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)

Propionyl-L-carnitine (PLC) is under development as a therapeutic for the treatment of peripheral artery disease, coronary heart disease and chronic heart failure. Three methods were examined for labelling PLC in its propionyl group with positron-emitting carbon-11 (t12 = 20.3 min), one chemical and two chemoenzymatic. The former was based on the preparation of [11C]propionyl chloride as labelling agent via 11C-carboxylation of ethylmagnesium bromide with cyclotron-produced [11C]carbon dioxide and subsequent chlorination. Reaction of carrier-added [11C]propionyl chloride with L-carnitine in trifluoroacetic acid gave [11C]PLC in 12% radiochemical yield (decay-corrected) from cyclotron-produced [11C]carbon dioxide. However, the radiosynthesis was unsuccessful at the no-carrier-added (NCA) level of specific radioactivity. [11C]Propionate, as a radioactive precursor for chemoenzymatic routes, was prepared via carboxylation of ethylmagnesium bromide with [11C]carbon dioxide and hydrolysis. NCA [11C]PLC was prepared in 68 min in 14% radiochemical yield (decay-corrected) from [11C]propionate via sequential conversions catalysed by acetate kinase, phosphotransacetylase and carnitine acetyltransferase. A superior chemoenzymatic synthesis of NCA [11C]PLC was developed, based on the use of a novel supported Grignard reagent for the synthesis of [11C]propionate and conversions by S-acetyl-CoA synthetase and carnitine acetyltransferase. This gave an overall radiochemical yield of 30-48% (decay-corrected). This synthesis was automated for radiation safety and provides pure NCA [11C]PLC in high radioactivities ready for intravenous administration within 25 min from radionuclide production. The [11C]PLC is suitable for pharmacokinetic studies in human subjects with PET and the elucidation of the fate of the propionyl group of PLC in vivo.
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PMID:Automated chemoenzymatic synthesis of no-carrier-added [carbonyl-11C]propionyl L-carnitine for pharmacokinetic studies. 937 26

Inherited and acquired cardiomyopathies are associated with marked intracellular lipid accumulation in the heart. To test the hypothesis that mismatch between myocardial fatty acid uptake and utilization leads to the accumulation of cardiotoxic lipid species, and to establish a mouse model of metabolic cardiomyopathy, we generated transgenic mouse lines that overexpress long-chain acyl-CoA synthetase in the heart (MHC-ACS). This protein plays an important role in vectorial fatty acid transport across the plasma membrane. MHC-ACS mice demonstrate cardiac-restricted expression of the transgene and marked cardiac myocyte triglyceride accumulation. Lipid accumulation is associated with initial cardiac hypertrophy, followed by the development of left-ventricular dysfunction and premature death. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining and cytochrome c release in transgenic hearts suggest that cardiac myocyte death occurs, in part, by lipid-induced programmed cell death. Taken together, our data demonstrate that fatty acid uptake/utilization mismatch in the heart leads to accumulation of lipid species toxic to cardiac myocytes. This novel mouse model will provide insight into the role of perturbations in myocardial lipid metabolism in the pathogenesis of inherited and acquired forms of heart failure.
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PMID:A novel mouse model of lipotoxic cardiomyopathy. 1128

Increasing evidence has indicated that the modulation of intracellular redox states has marked influence on cellular events such as proliferation, activation, growth inhibition and death via the regulation of intracellular signal transduction and gene expression. Thioredoxin(TRX) is a multifunctional stress-inducible protein which protects cells from various types of stresses. TRX shows not only scavenging activity for ROS, but also regulating activity for various intracellular molecules including transcription factors. Overexpression of TRX in transgenic mice attenuates adriamycin-induced cardiotoxicity by reducing oxidative stresses. We demonstrated that serum TRX levels are correlated with the severity of heart failure, and are negatively correlated with left ventricular ejection fractions in patients with heart failure. Moreover, we found that the serum TRX levels in patients with ACS were significantly higher than in SA, whereas no significant difference was found between patients with SA and control subjects. The expression of TRX is enhanced not only in endothelial cells and macrophages in the human atherosclerotic plaques, but also in balloon-injured rat arteries. These findings suggest that TRX and the redox system modulated by TRX play an important role in the cellular defense against oxidative stress in cardiovascular diseases including the progression of atherosclerosis.
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PMID:[Thioredoxin and atherosclerosis]. 1467 90

Presented in this paper is our experience in the diagnosis and management of abdominal compartment syndrome during severe acute pancreatitis. On the basis of the history of severe acute pancreatitis, after effective fluid resuscitation, if patients developed renal, pulmonary and cardiac insufficiency after abdominal expansion and abdominal wall tension, ACS should be considered. Cystometry could be performed to confirm the diagnosis. Emergency decompressive celiotomy and temporary abdominal closure with a 3 liter sterile plastic bag must be performed. It is also critical to prevent reperfusion syndrome. In 23 cases of ACS, 18 cases received emergency decompressive celiotomy and 5 cases did not. In the former, 3 patients died (16.7%) while in the later, 4 (80%) died. Total mortality rate was 33.3% (7/21). In 7 death cases, 4 patients developed acute obstructive suppurative cholangitis (AOSC). All the patients who received emergency decompressive celiotomy 5 h after confirmation of ACS survived. The definitive abdominal closure took place mostly 3 to 5 days after emergency decompressive celiotomy, with longest time being 8 days. 6 cases of ACS at infection stage were all attributed to infected necrosis in abdominal cavity and retroperitoneum. ACS could occur in SIRS stage and infection stage during SAP, and has different pathophysiological basis. Early diagnosis, emergency decompressive celiotomy and temporary abdominal closure with a 3L sterile plastic bag are the keys to the management of the condition.
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PMID:Diagnosis and management of severe acute pancreatitis complicated with abdominal compartment syndrome. 1501 46

The emergence of cardiac troponins has been an interesting step in the diagnosis of ACS. It has clearly helped us to better triage patients toward a more aggressive posture in performing early cardiac catheterization, and in some cases, early use of adjunctive Gp IIb/IIIa antagonists and percutaneous or surgical myocardial revascularization. However, with this step forward has come uncertainty and many cardiology consults regarding positive cardiac troponins in patients without ACS or myocardial infarction. In general, increased cardiac troponins imply a worse prognosis. This is clearly true of patients with ESRD and advanced heart failure. It is also true of patients with severe, noncardiac illnesses. In other situations, such as acute pericarditis and cardiac surgery, slightly elevated cardiac troponins do not seem to predict a worse prognosis, and can probably be disregarded. The elevation of cardiac troponins after successful percutaneous coronary interventions is not unexpected, and the level of cardiac troponin release seems to predict problems, but lively controversy persists. Last, monitoring cardiac troponins in cardiac transplant recipients and those receiving certain cardiotoxic chemotherapies may be of some diagnostic value, but clearly more experience and clinical research are needed.
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PMID:Cardiac troponins in renal insufficiency and other non-ischemic cardiac conditions. 1573 85

We evaluated the in-hospital and 1-year outcomes and predictors of admission heart failure in patients with non-ST-elevation acute coronary syndromes (NSTE-ACSs) without previous heart failure. We analyzed 4,825 patients with NSTE-ACS without a history of congestive heart failure who were included in the multicenter Canadian ACS Registries. Patients in Killip's class II/III on admission (n = 559, 11.6%) were compared with patients in Killip's class I. Patients with heart failure on admission were older (72 [64, 79] vs 64 [54, 73] years, p < 0.0001), with higher baseline creatinine levels (96 vs 88 mmol/dl, p <0.0001), more diabetes (32.2% vs 22.8%, p < 0.0001), hypertension (58% vs 52.4%, p = 0.014), previous myocardial infarction (MI; 38.9% vs 30.3%, p < 0.0001), previous stroke (13.5% vs 7.4%, p < 0.0001), and had more ST depression on admission (27.7% vs 17.3%, p < 0.0001). In-hospital treatment was similar except for a lower rate of aspirin therapy and fewer coronary interventions. Crude event rates were significantly higher in patients with heart failure (in-hospital death 3.6% vs 1.1%, p < 0.0001; death or MI 7.9% vs 4.7%, p = 0.0011; stroke 1.1% vs 0.4%, p = 0.03). One-year event rates were also higher in patients with heart failure (death 14.6% vs 4.4%, p < 0.0001; MI 9.3% vs 6.6%, p = 0.03; death or MI 21.5% vs 10.3%, p < 0.0001). Variables independently associated with heart failure were age (odds ratio 1.57, 95% confidence interval 1.43 to 1.73), diabetes mellitus (odds ratio 1.53, 95% confidence interval 1.24 to 1.89), admission ST depression (odds ratio 1.52, 95% confidence interval 1.22 to 1.90), previous MI, and baseline creatinine. Heart failure on admission was an independent predictor of in-hospital death, death or MI, and stroke and of 1-year death and death or MI. In conclusion, in patients with NSTE-ACS, heart failure on admission is associated with increased short- and long-term rates of death and MI.
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PMID:Prognostic significance of admission heart failure in patients with non-ST-elevation acute coronary syndromes (from the Canadian Acute Coronary Syndrome Registries). 1689 99

In the case of non-ST-segment elevation acute coronary syndromes (NSTE-ACSs), the acute use of certain antiplatelet agents is complicated by concerns about perioperative bleeding risks in patients requiring coronary artery bypass grafting (CABG) during the index hospitalization. As a result, clinicians often withhold potentially useful agents, such as clopidogrel, before determining patients' coronary anatomy. An accurate predictive model could allow for a better balance of this safety concern with the demonstrated benefits of agents such as clopidogrel. To create an accurate decision-making tool that would assess, at hospital presentation, the need for CABG in patients with NSTE-ACSs, we studied 61,974 high-risk patients with NSTE-ACS admitted to 311 CABG-capable hospitals participating in Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the American College of Cardiology/American Heart Association Guidelines (CRUSADE) from 2001 to 2003. A total of 8,395 patients (14%) underwent CABG during their initial hospital stay. A multivariate model was developed and identified 13 presenting clinical characteristics significantly associated with the likelihood of CABG (previous CABG, male gender, previous heart failure, diabetes, hyperlipidemia, renal insufficiency, ST depression and transient ST elevation, age > or = 75 years, previous percutaneous coronary intervention, family history of coronary artery disease, hypertension, trends in CABG rates, and previous stroke). This model had only modest predictive accuracy and calibration (c-index = 0.67). In conclusion, although certain presenting clinical features are associated with an increased likelihood of CABG in patients with NSTE-ACSs during the index hospitalization, it remains difficult to reliably identify, before diagnostic angiography, those who will subsequently undergo surgical revascularization.
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PMID:Challenges in predicting the need for coronary artery bypass grafting at presentation in patients with non-ST-segment elevation acute coronary syndromes. 1692 49

Myotrophin is a 12 kDa protein initially isolated from hypertrophied hearts of spontaneously hypertensive rats and acts by modulating NF-kappaB (nuclear factor kappaB) activity. We have reported previously the presence of myotrophin in patients with human systolic heart failure; however, its role as a predictor of MACE (major adverse cardiac events) in patients with ACS (acute coronary syndrome) is unclear. In the present study, we sought to investigate this and compared myotrophin with NTproBNP (N-terminal pro-B-type natriuretic peptide), a marker of MACE. We studied 356 patients with ACS {276 men; mean age, 63.0+/-12.8 years; 80.6% STEMI [ST segment elevation MI (myocardial infarction)]; and 19.4% NSTEMI (non-STEMI)}. Blood measurement was made at 25-48 h after the onset of chest pain. The plasma concentration of myotrophin and NTproBNP was determined using in-house non-competitive immunoassays. Patients were followed-up for the combined end point of death, MI or need for urgent revascularization. Over the median follow-up period of 355 (range 0-645) days, there were 28 deaths, 27 non-fatal MIs and 73 patients required urgent revascularization. Myotrophin was raised in patients with MACE compared with survivors [510.7 (116.0-7445.6) fmol/ml compared with 371.5 (51.8-6990.4) fmol/ml respectively; P=0.001; values are medians (range)]. Using a Cox proportional hazards model, myotrophin {HR (hazard ratio), 1.64 [95% CI (confidence interval), 0.97-2.76]; P=0.05} and Killip class above 1 [HR, 1.52 (95% CI, 0.93-2.42); P=0.10] were the only independent predictors of MACE. A Kaplan-Meier survival curve revealed a significantly better clinical outcome in patients with myotrophin below the median compared with those with myotrophin above the median (log rank, 7.63; P=0.006). In conclusion, after an ACS, levels of myotrophin are more informative at predicting MACE than NTproBNP and may be useful to risk stratify patients.
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PMID:Myotrophin is a more powerful predictor of major adverse cardiac events following acute coronary syndrome than N-terminal pro-B-type natriuretic peptide. 1701 19

Previous studies of non-ST-segment elevation acute coronary syndromes (NSTE ACSs) complicated by heart failure (HF) have focused primarily on patients with left ventricular systolic dysfunction defined by an ejection fraction (EF) <40%. Little is known about HF with preserved systolic function (EF > or =40%) in the NSTE ACS population. We identified high-risk patients with NSTE ACS (ischemic electrocardiographic changes and/or positive cardiac markers) from the CRUSADE quality improvement initiative who had an EF recorded and who had information on HF status. Management and outcomes were analyzed and compared based on the presence or absence of HF and whether left ventricular EF was > or =40%. Of 94,558 patients with NSTE ACS, 21,561 (22.8%) presented with signs of HF, and most had HF with preserved systolic function (n = 11,860, 55%). Mortality rates were 10.7% for HF/systolic dysfunction, 5.8% for HF/preserved systolic function, 5.7% for no HF/systolic dysfunction, and 1.5% for no HF/preserved systolic function. Use of guideline-recommended medical therapies and interventions was frequently significantly lower in those with HF regardless of EF compared with those without HF, except for use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. In conclusion, NSTE ACS complicated by HF with preserved systolic function is common and associated with a 2.3-fold higher mortality compared with NSTE ACS without HF or systolic dysfunction. Guideline-recommended therapies and interventions are under-utilized in patients with NSTE ACS and HF, with and without preserved systolic function, compared with those without HF.
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PMID:Heart failure with preserved left ventricular systolic function among patients with non-ST-segment elevation acute coronary syndromes. 1749 58

The Clinical Trials described in this article were presented at the Hotline and Clinical Trial Update Sessions of the European Society of Cardiology Congress held in September 2007 in Vienna, Austria. The sessions chosen for this article represent the scope of interest of Cardiovascular Drugs and Therapy. The presentations should be considered preliminary, as further analyses could alter the final publication of the results of these studies. PROSPECT evaluated echocardiographic criteria for optimal selection of patients with moderate to severe heart failure who may benefit from cardiac resynchronisation therapy, however concluded that no single echocardiographic measure can be recommended. EVEREST found that tolvaptan, a vasopressin V(2) antagonist, resulted in early weight reduction and improvement of dyspnoea in patients with acute heart failure, but lacked long term improvement. In ARISE, the anti-oxidant succinobucal did not affect the primary outcome in high risk cardiovascular patients, but improved the combination of cardiovascular death, myocardial infarction and stroke, and diabetic control in diabetics. ALOFT showed that the addition of the renin inhibitor aliskiren to an ACE inhibitor or ARB and a beta-blocker leads to favourable effects on neurohormonal actions in heart failure. FINESSE markedly improved coronary patency before PCI with half-dose reteplase/abciximab in STEMI patients, however without significantly improving short-term outcome. The Prague-8 Study evaluated whether routine clopidogrel administered >6 h pre-angiography would be a safe way to achieve therapeutic drug levels in case a follow-up intervention would be considered immediately, but appeared not justified because of bleeding complications. CARESS in MI showed that high risk patients with evolving STEMI who undergo thrombolytic therapy should undergo PCI early after the thrombolysis. Finally, the ACUITY trial found that in moderate or high risk Non ST elevation ACS patients triaged to PCI, coronary artery bypass graft (CABG) surgery, or medical management, bivalirudin, with or without associated GPIIb/IIIa inhibitor therapy, resulted in a marked reduction of bleeding at 30 days whilst preserving the ischemic and mortality benefit at 1 year follow up.
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PMID:Clinical trials update from the European Society of Cardiology Congress in Vienna, 2007: PROSPECT, EVEREST, ARISE, ALOFT, FINESSE, Prague-8, CARESS in MI and ACUITY. 1799 67


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