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)

p38 Mitogen-activated protein kinase (MAPK) is one of the most ancient signaling molecules and is involved in multiple cellular processes, including cell proliferation, cell growth, and cell death. In the heart, enhanced activation of p38 MAPK is associated with ischemia/reperfusion injury and the onset of heart failure. In the present study, we investigated the function of p38 MAPK in regulating cardiac contractility and its underlying mechanisms. In cultured adult rat cardiomyocytes, activation of p38 MAPK by adenoviral gene transfer of an activated mutant of its upstream kinase, MKK3bE, led to a significant reduction in baseline contractility, compared with uninfected cells or those infected with a control adenoviral vector (Adv-beta-galactosidase). The inhibitory effect of MKK3bE on contractility was largely prevented by coexpressing a dominant-negative mutant of p38 MAPK or treating cells with a p38 MAPK inhibitor, SB203580. Conversely, inhibition of endogenous p38 MAPK activity by SB203580 rapidly and reversibly enhanced cell contractility in a dose-dependent manner, without altering L-type Ca(2+) currents or Ca(2+)(i) transients. MKK3bE-induced p38 activation had no significant effect on pH(i), whereas SB203580 had a minor effect to elevate pH(i). Furthermore, activation of p38 MAPK was unable to increase troponin I phosphorylation. Thus, we conclude that the negative inotropic effect of p38 MAPK is mediated by decreasing myofilament response to Ca(2+), rather than by altering Ca(2+)(i) homeostasis and that the reduced myofilament Ca(2+) sensitivity is unlikely attributable to troponin I phosphorylation or alterations in pH(i). These findings reveal a novel function of p38 MAPK and shed a new light on our understanding of the coincidence of p38 MAPK activation and the onset of heart failure.
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PMID:p38 Mitogen-activated protein kinase mediates a negative inotropic effect in cardiac myocytes. 1183 12

Troponin T is a central component of the thin filament-associated troponin-tropomyosin system and plays an essential role in the Ca(2+) regulation of striated muscle contraction. The importance of the structure and function of troponin T is evident in the regulated isoform expression during development and the point mutations resulting in familial hypertrophic and dilated cardiomyopathies. We report here that turkeys with inherited dilated cardiomyopathy and heart failure express an unusual low molecular weight cardiac troponin T missing 11 amino acids due to the splice out of the normally conserved exon 8-encoded segment. The deletion of a 9-bp segment from intron 7 of the turkey cardiac troponin T gene may be responsible for the weakened splicing of the downstream exon 8 during mRNA processing. The exclusion of the exon 8-encoded segment results in conformational changes in cardiac troponin T, an altered binding affinity for troponin I and tropomyosin, and an increased calcium sensitivity of the actomyosin ATPase. Expression of the exon 8-deleted cardiac troponin T prior to the development of cardiomyopathy in turkeys indicates a novel RNA splicing disease and provides evidence for the role of troponin T structure-function variation in myocardial pathogenesis and heart failure.
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PMID:Exon skipping in cardiac troponin T of turkeys with inherited dilated cardiomyopathy. 1188 65

Contractility of the myocardium is altered in end-stage heart failure. We investigated whether this was related to functional changes in troponin. We isolated troponin from 1 g samples of end-stage failing, non-failing and foetal human heart and studied its regulation of actin-tropomyosin movement over immobilised HMM by in vitro motility assay. At pCa5.4 the sliding velocity of thin filaments reconstituted with non-failing heart troponin was 52+/-4% more than actin-tropomyosin, with failing heart troponin velocity increased by 35+/-2% and with foetal heart troponin velocity increased by 11+/-4%. Thin filaments containing troponin from failing hearts were more Ca(2+)-sensitive than non-failing heart troponin. EC(50) for the fraction of filaments motile and filament velocity decreased 1.76+/-0.20 and 1.89+/-0.62-fold respectively relative to non-failing heart troponin. With foetal heart troponin the EC(50) decreased 2.16+/-0.23 and 3.50+/-1.73-fold for fraction and velocity respectively. Western blots revealed no difference in troponin T or troponin I isoform expression in troponin from failing and non-failing adult hearts but foetal isoforms of troponin I and T were observed in troponin from foetal heart. The level of PKA phosphorylation of troponin from failing and non-failing heart was not significantly different, however, complete non-specific dephosphorylation of troponin abolished most of the difference between failing and non-failing heart troponin. These findings show functional alterations in troponin in failing hearts which could account for the reduced contractile function but there is no change in troponin isoform expression or PKA phosphorylation. Differential phosphorylation by other kinases may account for altered troponin function.
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PMID:In vitro motility analysis of thin filaments from failing and non-failing human heart: troponin from failing human hearts induces slower filament sliding and higher Ca(2+) sensitivity. 1209 6

Hydroxyl radicals (OH) are involved in the development of reperfusion injury and myocardial failure. In the acute phase of the OH-mediated diastolic dysfunction, increased intracellular Ca(2+) levels and alterations of myofilaments may play a role, but the relative contribution of these systems to myocardial dysfunction is unknown. Intact contracting cardiac trabeculae from rabbits were exposed to OH, resulting in an increase in diastolic force (F(dia)) by 540%. Skinned fiber experiments revealed that OH-exposed preparations were sensitized for Ca(2+) (EC(50): 3.27+/-0.24 x 10(-6) versus 2.69+/-0.15 x 10(-6) mol/L; P<0.05), whereas maximal force development was unaltered. Western blots showed a proteolytic degradation of troponin T (TnT) with intact troponin I (TnI). Blocking of calpain I by MDL-28.170 inhibited both TnT-proteolysis and Ca(2+) sensitization, but failed to prevent the acute diastolic dysfunction in the intact preparation. The OH-induced diastolic dysfunction was similar in preparations with intact (540+/-93%) and pharmacologically blocked sarcoplasmic reticulum (539+/-77%), and was also similar in presence of the L-type Ca(2+)-channel antagonist verapamil. In sharp contrast, inhibition of the reverse-mode sodium-calcium exchange by KB-R7943 preserved diastolic function completely. Additional experiments were performed in rat myocardium; the rise in diastolic force was comparable to rabbit myocardium, but Ca(2+) sensitivity was unchanged and maximal force development was reduced. This was associated with a degradation of TnI, but not TnT. Electron microscopic analysis revealed that OH did not cause irreversible membrane damage. We conclude that OH-induced acute diastolic dysfunction is caused by Ca(2+) influx via reverse mode of the sodium-calcium exchanger. Degradation of troponins appears to be species-dependent but does not contribute to the acute diastolic dysfunction.
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PMID:Hydroxyl radical-induced acute diastolic dysfunction is due to calcium overload via reverse-mode Na(+)-Ca(2+) exchange. 1201 65

Myocardial contrast echocardiography is a promising diagnostic tool for detecting microvascular integrity. Multiple experimental laboratories have shown that diagnostic combined microbubble contrast and ultrasound exposure can cause vessel rupture and myocardial damage in laboratory animals. This study investigated the phenomenon of contrast ultrasonically induced myocardial damage in human beings. Twenty consecutive patients (mean age of 60 +/- 12 years, 14 men) underwent contrast echocardiography with intravenous Optison using a mechanical index of at least 1.4 (Vivid Five System (GE, Vingmed Ultrasound, Horton, Norway). Creatine kinase (CK), creatine kinase-isoenzyme MB (CK-MB); CK-MB mass, myoglobin, and troponin I were measured before and 2, 4, 8, and 24 hours after contrast echocardiography. There was no significant correlation concerning the response to contrast echocardiography for any pair of parameters at any time after the intervention. Only in 2 patients were there higher values for troponin I before and after contrast echocardiography without an increase of myoglobin, CK, or CK-MB mass and activity. These values were therefore interpreted as false positive because of renal failure and severe heart failure. The use of contrast echocardiography is without demonstrated risk of myocardial damage even in patients with different cardiologic entities.
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PMID:Does contrast echocardiography with Optison induce myocardial necrosis in humans? 1237 50

Molecular switches between the troponin T and I isoforms are known to occur in various conditions, but the results from studies of failing human hearts with various etiologies are contradictory and it is not certain whether troponin isoform changes occur. Therefore, the molecular switching of troponin isoforms during normal development and heart failure (HF) after myocardial infarction were investigated in Sprague-Dawley rats at the fetal, neonate, and normal adult stages, and in a postinfarction adult HF group. During normal development, switching from the fetal to the adult pattern of the troponin T and I isoforms was observed. Immunoblotting of postinfarction failing hearts revealed a marked increase in the fetal isoform of cardiac TnT (cTnT) (fetal/adult cTnT isoforms: normal adult = 0.61 +/- 0.09 vs postinfarction HF = 1.59 +/- 0.13, p < 0.001). Also, the amount of the adult troponin I (TnI) isoform decreased significantly in the postinfarction failing heart. In the semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) with glyceraldehyde-3-phosphate-dehydrogenase (GAPDH) as an internal standard, the mRNA of fetal cTnT increased in the postinfarction failing heart (fetal cTnT/GAPDH: control = 0.22 vs HF rat = 0.84, p < 0.05). Therefore, molecular switching of the troponin T and I isoforms occurred during the normal development of the rat, and there was re-expression of the fetal pattern of the isoforms in the postinfarction failing heart of the adult rat.
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PMID:Re-expression of fetal troponin isoforms in the postinfarction failing heart of the rat. 1238 Oct 93

The objective of this study was to determine the safety of the glycoprotein IIb/IIIa receptor inhibitor eptifibatide in patients at high risk for adverse clinical outcomes and to determine risk factors for eptifibatide-associated bleeding. Consecutive patients (n = 175) who presented with an acute coronary syndrome and who were at high risk for adverse clinical outcomes were prospectively observed for eptifibatide-associated bleeding, which was classified according to Thrombolysis in Myocardial Infarction (TIMI) and Global Use of Strategies to Open Occluded arteries (GUSTO) criteria. High risk was defined as unstable angina or non-Q-wave myocardial infarction with at least one of the following: left ventricular ejection fraction < 40%, diabetes mellitus, ST segment depression or transient ST segment elevation, serum [troponin I] > 2.5 ng/mL, and recurrent angina symptoms after initiation of conventional antianginal therapy. Bleeding incidences in the patients in this study were compared with those in the 4722 eptifibatide-treated patients in the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial. Compared to PURSUIT patients, the population in this study was similar in age but had a higher proportion of females, African Americans, hypertension, diabetes, prior myocardial infarction, heart failure, and revascularization. Bleeding incidences in this study's patients were similar to or lower than those in the PURSUIT population: TIMI major 1.1% versus 10.8%, TAMI minor 12.6% versus 13.1%, GUSTO severe 1.7% versus 1.5%, GUSTO moderate 3.9% versus 11.3%, and GUSTO mild 19.7% versus 26.1%. Renal dysfunction was an independent risk factor for TIMI (odds ratio = 9.1 ([95% CI= 1.6-52.5]) and GUSTO (odds ratio = 6.1 [95% CI = 1.2-30.0]) bleeding. In conclusion, despite being at higher risk for adverse outcomes, patients administered eptifibatide according to this study's institutional guidelines had comparable or lower bleeding rates than in the PURSUIT trial. Renal dysfunction is an independent risk factor for eptifibatide-induced bleeding.
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PMID:Bleeding associated with eptifibatide targeting higher risk patients with acute coronary syndromes: incidence and multivariate risk factors. 1246 32

Troponins I and T represent the current biomarker standard for diagnosis of myocardial infarction. Even small increases of cardiac troponins have prognostic implications, but not all patients at risk are correctly classified, particularly at admission. We identified elevated whole-blood choline as a promising marker and performed a prospective study of 327 patients with a suspected acute coronary syndrome that focused on the analysis of troponin-negative patients. Diagnostic classification of patients and the definition of troponin cutoffs were performed according to the new European Society of Cardiology/American College of Cardiology criteria. Blood was sampled serially and choline was measured using high-performance liquid chromatography mass spectrometry in whole blood. Patients were followed for 30 days. In patients with negative troponin I test results at admission (n = 250), choline was a predictor of cardiac death and nonfatal cardiac arrest (hazard ratio 6.0, p = 0.003), life-threatening arrhythmias (hazard ratio 3.75, p = 0.004), heart failure (hazard ratio 2.87, p = 0.002), and coronary angioplasty (hazard ratio 2.57, p = 0.001). In multivariate analysis of troponin-negative patients, choline was the strongest predictor of cardiac death or arrest (odds ratio 6.05, p = 0.01). Choline was not a marker for myocardial necrosis but indicated high-risk unstable angina in patients without acute myocardial infarction (sensitivity 86.4%, specificity 86.2%). Thus, an increased concentration of choline at hospital admission is a predictor of adverse cardiac events in patients with suspected acute coronary syndromes. Whole blood choline may be useful for early risk stratification of these patients, particularly if troponin results are negative on admission.
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PMID:Prognostic implications of elevated whole blood choline levels in acute coronary syndromes. 1271 47

A 41 year old woman with type 2 diabetes, hypertension, and hyperlipidaemia but no known heart disease received 130 DC shocks for repeated cardiac arrests due to ventricular tachyarrhythmias over 48 hours. She was stabilised by intravenous amiodarone and had a defibrillator implanted. Serial ECGs did not change, but raised troponin I confirmed myocardial infarction as the underlying cause. Electrical storm is an uncommon and dramatic but usually treatable syndrome of recurrent ventricular arrhythmias. Frequent precipitants of electrical storm include recent worsening heart failure, hypokalaemia, hypomagnesaemia and myocardial ischaemia. Amiodarone is the antiarrhythmic agent of choice and implantable cardioverter defibrillator improves long term outcome.
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PMID:Successful resuscitation of a patient with electrical storm. 1274 67

Laboratory monitoring with damage markers of brain and of non-nervous tissues in blood serum of 401 acute care patients showed increased contents of neuron-specific enolase (NSE) and S100B besides raised levels of markers of heart, skeletal muscle, bile duct, liver, prostate, kidney, salivary gland damage or of inflammatory stress to varying frequencies. Correlation between raised NSE and S100B contents ascertained brain damage. Correlation between raised NSE and troponin I (cTnI) values indicated brain damage induced by heart failure (probably caused by hypoxia and anemia); this was assessed with correlations between NSE and other heart markers, e.g. creatine kinase (CK) isoenzymes, alpha-hydroxybutyrate dehydrogenase. S100B did not show such correlations: data indicated S100B release from non-nervous tissues having high S100B content, e.g. fat, cartilage, skin. S100B release might be triggered by inflammatory stress and tissue damage. This was further supported by low NSE/S100B concentration ratios in serum compared to cerebrospinal fluid (CSF) of patients with comatose state, convulsive status, or intracerebral hemorrhage. Our data revealed CSF to be the relevant sample to monitor brain damage with NSE and S100B, whereas in serum raised S100B levels together with normal NSE levels indicated release from non-nervous tissues of acute care patients pointing out multi-organ dysfunction.
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PMID:Studies of the brain specificity of S100B and neuron-specific enolase (NSE) in blood serum of acute care patients. 1290 97


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