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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In heart failure, many alterations occur in the ventricle as a whole, as well as in the myocardial cell. In the first part of this review we report on the macroscopic structure of the left ventricle by analysing the relation between left ventricular dilatation and left ventricular hypertrophy in terms of ventricular wall stress. Peak systolic stress in dilated ventricles of patients with compensated heart failure does not differ from values obtained in normal ventricles, whereas the systolic stress-time integral is increased by more than 40%. The stress-time integral is a major determinant of myocardial oxygen consumption, and its reduction by peripheral vasodilation leads to a proportional decrease in left ventricular oxygen consumption. In contrast, the phosphodiesterase inhibitor, enoximone, decreases the stress-time integral without a proportional decrease in myocardial oxygen consumption, due to the competition between positive inotropic effect with increased oxygen consumption and a vasodilating effect with decreased oxygen consumption. Beta-1 adrenoceptor agonists increase myocardial oxygen consumption. In the second part of this review we report on the functional alterations of the following subcellular and molecular structures in the failing myocardium: (1) adrenoceptors and G-proteins; (2) sarcoplasmic reticulum with an altered force-frequency relationship; (3) the acto-myosin system with decreased velocity of shortening and increased economy of force generation. On the basis of these alterations, a disadvantageous chain of events develops in the failing myocardial cell.
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PMID:The heart in heart failure. Ventricular and myocardial alterations. 183 95

Beta-blockers without partial agonist activity are now considered to be strategic therapy for patients with chronic heart failure, but many issues remain to be clarified. The objective of the double-blind, randomized, placebo-controlled cardiac insufficiency talinolol study (CITAS) is to assess efficacy and safety of talinolol - a selective beta-1 adrenoreceptor blocker - in patients with ischemic and non-ischemic heart failure. The primary end-point refers to the influence of talinolol on exercise capacity, evaluated by 6-min walking-test. Secondary end-points consist of left ventricular function, cardiovascular and all-cause mortality, hospitalizations, quality of life, combined clinical end-points and adverse events. There were enrolled 294 patients with stable heart failure in NYHA class II-IV, LVEF <40%, receiving diuretics, ACE-inhibitors and optionally nitrates and digoxin. Talinolol was titrated up to 100 mg/day (one arm) or to 150 mg/d (the other arm), starting with 12.5 mg daily. Enrollment began in November 1997 and the last visit will be in December 2000.
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PMID:The cardiac insufficiency talinolol study (CITAS) study design. 1137 11

To determine the cardiovascular molecular events associated with acute exposure to cocaine, the present study utilized in vivo analysis of left-ventricular heart function in adult rabbits, fluorescence confocal microscopy of fluo-2, rhod-2, (5-(and-6) carboxy 2',7' dichlorodihydrofluores-cein diacetate (carboxy-H2DCFDA), and JC-1 in H9C2 cells and gene expression microarray technology for analysis of gene activation in both rabbit ventricular tissue and H9C2 cells. In the rabbit, acute cocaine exposure (2 mg/kg) caused left-ventricular dysfunction and 0.1-10 mM cocaine increased cytosolic and mitochondrial calcium activity and mitochondrial membrane depolarization in H9C2 cells. A 3-min pretreatment of H9C2 cells by 10 microM verapamil, nifedipine, or nadolol inhibited calcium increases, but only 1 mM N-acetylcysteine (NAC) or 1 mM glutathione blocked mitochondrial membrane depolarization. Cocaine induced activation of genes in the rabbit heart and H9C2 cells including angiotensinogen, ADRB1, and c-reactive protein (CRP). In H9C2 cells, NAC pretreatment blocked cocaine-mediated increases in CRP, FAS, FAS ligand, and cytokine receptor-like factor1 (CRLF1) expression. Collectively, these data suggest that acute cocaine administration initiates cellular and genetic changes that, if chronically manifested, could cause cardiac deficits similar to those seen in heart failure and ischemia, such as ventricular dysfunction, cardiac arrhythmias, and cardiac remodeling.
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PMID:Cocaine increases intracellular calcium and reactive oxygen species, depolarizes mitochondria, and activates genes associated with heart failure and remodeling. 1638 75

The beta-adrenergic receptors (ADRBs) are cell surface receptors that play central roles in the sympathetic nervous system. Pharmacological targeting of two of these receptors, ADRB1 and ADRB2, represents a widely used therapeutic approach for common and important diseases including asthma, hypertension and heart failure. Genetic variation in both ADRB1 and ADRB2 has been linked to both in vitro and clinical disease phenotypes. More recently, interest has shifted to studies that explore potential interaction between variation in ADRBs and medications directed at these important receptors. This paper reviews the current state of knowledge and understanding of ADRB genetic variation and explores the likely direction of future studies in this area.
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PMID:Pharmacogenetics of the human beta-adrenergic receptors. 1663 83

Heart failure (HF) is characterized by neurohormonal activation of the sympathetic nervous and renin-angiotensin systems. Genetic polymorphisms in these systems could alter the prognosis in HF. We hypothesized the genetic polymorphisms in the sympathetic nervous and renin-angiotensin systems are associated with adverse outcomes, defined as death or heart transplantation in patients with HF. A total of 227 patients with HF were enrolled from a tertiary care clinic and followed for outcomes for < or =4 years. Eight polymorphisms in 6 genes were genotyped: beta(1)-adrenergic receptor (ADRB1, S49G, R389G), beta(2)-adrenergic receptor (ADRB2, G16R, Q27E), alpha(2c)-adrenergic receptor (ADRA2C, insertion/deletion 322-325), angiotensinogen (AGT, M235T), angiotensin receptor type 1 (AGTR1, 1166A>C), and angiotensin-converting enzyme (ACE, insertion/deletion in intron 16). Most patients were treated according to consensus guidelines. Male gender (hazard ratio 2.24, 95% confidence interval 1.27 to 3.94), higher New York Heart Association functional class (hazard ratio 2.54, 95% confidence interval 1.84 to 3.52), and 2 copies of ADRB2 Arg16Gln27 haplotype (hazard ratio 1.91, 95% confidence interval 1.09 to 3.36) increased the risk of adverse outcomes. In contrast, a higher serum sodium level (hazard ratio 0.91, 95% confidence interval 0.86 to 0.97) and higher creatinine clearance (hazard ratio 0.99, 95% confidence interval 0.98 to 0.99) decreased the risk of adverse outcomes. None of the other genotypes/haplotypes were associated with adverse outcomes. In conclusion, ADRB2 Arg16Gln27 haplotype may significantly increase the risk of adverse outcomes in patients with HF receiving contemporary HF pharmacotherapy.
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PMID:Relation of beta(2)-adrenoceptor haplotype to risk of death and heart transplantation in patients with heart failure. 1722 28

The ischemic etiology of heart failure is an independent prognostic factor associated with worse long-term outcome. Recent evidence indicates a role for genetic susceptibility to ischemic heart failure. The authors systematically reviewed all known case-control studies that investigated the association between genetic variants and ischemic heart failure. Twenty-two articles, which examined 24 gene polymorphisms, were identified. In 22 polymorphisms, the variant form had a functional effect. Twenty-two polymorphisms were variants of genes involved in the maladaptive neurohormonal activation. Seven polymorphisms (ACE I/D, AGT M235T, ADRA2C Del322-325, ADRB2 Arg16Gly, ADRB2 Gln27Glu, EDN1 Lys198Asn, VEGF G-405C) showed a significant association in individual studies. Five polymorphisms (ACE I/D, ADRB1 Arg389Gly, ADRB2 Arg16Gly, ADRB2 Gln27Glu, TNF G308A) were examined by more than one study, and meta-analyses were performed. The meta-analyses showed no significant sign of heterogeneity. In all settings, there was no significant association, except for polymorphism ADRB2 Arg16Gly under a recessive model (fixed-effects odds ratio = 1.32, 95% confidence interval: 1.05, 1.65). Taking into account that ischemic heart failure is a complex disease with multifactorial etiology, a minor contributing pathogenetic role of the investigated gene polymorphisms cannot be totally excluded. Case-control studies that investigate gene-gene and gene-environment interactions might further elucidate the genetics of ischemic heart failure.
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PMID:Genetic variation associated with ischemic heart failure: a HuGE review and meta-analysis. 1764 25

Heart Failure (HF) is a common disorder associated with substantial morbidity and mortality. beta adrenergic receptors (betaAR) are the primary pathway through which cardiac function is influenced. Chronic beta(1)AR activation is implicated in the pathogenesis of HF and betaAR blockade improves survival in left ventricular systolic dysfunction. Common functional polymorphisms in beta adrenergic receptor genes (ADRB) have been associated with HF phenotypes, and with pharmacogenetic interaction with beta adrenergic receptor blockers (beta blockers). However, these associations have not been consistently replicated. The evidence for ADRB variant involvement in pathogenesis, progression and response to beta blockers in HF is reviewed. In addition, a meta-analysis of three studies analysing the effect of ADRB1 Arg389Gly polymorphism on left ventricular remodelling with the use of beta blockers, demonstrating a 5% improvement in left ventricular ejection fraction in Arg389 homozygotes, is presented. There is now accumulating molecular evidence for a different functional response to beta blockers associated with this polymorphism. In the future, confirmed genotypic associations may enable patients to be identified who are either at greater risk of developing HF, whose HF may rapidly progress, or who are unlikely to benefit from beta blockers, and such patients may benefit from targeted aggressive therapy.
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PMID:Role of beta adrenergic receptor polymorphisms in heart failure: systematic review and meta-analysis. 1815 68

Numerous studies have demonstrated that beta(1)- and beta(2)-adrenergic receptor gene (ADRB1 and ADRB2) variants influence cardiovascular risk and beta-blocker responses in hypertension and heart failure. We evaluated the relationship between ADRB1 and ADRB2 haplotypes, cardiovascular risk (death, nonfatal myocardial infarction (MI), and nonfatal stroke), and atenolol-based vs. verapamil sustained-release (SR)-based antihypertensive therapy in 5,895 coronary artery disease (CAD) patients. After an average of 2.8 years, death rates were higher in patients carrying the ADRB1 Ser49-Arg389 haplotype (hazard ratio (HR) 3.66, 95% confidence interval (95% CI) 1.68-7.99). This mortality risk was significant in patients randomly assigned to verapamil SR (HR 8.58, 95% CI 2.06-35.8) but not atenolol (HR 2.31, 95% CI 0.82-6.55), suggesting a protective role for the beta-blocker. ADRB2 haplotype associations were divergent within the treatment groups but did not remain significant after adjustment for multiple comparisons. ADRB1 haplotype variation is associated with mortality risk, and beta-blockers may be preferred in subgroups of patients defined by ADRB1 or ADRB2 polymorphisms.
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PMID:beta-adrenergic receptor gene polymorphisms and beta-blocker treatment outcomes in hypertension. 1861 4

The beta(1)-adrenergic receptor (beta(1)AR; ADRB1) polymorphism Arg389Gly is located in an intracellular loop and is associated with distinct human and mouse cardiovascular phenotypes. To test the hypothesis that beta(1)-Arg389 and beta(1)-Gly389 alleles could differentially couple to pathways beyond that of classic G(s)-adenylyl cyclase (AC)/cAMP signaling, we performed comparative gene expression profile analyses on hearts from wild-type and transgenic mice that expressed either human beta(1)-Arg389 or beta(1)-Gly389 receptors, or AC5, sampling at an early age prior to the onset of pathological features. All three models upregulated the expression of genes associated with RNA metabolism and translation and downregulated genes associated with mitochondria and energy metabolism, consistent with shared cAMP-driven increase in cardiac contractility, protein synthesis, and compensatory downregulation of mitochondrial energy production. Both beta(1)AR alleles activated additional genes associated with other pathways. Uniquely, beta(1)-Arg389 hearts exhibited upregulated expression of genes associated with inflammation, programmed cell death, and extracellular matrix. These observations expand the scope of 7-transmembrane domain receptor signaling propagation beyond known cognate G protein couplings. Moreover, they implicate alterations of a repertoire of processes evoked by a single amino acid variation in the cardiac beta(1)AR that might be exploited for genotype-specific heart failure diagnostics and therapeutics.
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PMID:Differential coupling of Arg- and Gly389 polymorphic forms of the beta1-adrenergic receptor leads to pathogenic cardiac gene regulatory programs. 1866 29

Beta-arrestin is a multifunctional adapter protein well known for its role in G-protein-coupled receptor (GPCR) desensitization. Exciting new evidence indicates that beta-arrestin is also a signaling molecule capable of initiating its own G-protein-independent signaling at GPCRs. One of the best-studied beta-arrestin signaling pathways is the one involving beta-arrestin-dependent activation of a mitogen-activated protein kinase cascade, the extracellular regulated kinase (ERK). ERK signaling, which is classically activated by agonist stimulation of the epidermal growth factor receptor (EGFR), can be activated by a number of GPCRs in a beta-arrestin-dependent manner. Recent work in animal models of heart failure suggests that beta-arrestin-dependent activation of EGFR/ERK signaling by the beta-1-adrenergic receptor, and possibly the angiotensin II Type 1A receptor, are cardioprotective. Hence, a new model of signaling at cardiac GPCRs has emerged and implicates classical G-protein-mediated signaling with promoting harmful remodeling in heart failure, while concurrently linking beta-arrestin-dependent, G-protein-independent signaling with cardioprotective effects. Based on this paradigm, a new class of drugs could be identified, termed "biased ligands", which simultaneously block harmful G-protein signaling, while also promoting cardioprotective beta-arrestin-dependent signaling, leading to a potential breakthrough in the treatment of chronic cardiac disease.
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PMID:Beta-arrestin-mediated signaling in the heart. 1883 25


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