum concentrations of the cardiac troponins T, specific markers of myocardial injury. Plasma levels of brain natriuretic peptide (BNP) are elevated in fluid volume overload and heart failure, and decreased during dialysis. Currently, LV hypertrophy and LV dysfunction are considered the strongest predictors of cardiovascular mortality in dialysis population, and the synthesis of cardiac natriuretic peptides is high in the presence of alterations in the left ventricular (LV) mass and function. The aim of this study was to investigate the factors associated with the increased serum levels of BNP and CTN in haemodialysis patients, and their impact on cardiovascular morbidity. In this cross-sectional study we included 30 patients with ESRD, without coronary symptoms, who were subjected to regular dialysis treatment three times a week for the duration of four hours. Heart failure was defined as an ejection fraction (EF) of < 35%, and dyspnoea associated with either elevated jugular pressure or interstitial oedema evidenced in chest X-ray. All patients were in sinus rhythm at the time of the study. Twenty-five patients were on erythropoietin treatment. Blood samples were taken before and after the dialysis session. Our study included 30 patients (17 males, 13 females). The average age was 53,8 years (total range 31-74) divided into two groups: euvolemic and hypervolemic. The average dialysis time was 70,3+/-46,95 months. All haemodialysis patients had excessively high levels of BNP 2196,66+/-4553,86 ng/cm3. Plasma cTnT was found to be increased in 33,3% of patients. Patients with hypervolemia had significantly higher cTnT levels (0,0577+/-0,0436), as compared to the euvolemic patients 0,0184+/-0,0259 p<0,05. The elevated cTnT significantly correlated with the level of BNP (p<0,01), while average post-dialysis BNP was not significantly lower (1698,06+/-3499,15; R=0,191; p-ns.) as compared to the pre-dialysis BNP (1839,13+/-3691,55; R=432; p<0,01). The pre-dialysis cTnT was lower (0,0315+/-0,0372) as compared to the post-dialysis cTnT (average 0,0399). Euvolemic patients had BMI 24,28+/-3,15, as compared to the hypervolemic patients BMI 25,71+/-4,20 (p-n.s.). Increased BNP was not in correlation with older age (R-0,271 p-ns.) and duration of dialysis (R-0,198). The hematocrit level increases significantly during haemodialysis (39,9%; p<0,05). Patients with higher BNP and cTnT have significantly higher indexed left ventricular mass, as compared to the patients with normal ventricular function. Our study shows that 33,3% of asymptomatic patients on haemodialysis have elevated cTnT while all patients have elevated BNP. Measuring the plasma concentration of brain natriuretic hormones may be useful for identification of the dialysis patients with LVH.
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PMID:Plasma levels of brain natriuretic peptides and cardiac troponin in hemodialysis patients. 1948 46


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