UMLS:C0018801 - FACTA Search

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

The progress made in our understanding of the pathophysiology and treatment of congestive heart failure (CHF) would not have been possible without a number of animal models of heart failure and hypertrophy, each one having unique advantages as well as disadvantages. The species and interventions used to create CHF depends on the scientific question as well as on factors such as ethical and economical considerations, accessibility and reproducibility or the model. How closely the model should mimic the human syndrome of CHF depends on the scientific question under investigation. If the goal is to study pathophysiological processes like remodeling or the function of subcellular systems such as excitation contraction-coupling processes, contractile protein function or energetics, the model of heart failure should mimic the clinical setting as closely as possible. However, if defined causal connections are under investigation such as structure-function analyses or regulation of gene expression, exact reflection of the clinical setting by the animal model may be less important. In this review, animal models of heart failure are discussed with particular focus on similarities between the animal model and the failing human heart regarding myocardial function as well as molecular and subcellular mechanisms. In addition, new models of heart failure and hypertrophy, and finally some recent animal models of myocarditis are reviewed.
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PMID:Animal models of human cardiovascular disease, heart failure and hypertrophy. 976 90

This study aimed to determine structural alterations occurring in cardiac myofilaments after exogenous application of oxidants and the effects of oxidants on contractile protein function in a rabbit coronary artery ligation model of heart failure. Myocardial "stiffness" was higher in the ligated animals (Lig) than sham-operated controls (Sh, 4.9+/-1.5 versus 1.6+/-0.8 mN.mm-1). Superoxide anion (O2-) exposure decreased active stiffness in both groups, whereas hypochlorous acid (HOCl) had no effect in Lig but increased stiffness in Sh. Resting stiffness was higher in Lig than Sh (0.6+/-0.2 versus 0.2+/-0.1 mN.mm-1), remaining unchanged after O2- exposure but increasing after HOCl in both groups. The frequency at minimum stiffness was lower in Lig than Sh (0.9+/-0.2 versus 1. 7+/-0.6 Hz) and was reduced in both groups after oxidant exposure. Myofilament calcium sensitivity (pCa50) was not altered by O2- in Sh but increased in Lig (pCa50 increased from 5.41+/-0.05 to 5.56+/-0. 06). Protease contamination in the xanthine oxidase used to generate O2- did not affect myofilament ultrastructure at the concentrations used here. These data demonstrate that contractile proteins from "failed" myocardium have a similar response to exogenously applied oxidants as controls and that application of protease-contaminated xanthine oxidase system does not degrade the contractile protein structure.
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PMID:Effects of reactive oxygen species on myofilament function in a rabbit coronary artery ligation model of heart failure. 1039 58

To investigate the molecular basis of the decrease in myocardial contractility during heart failure, an animan model of heart failure was set up by means of deoxycorticosterone-acetate impregnated silicone rubber implants in wistar rats. Cardiac contractility in normal and heart failure rats was examined, and gene expression of its myocardial contractile protein, alpha-MHC, was quantitatively analyzed at gene transcription level by using RNA slot blot hybridization. The results showed that the cardiac contractility and the alpha-MHC mRNA levels in heart failure rats were all lower than those in the normal. Statistical analysis showed a positive correlation between the cardiac contractility and the gene expression of alpha-MHC (r = 0.4143, n = 43, P < 0.05). The above results indicate that gene expression level of alpha-MHC is one of the key factors determining cardiac contractility.
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PMID:[Relationship between the expression level of alpha-MHC gene and cardiac contractility during heart failure]. 1068 70

Skinned and hybrid myocardial fibers were studied by methods of tensometry, determination of the ATP hydrolysis intensity, and resonance fluorescent energy transfer between highly selective labels bound to various amino acid residues. It was established that development of the early stage of heart failure in the case of acute myocardial ischemia caused by 15-min coronary artery occlusion (CAO) is related to a reversible damage or adaptive (functional) depression of the contractile protein system. As a result, the system features isolated submolecular post-translational variation in the properties of major proteins in a thin actin filament (myosin is not significantly damaged). This leads to a decrease in the force developed by the hybrid fibers (reconstructed using ghost myocardial fibers taken from ischemic area and normal myosin) and in the ATPase activity of actomyosin (ATP hydrolysis intensity) without any significant change in the Ca-sensitivity, cooperativity of the Ca-response of the actomyosin ensemble, and efficiency of the contractile process. In actin of the ischemic area, CAO results in a serious damage of the Lys61 and Cys374 regions and in a less pronounced damage of the Tyr69 and Cys10 regions. These results suggest that the Lys61 and, probably, Cys374-Lys61 regions are included in the actin monomer as a protomer, without adequate prepolymerization structural-conformational changes necessary to provide for the normal functioning of the filament. In the CAO-induced early stage of heart failure, cardiac glycosides (beta-acetyldigoxin, beta-methyldigoxin, and strophanthin K) produce a direct effect upon the intramolecular structure of myocardial actin, restore the generated force level, and increase the intensity of ATP hydrolysis by actomyosin ensemble. This is achieved by improving or normalizing the structural-conformational state and conformational mobility of the Lys61 and Cys374 region of actin.
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PMID:[A disorder of myocardial contractile function in acute experimental coronary failure: the submolecular mechanisms and the action of cardiac glycosides]. 1083 90

It remains unknown whether angiotensin-converting enzyme (ACE) inhibition can prevent heart failure in rats with a fixed high pressure load of the left ventricle and if this effect could be attributed to normalization of contractile protein phenotype and cardiac collagen content. Rats with constriction of the ascending aorta were treated with the ACE inhibitor quinapril (6 mg kg(-1) day(-1)) (n=95) or placebo (n=96) (starting 6 weeks post surgery. Quinapril treatment improved survival markedly (P<0.0000001) during the 24 weeks observation period. There were 69 deaths with placebo and only 25 deaths with quinapril. At the end of the observation period signs of left ventricular backward failure were, however, detected in 75 rats with placebo and in 67 rats treated with quinapril (P=0.229). Cox proportional hazard model with time-dependent covariates was used to document that the effect of quinapril treatment had been dependent on time. Quinapril had no significant effect on the development of morphological signs of left ventricular dysfunction after the first 54 days of treatment. The increased isomysin V(3) proportion of hypertrophied non-failing hearts was also not affected by quinapril treatment. Irrespective of treatment, failing hypertrophied hearts were characterized by an increase in left ventricular volume (P<0.05), percentage of the 'foetal' isomyosin V(3) (P<0.05), and hydroxyproline concentration (P<0.05). While the cause of the improved survival remains unknown, quinapril did apparently not interfere with the restitution of 'foetal' gene expression of pressure overloaded cardiomyocytes leading to depressed myocardial performance, ventricular dysfunction and the consecutive myocardial fibrosis.
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PMID:Heart failure development in rats with ascending aortic constriction and angiotensin-converting enzyme inhibition. 1092 73

Two main troponin I genes, cardiac (cTnI) and slow skeletal (ssTnI), are expressed in the mammalian heart under the control of a developmentally regulated program. ssTnI is expressed first in embryonic and fetal heart, and is then downregulated by an unknown mechanism after birth. Unlike other contractile protein genes, ssTnI is not re-expressed during hypertrophy or end-stage heart failure in rats and humans. In the present study, we also show that ssTnI re-expression does not occur in hypertrophic mouse heart. To investigate ssTnI downregulation further, cTnI knockout mice were used to examine a possible role for thyroid hormone. Northern blot analysis of euthyroid animals showed a time-dependent loss of ssTnI mRNA that was similar for wild-type, heterozygous and homozygous cTnI mutant mice. In cTnI null mice made hyperthyroid by l -thyroxine, the duration of ssTnI expression assessed by both mRNA and protein content was abbreviated compared with the euthyroid group. Hyperthyroid cTnI null mice also died significantly earlier than euthyroids (postnatal day 14 v day 18). In cTnI null mice made hypothyroid by addition of phenylthiouracil to the drinking water, ssTnI expression was prolonged and mice survived until day 20 or 21. Overall, the results indicate that inactivation of the ssTnI gene occurs even in the absence of cTnI mRNA and protein indicating that these are not critical signals for ssTnI down regulation in the heart. In contrast, thyroid hormone influences the time course of ssTnI expression and the life span of cTnI null mice probably through a transcriptional regulation of ssTnI in the heart.
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PMID:Thyroid hormone regulates slow skeletal troponin I gene inactivation in cardiac troponin I null mouse hearts. 1111 97

Release of bacterial endotoxin and cytokines induce cardiac failure during sepsis. We investigated the direct effects of E. coli endotoxin (lipopolysaccharide, LPS) and cytokines induced by LPS on the cardiac myocyte gene program. For in vivo-experiments adult Wistar rats were given 600 microg/day LPS i.v. for 24 h or 7 days. In addition, cultured adult rat cardiac myocytes were treated with LPS, interleukin-1beta (IL-1beta), tumour necrosis factor-alpha (TNFalpha), interferon-gamma (IFNgamma) or IL-6 for 24 h. mRNA expression was evaluated for cardiac-alpha-actin (cAct), skeletal-alpha-actin (skAct), beta- and alpha-myosin heavy chain (MHC). LPS induced betaMHC-mRNA 3.6-fold and repressed alphaMHC 2.7-fold and cAct 2.5-fold after 24 h in vivo. Up-regulation of betaMHC (3-fold) and repression of cAct (2.5-fold) were still observed after 7 days LPS infusion, whereas alphaMHC-mRNA levels had returned to normal. At the protein level, increased expression of betaMHC by LPS treatment occurred already after 24 h and was maintained thereafter. LPS had no influence on skAct-mRNA. Similar changes in contractile protein mRNA expression were observed in LPS-treated cardiomyocytes in culture, whereas the tested cytokines either activated (IL-1beta, IFNgamma) or repressed (TNFalpha, IL-6) both MHC-isoforms and cAct. In conclusion, LPS and proinflammatory cytokines induce changes in contractile protein expression that may contribute to the acute heart failure observed during endotoxaemia.
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PMID:Endotoxin and cytokines alter contractile protein expression in cardiac myocytes in vivo. 1168 Jun 26

In experimental studies in the dog, total proximal coronary artery occlusions of up to 15 minutes result in reversible injury, meaning that the myocytes survive this insult. The 15 minutes of ischemia, however, induce numerous changes in the myocardium, including certain monuments to the brief episode of ischemia that may persist for days. One of these monuments is stunned myocardium, which represents "prolonged postischemic contractile dysfunction of myocardium salvaged by reperfusion." The mechanism of stunning involves generation of oxygen radicals as well as alteration in calcium homeostasis and possibly alteration in contractile protein structure. Stunning has been observed in several clinical scenarios, including after percutaneous transluminal coronary angioplasty, unstable angina, stress-induced ischemia, after thrombolysis, and after cardiopulmonary bypass. Oxygen radical scavengers and calcium channel blockers have been shown to enhance function of stunned myocardium in experimental studies, and in a few clinical studies, calcium channel blockers have been shown to ameliorate stunning. Although brief periods of ischemia can contribute to prolonged left ventricular dysfunction and even heart failure, they paradoxically play a cardioprotective role. Episodes of ischemia as short as 5 minutes, followed by reperfusion, protect the heart from a subsequent longer coronary artery occlusion by markedly reducing the amount of necrosis that results from the test episode of ischemia. This phenomenon, called ischemic preconditioning, has been observed in virtually every species in which it has been studied and is a powerful cardioprotective effect. The mechanism of ischemic preconditioning involves both triggers and mediators and involves complex second messenger pathways that appear to involve such components as adenosine, adenosine receptors, the epsilon isoform of protein kinase C, the ATP-dependent potassium channels, as well as others, including a paradoxical protective role of oxygen radicals. Both an early and a late phase of preconditioning have been described, and the mechanisms underlying their induction are under investigation. That preconditioning may occur in humans is suggested by the observations that repetitive balloon inflations in the coronary artery are associated with progressively less chest pain, ST-segment elevation, lactate production, the protective effects of preinfarction angina, the anginal "warm-up phenomenon," and studies performed on human cardiac biopsies that show metabolic properties suggesting preconditioning. Development of pharmacological agents that stimulate second messenger pathways thought to be involved in preconditioning, but without causing ischemia, could result in novel approaches to treating ischemia. Hence, on one hand, brief episodes of ischemia can have a negative effect on the heart: stunning; and on the other hand, they have a protective effect: preconditioning. The future challenge is how to minimize the stunning phenomenon and maximize the preconditioning phenomenon in clinical practice.
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PMID:Consequences of brief ischemia: stunning, preconditioning, and their clinical implications: part 1. 1173 16

In experimental studies in the dog, total proximal coronary artery occlusions of up to 15 minutes result in reversible injury, meaning that the myocytes survive this insult. The 15 minutes of ischemia, however, induce numerous changes in the myocardium, including certain monuments to the brief episode of ischemia that may persist for days. One of these monuments is stunned myocardium, which represents "prolonged postischemic contractile dysfunction of myocardium salvaged by reperfusion." The mechanism of stunning involves generation of oxygen radicals as well as alteration in calcium homeostasis and possibly alteration in contractile protein structure. Stunning has been observed in several clinical scenarios, including after percutaneous transluminal coronary angioplasty, unstable angina, stress-induced ischemia, after thrombolysis, and after cardiopulmonary bypass. Oxygen radical scavengers and calcium channel blockers have been shown to enhance function of stunned myocardium in experimental studies, and in a few clinical studies, calcium channel blockers have been shown to ameliorate stunning. Although brief periods of ischemia can contribute to prolonged left ventricular dysfunction and even heart failure, they paradoxically play a cardioprotective role. Episodes of ischemia as short as 5 minutes, followed by reperfusion, protect the heart from a subsequent longer coronary artery occlusion by markedly reducing the amount of necrosis that results from the test episode of ischemia. This phenomenon, called ischemic preconditioning, has been observed in virtually every species in which it has been studied and is a powerful cardioprotective effect. The mechanism of ischemic preconditioning involves both triggers and mediators and involves complex second messenger pathways that appear to involve such components as adenosine, adenosine receptors, the epsilon isoform of protein kinase C, the ATP-dependent potassium channels, as well as others, including a paradoxical protective role of oxygen radicals. Both an early and a late phase of preconditioning have been described, and the mechanisms underlying their induction are under investigation. That preconditioning may occur in humans is suggested by the observations that repetitive balloon inflations in the coronary artery are associated with progressively less chest pain, ST-segment elevation, lactate production, the protective effects of preinfarction angina, the anginal "warm-up phenomenon," and studies performed on human cardiac biopsies that show metabolic properties suggesting preconditioning. Development of pharmacological agents that stimulate second messenger pathways thought to be involved in preconditioning, but without causing ischemia, could result in novel approaches to treating ischemia. Hence, on one hand, brief episodes of ischemia can have a negative effect on the heart: stunning; and on the other hand, they have a protective effect: preconditioning. The future challenge is how to minimize the stunning phenomenon and maximize the preconditioning phenomenon in clinical practice.
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PMID:Consequences of brief ischemia: stunning, preconditioning, and their clinical implications: part 2. 1174 17

Congestive heart failure occurs more frequently in older individuals. This higher incidence of heart failure may be caused by the diminished capacity of aged hearts to adapt to increased hemodynamic overload and ischemia which are the most important triggers for heart failure in the aged. In the immediate early phase after the imposition of ascending aortic banding, the mRNA expression of proto-oncogenes (c-fos, c-jun and c-myc) was diminished in aged rat hearts compared with young adult hearts. In the later phase, the pattern of expression of contractile protein genes in aged hearts differed quantitatively from that in adult hearts. The hypertrophic responses to the imposition of not only pressure-overload but also volume-overload were also diminished at the organ and cellular levels. In addition, this diminution was observed both in the left and right ventricles. Against ischemic insults, aged hearts responded with a diminished expression of proto-oncogenes and heat shock proteins. Thus, aged hearts are characterized by poor adaptation to hemodynamic overload and by a poor self-protective mechanism against cell death through necrosis and apoptosis. Of interest, more severe hemodynamic overload elevated the diminished responses to a level similar to that in adult hearts, suggesting that the threshold for the heart to respond to hemodynamic overload or ischemia is elevated in aged hearts. In addition, even in aged hearts ischemic preconditioning upregulated the diminished gene expression in a gene-dependent manner. Thus, the capacity for adaptation to hemodynamic overload and ischemia is diminished in aged hearts, but aged hearts preserve the ability to respond to these under some conditions.
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PMID:Acute and chronic adaptation to hemodynamic overload and ischemia in the aged heart. 1179 Sep 23

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