UMLS:C0018801 - FACTA Search

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Query: UMLS:C0018801 (heart failure)
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Serum levels endothelin-1,2 aldosterone, renin activity were performed in 52 patients with chronic congestive heart failure during captopril therapy. The investigations were done before therapy, after 10-15 days therapy and after disappearance symptoms of heart failure. The levels endotelin-1,2,aldosterone and renin activity were determined using radioimmunologic methods. Fraction ejection and peripheral vascular resistance were determined by echocardiography technics. It was found that serum endothelin levels in patients with chronic congestive heart failure were increased proportionally to functional class of heart failure and decreased after disappearance symptoms of heart failure. An increase in plasma endothelin concentration has not correlated with ejection fraction, aldosterone concentration and renin activity. These studies have demonstrated that in patients with congestive heart failure on captopril therapy endothelin serum levels positively correlates with peripheral vascular resistance. No correlation was found between ejection fraction and activity renin-angiotensin-aldosterone system. These findings indicated that captopril therapy decreases endothelin production.
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PMID:[Does captopril decrease endothelial production of endothelin?]. 946 3

Patients with heart failure have, in spite of improved palliative therapies, bad prognosis. Cardiac tissue engineering by use of a temporary bioscaffold and cardiomyocytes may help to find answers for future treatments in heart failure. For that purpose two neonatal rat heart ventricular cell fractions were obtained after a gradient cell separation. Time related characteristics of Fractions I and II were established in two-dimensional (2-D) and three-dimensional (3-D) cell cultures. The 3-D cardiac constructs were obtained by use of a bovine type I collagen matrix after culturing either under static conditions or in the HARV bioreactor. With the 2-D cultures contracting cells were present after 1 day, and reached confluency from day 5 on and this was maintained up to 135 days. In Fraction-I some non-contracting cells were always noticed between the (in time in unison) contracting cells. Transmission electron microscopy (TEM) revealed that these mainly concerned fibroblasts. Differences in the expression of alpha-SM-1 actin and troponin-T were observed between the two fractions. In both fractions endothelial cells and macrophages were only sporadically observed. All through the 3-D matrix pendant-like single cell and clustered cell contractions were present after 1-2 days, resulting in time in unison contracting of cells with the collagen matrices. The whole event was faster with Fraction-I and was observed up to 3 weeks. At this time point clusters of troponin-T positive cells were found scattered through the collagen matrices. Additionally, TEM revealed healthy layers of connected cardiomyocytes with intercalated discs, in this case on and in between the collagen fibres. These findings provide evidence that in unison contracting structurally organized cell-matrix cardiac constructs can be engineered by use of co-cultures (neonatal cardiomyocytes and fibroblasts) and collagen matrices, which is very promising for the repair of larger scar areas of the myocardium.
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PMID:Cardiac tissue engineering: characteristics of in unison contracting two- and three-dimensional neonatal rat ventricle cell (co)-cultures. 1236 18

From May 1998 to April 2000, we performed partial left ventriculectomy (PLV) in 3 pediatric patients with dilated cardiomyopathy (DCM). At the time of the surgery, their age ranged from eight months to three years. The first patient eventually had to receive a heart transplant, but all patients treated with PLV are alive to this day. Patient #1 was diagnosed with DCM at the age of five months, PLV was done on a semi-urgent basis at the age of eight months, when medium dose IV catecholamine therapy and mechanical ventilation were required. Fraction shortening (FS) as shown by echocardiography increased postoperatively from 8% to 15% along with marked clinical improvement. Her heart failure deteriorated three months after the surgery, and received a heart transplant in the United States when she was one year and two months old. Patient #2 developed severe heart failure two months after correction of a ventricular septal defect. Aggressive medical therapy failed to improve his condition, therefore PLV was done on an elective basis at the age of three years and five months. [The patient was initially hospitalized and underwent low dose catecholamine.] Postoperative course was well. The ventriculography one year after surgery showed an improvement of the left ventricular FS from 12% to 27% after PLV. He was still doing well at his most recent check up. Patient #3 was diagnosed with DCM as a neonate. PLV was done on an elective basis at the age of two years and five months. Her postoperative course was generally well. FS on echocardiography increased postoperatively from 10% to 25% along with marked clinical improvement. The timing of performing PLV is the most essential factor for postoperative course in our experiences. We consider that the best timing is when aggressive catecholamine infusion or mechanical ventilation is required. The mid-term outcome of PLV of pediatric patients is considered to be acceptable. We believe that PLV should be considered as a viable option for severe DCM patients.
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PMID:Mid-term outcome after partial left ventriculectomy in pediatric patients. 1239 1

Recent observational data suggest that mild or moderate heart failure is associated with an annual risk of stroke of approximately 1.2%. Indeed, it is possible that the major cause of sudden death in chronic heart failure is not related to arrhythmias, but to vascular occlusion. Anticoagulation may reduce the rate of embolic events, but there is controversy about the mandatory use of antithrombotic therapy for all patients with ventricular dysfunction in sinus rhythm. At present antithrombotic therapy is indicated only in "high risk" subgroups of patients: atrial fibrillation, mobile/protruding/irregular thrombi, acute post-myocardial infarction thrombi or a recent history of thromboembolism. Actually there is no evidence to recommend the use of aspirin to prevent thromboembolism in patients with ventricular dysfunction in sinus rhythm. Further trials of both antiplatelet agents and anticoagulation are sorely needed and we are waiting for the results of large trials such as the WATCH trial (Warfarin and Antiplatelet Therapy in Chronic Heart Failure) and the WARCEF trial (Warfarin Versus Aspirin in Reduced Ejection Fraction). The future appears promising due to the advent of a new oral direct thrombin inhibitor, ximelagatran, with good efficacy and safety profile for the treatment and prevention of thromboembolism.
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PMID:[Antithrombotic prophylaxis in patients with ventricular dysfunction: critical review of the literature and new perspectives]. 1278 54

Oxipurinol [alloxanthine, Oxyprim, oxypurinol] is the active metabolite of the only commercially available xanthine oxidase inhibitor, allopurinol. Oxipurinol is also a xanthine oxidase inhibitor. Oxipurinol is currently being developed by Cardiome Pharma. It is waiting for approval in the US for the treatment of allopurinol-intolerant hyperuricaemia (gout) and is in phase III trials for the treatment of congestive heart failure. Allopurinol is indicated for the treatment of symptomatic hyperuricaemia, or gout. Approximately 3-5% of patients receiving allopurinol develop intolerance to the drug. Oxipurinol was originally developed by Burroughs Wellcome (later GlaxoSmithKline), and has been available on a compassionate-use basis since 1967 for use in allopurinol-intolerant patients. The licensee company ILEX Oncology has stated that oxipurinol does not have patent protection. Oxipurinol's potential for treatment of congestive heart failure is based on the possibility that xanthine oxidase inhibitors may improve myocardial work efficiency by sensitising cardiac muscle cells to calcium ions, which are a key determinant of cardiac muscle function. This results in more efficient contraction of cardiac muscle cells, without the same increase in oxygen demand. At the second annual BioPartnering North America conference (BPN-2004) [February 2004, Vancouver, Canada], Cardiome Pharma stated that it was seeking a commercialisation partner to market and distribute oxipurinol in the US for the treatment of allopurinol-intolerant hyperuricaemia. In 1995, ILEX Oncology obtained an exclusive licence to oxipurinol from Burroughs Wellcome. Burroughs Wellcome later became part of Glaxo Wellcome, which merged with SmithKline Beecham in December 2000 to form GlaxoSmithKline. ILEX's licence agreement is now with GlaxoSmithKline and The Wellcome Foundation. In December 2001, ILEX granted Paralex, a privately held New York-based company, an exclusive sublicence to all of ILEX's rights to oxipurinol for the treatment of hyperuricaemia in allopurinol-intolerant patients. Paralex additionally gained the right to develop and commercialise oxipurinol in all fields, under data and technology owned by ILEX. Furthermore, Paralex had licensed certain intellectual property rights from The John Hopkins University relating to cardiovascular applications of xanthine oxidase inhibitors. Paralex was acquired by Cardiome Pharma in March 2002. Cardiome Pharma announced early in May 2002 that it had exercised its option to acquire from ILEX Oncology Inc. rights to clinical trial data for oxypurinol for the treatment of gout in allopurinol-intolerant patients. ILEX completed its open-label phase II clinical study of Oxyprim in allopurinol-intolerant gout patients, and the trial data were transferred to Cardiome. Cardiome stated in May 2002 that it intended to commence a further phase II trial of oxypurinol in gout. Phase III trials were in progress in 2003 in this indication. In 1995, ILEX Oncology continued the compassionate use distribution of oxipurinol while establishing a US FDA-approved registration plan for the agent. In November 1998, ILEX received Orphan Drug status for the use of oxipurinol in patients with symptomatic hyperuricaemia. ILEX Oncology's Development Pipeline for 1998 stated that oxipurinol had entered phase II clinical trials for the treatment of hyperuricaemia. In 2001, the clinical trials listing service CenterWatch stated that oxipurinol was in a phase II clinical trial with ILEX Oncology for the treatment of symptomatic hyperuricaemia in patients who are intolerant to allopurinol. The trial appeared to be taking place in the US, and was a multicentre, open-label, 14-week study in 90 patients. In February 2003, Cardiome confirmed beginning patient enrollment in three smaller phase II studies, with the first trial (EXOTIC) now completed. These three smaller proof-of-concept studies will observe surrogate endpoints such as cardiac output and exercise tolerance. The second proof-of-concept study in patients with CHF of ischemic aetiology (IV), known as EXOTIC-EF (Evaluation of XanThine Oxidase Inhibition on Cardiac Ejection Fraction), will assess the effects of oxypurinol on left ventricular performance. The EXOTIC-EF trial will start in the first quarter of 2004 and be completed by the second quarter of 2004. The third, LA PLATA, proof-of-concept study will explore the effects of 1 month of oral oxypurinol therapy on exercise capacity and left ventricular performance. It is projected that the LA PLATA study will start in the first quarter of 2004 and be completed by the third quarter of 2004. During the Heart Failure Society of America's meeting on 21 September 2003, Cardiome presented clinical data from its first proof-of-concept EXOTIC (European Xanthine Oxidase Inhibitors Trial In Cardiac Disease) study. Cardiome intends to conduct a second trial, at the Eppendorf Clinic at the University of Hamburg, to determine the effect of oxypurinol on left ventricular performance in patients with CHF of ischaemic aetiology. This study will be an extension of the original proof-of-concept study. According to the 1st Annual BioPartnering conference held in Vancouver, Canada, in February 2003, Cardiome is seeking co-development partners for oxipurinol in the treatment of congestive heart failure. In July 2003, the US Patent and Trademark Office issued a new patent providing additional protection to Cardiome's programme focused on treatment of congestive heart failure with oxypurinol. The patent, No. 6,569,862, was the second issued to the Johns Hopkins University (JHU) in this field. The key claims in the new patent cover use of the entire family of drugs known as xanthine oxidase inhibitors applied to contractile disorders of the heart, including congestive heart failure. An earlier patent issued to JHU contained provisions relating to a specific mechanism of action and to specific forms of heart disease. Both patents and related intellectual property are licensed exclusively to Cardiome.
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PMID:Oxipurinol: alloxanthine, Oxyprim, oxypurinol. 1513 81

Chronic left ventricular systolic dysfunction is a well recognized problem with an increasingly significant impact on healthcare in the form of congestive heart failure (CHF). Advances in medicine have led to improved survival after myocardial infarction (MI) and as a result, an increased prevalence of left ventricular systolic dysfunction. An increased incidence of thromboembolism, especially stroke, in patients with left ventricular systolic dysfunction is also well recognized. Pharmacological strategies to prevent stroke have been proposed in numerous studies. For example, anticoagulation in patients with atrial fibrillation and heart failure has been shown to reduce mortality rates and the incidence of stroke; however, its role in patients with left ventricular dysfunction and normal sinus rhythm is unclear and utilization of anticoagulation in these patients varies widely. The role of aspirin to prevent thromboembolism in patients with CHF is controversial. The relatively new pharmacological agent ximelagatran, which has an advantage of unmonitored oral administration has the potential to change the anticoagulation strategy in patients with heart failure. Important trials to define optimal therapy for reducing the risk of thromboembolism and death in patients with left ventricular systolic dysfunction and sinus rhythm include the recently reported WATCH (Warfarin and Antiplatelet Therapy in Chronic Heart failure) trial and the WARCEF (Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction) trial, which is currently underway. The WATCH trial failed to outline significant differences between aspirin (acetylsalicylic acid), warfarin, and clopidogrel in the primary composite endpoint of all-cause mortality, nonfatal MI, and nonfatal stroke. Combined data from WATCH and WARCEF may provide sufficient statistical power to clarify outcomes such as stroke and death in patients with reduced cardiac ejection fraction. The pooled data may also help define optimal preventative measures for thromboembolism in patients with left ventricular systolic dysfunction and sinus rhythm.
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PMID:Pharmacological prevention of thromboembolism in patients with left ventricular dysfunction. 1648 47

Aldosterone is a mineralocorticoid primarily produced in the zona glomerulosa of the adrenal gland. For many years, aldosterone (Aldo) was thought to have its sole site of action in the kidney, where it regulated sodium excretion and potassium reabsorption. It is now known that Aldo is produced in cardiovascular tissues, and has been implicated in the development of ventricular hypertrophy and cardiac fibrosis. The precise mechanisms whereby Aldo acts in cardiac tissues are diverse. It was assumed that Aldo production could be limited by angiotensin-converting enzyme (ACE) inhibition, but serial measurements during therapy reveal only a transient decrease in Aldo levels. Moreover, the effects of Aldo on cardiac tissues occur even when angiotensin II (Ang II) has been suppressed or eliminated. Multiple investigators have examined effects of Aldo receptor blockade in human subjects and various animal models using the two Aldo receptor antagonists (ARAs), spironolactone and eplerenone. Major clinical trials involving spironolactone (RALES) and eplerenone (EPHESUS) ARAs have shown significant benefits in the treatment of congestive heart failure (CHF). In RALES, patients with New York Heart Association (NYHA) Class III or IV systolic heart failure treated with spironolactone had a 30% relative risk decrease in mortality. Although spironolactone is an effective competitive inhibitor of the mineralocorticoid receptor (MR), progestational and antiandrogenic side effects limit its use in some patients. Eplerenone, a more selective ARA, lacks these undesirable side effects. Although eplerenone is 20-fold less potent at the MR, it demonstrates efficacy similar to spironolactone, possibly due to decreased protein binding. Eplerenone has fewer side effects than spironolactone, which has been attributed to the low cross-reactivity with androgen and progesterone receptors. In EPHESUS, patients with left ventricular systolic dysfunction [Ejection Fraction (EF) <40%] and CHF following an acute myocardial infarction (AMI), were treated with eplerenone, resulting in a 17% reduction in cardiovascular mortality. However, these studies were limited in that diastolic function was not evaluated, although approximately 1/2 of CHF is due to diastolic dysfunction alone. To date, neither ARA has been studied for the treatment of diastolic dysfunction in a major clinical trial. However, numerous animal studies employing ARAs have shown a decrease in cardiac hypertrophy and fibrosis, indicating the potential benefits of these agents in the treatment of diastolic heart failure. In this review, we discuss possible underlying mechanisms responsible for Aldo effects on cardiovascular function and compare the beneficial effects of spironolactone and eplerenone in the treatment of heart disease.
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PMID:Aldosterone receptor antagonists and cardiovascular disease: do we need a change of the guard? 1661 Oct 48

Diastolic Heart Failure: perception of the syndrome and scope of the problem. As a result of the recent publications of the CHARM-Preserved trial, the upcoming I-PRESERVE and other still ongoing clinical trials in patients with Heart Failure and Normal (or Preserved) Left Ventricular Ejection Fraction, numerous questions have arisen as for the conceptual rationale and pathophysiological basis of such trials. The present symposium is a synopsis of the most important remaining controversies. We gratefully acknowledge all authors for their contribution as summarized in this Introduction Paper.
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PMID:Diastolic heart failure: perception of the syndrome and scope of the problem. 1708 76

Congestive heart failure (CHF) is a major public health problem that results in tremendous economic burden. Diastolic heart failure (DHF) forms an important subset with increasing incidence and prevalence. There are widely variable estimates of the prevalence, ranging from 13% to 74% of all CHF presentations, and this is predominantly a result of a lack of uniform criteria for establishing a diagnosis. New developments in management of DHF have lagged behind those for systolic heart failure (SHF), for which numerous new therapeutic and device strategies have been instituted. The renin-angiotensin-aldosterone system (RAAS) plays an important role in the pathophysiology of both SHF as well as DHF. The beneficial role of ACE inhibitors as well as aldosterone antagonists in SHF has been well established. Because of its unique role of the RAAS in establishing fibrosis at a molecular level, RAAS blockade provides an opportunity to expand the therapeutic options for DHF. Thus far, in patients with primary DHF only the angiotensin receptor type 1 antagonist candesartan has been reported to decrease morbidity and probably mortality. Large, ongoing randomized trials including TOPCAT (Trial of Aldosterone Antagonist Therapy in Adults with Preserved Ejection Fraction Congestive Heart) and the I-PRESERVE (Irbesartan in Heart Failure with Preserved Systolic Function) are currently underway to establish the role of aldosterone antagonists in patients with DHF.
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PMID:Role of the renin-angiotensin-aldosterone system in diastolic heart failure: potential for pharmacologic intervention. 1719 27

Thyroid hormone (TH) and insulin growth factor 1 (IGF1) systems both play crucial roles in the regulation of cardiac remodeling and hypertrophy processes. The mediation of this regulation is attributed to specific thyroid hormone receptors (TRs) and to the IGF1 receptor (IGF1R). In humans, two TR genes are expressed in the heart, TRalpha and TRbeta. Each gene generates two isoforms: TRalpha1, TRalpha2 and TRbeta1, TRbeta2. The aim of the present work was to study the local thyroid hormone and IGF1 signaling in human myocardium through the evaluation of the gene expression of TRalpha1, TRalpha2, TRbeta1 and IGF1R among atrial and ventricular biopsies obtained from patients undergoing cardiac surgery. Moreover, we evaluated possible correlations between TR and IGF1/IGF1R systems. Eighteen clinically and biochemically euthyroid patients (aged 68.3+/-3.2years, mean+/-SEM) without overt heart failure (Ejection Fraction (EF), 46.4+/-2.8%; Left Ventricular End Diastolic Diameter (LVEDD), 54.3+/-1.2mm, mean+/-SEM; NYHA I-II) were enrolled in the study: 13 undergoing aorto-coronary bypass and 5 undergoing valve replacement (aortic/mitral valve). The examination of total RNA, using real time PCR (LightCycler Technology) confirmed the expression of specific mRNAs encoding TRalpha1, TRalpha2, TRbeta1 and both IGF1 and IGF1R. We found that the three TR genes are co-expressed in the human atrium and ventricle. The finding of a strong correlation among IGF1R and the three TR genes expressed in the atrium (p<0.001) and among the three TRs in the atrium (p<0.001) suggests the interesting possibility that the two systems, TRs and IGF1R could also be functionally associated.
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PMID:Thyroid hormone receptor and IGF1/IGFR systems: possible relations in the human heart. 1756 Jul 56

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