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)

We have tested the hypothesis that decreased functioning of creatine kinase (CK) at sites of energy production and utilization may contribute to alterations in energy fluxes and calcium homeostasis in congestive heart failure (CHF). Heart failure was induced by aortic banding in 3-week-old rats. Myofilaments, sarcoplasmic reticulum (SR), mitochondrial functions, and CK compartmentation were studied in situ using selective membrane permeabilization of left ventricular fibers with detergents (saponin for mitochondria and SR and Triton X-100 for myofibrils). Seven months after surgery, animals were in CHF. A decrease in total CK activity could be accounted for by a 4-fold decrease in activity and content (Western blots) of mitochondrial CK and a 30% decrease in M isoform of CK (MM-CK) activity. In myofibrils, maximal force, crossbridge kinetics, and alpha-myosin heavy-chain expression decreased, whereas calcium sensitivity of tension development remained unaltered. Myofibrillar CK efficacy was unchanged. Calcium uptake capacities of SR were estimated from the surface of caffeine-induced tension transient (SCa) after loading with different substrates. In CHF, SCa decreased by 23%, and phosphocreatine was 2 times less efficient in enhancing calcium uptake. Oxidative capacities of the failing myocardium measured as oxygen consumption per gram of fiber dry weight decreased by 28%. Moreover, the control of respiration by creatine, ADP, and AMP was severely impaired. Our observations provide evidence that alterations in CK compartmentation may contribute to alterations of energy fluxes and calcium homeostasis in CHF.
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PMID:Subcellular creatine kinase alterations. Implications in heart failure. 1040 Sep 12

The importance of endogenous and exogenous estrogen levels to the development of cardiovascular disease in women in controversial. The purpose of our study was to examine the effect of estrogen on the development of hypertension, cardiac hypertrophy, ventricular function, and gene expression for atrial natriuretic peptide (ANP) and components of the renin angiotensin system in spontaneously hypertensive heart failure rats (SHHF/Mcc- facp). Development of hypertension was prevented in 3-month-old ovariectomized rats receiving subcutaneous 17 beta -estradiol implants (EST) compared to ovariectomized (OVX) and controls (CON). EST had the least left ventricular hypertrophy, CON were intermediate, and OVX had the most (P<0.05), correlating well with systolic blood pressure. OVX had significantly lower percentage V(1)myosin isoform compared to EST and CON, indicating reversion to a more immature phenotype associated with hypertrophy. Similarly, OVX had decreased percentage left ventricular shortening fraction by echocardiography compared to EST and CON. These changes were not accompanied by alterations in plasma ANP, or in expression of mRNA for left ventricular ANP, renal renin, or hepatic angiotensinogen. Serum angiotensin converting enzyme activity was lower in EST compared to CON or OVX. When 17 beta -estradiol was given to 17-month-old rats that had naturally ceased estrous cycling, there was no effect on hypertension, progression of cardiac functional decline, or survival. In conclusion, estradiol treatment given prior to the development of hypertension in SHHF prevented left ventricular hypertrophy and hypertension. Development of congestive heart failure was not delayed if 17 beta -estradiol was begun in the post-menopausal period. Effectiveness of estrogen therapy may depend on age or whether hypertension is already established at the time treatment is begun.
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PMID:Effect of ovariectomy and estrogen replacement on cardiovascular disease in heart failure-prone SHHF/Mcc- fa cp rats. 1042 50

The use of anthracyclines, a group of potent anti-cancer agents incorporated into the treatment of a wide variety of solid and haematological tumours, is limited by its cardiotoxicity that can result in congestive heart failure (CHF). The best method to detect cardiotoxicity at an early stage in order to prevent severe deterioration, is still an unsolved problem. Although endomyocardial biopsy is considered to be the most sensitive and specific test for this purpose, its use is limited by its invasiveness. In daily practice, oncologists make use of parameters of systolic function (left ventricular ejection fraction, or fractional shortening) to detect cardiotoxicity, but these methods are not able to identify cardiotoxicity at an early stage. Based on increasing knowledge into the pathophysiology of anthracycline-induced cardiotoxicity and heart failure in general, new methods including the determination of diastolic function parameters, anti-myosin scintigraphy, assessment of heart rate variability, and the determination of biochemical markers have been proposed to identify patients at risk of the development of CHF in an early stage. However, most of these newer methods have not yet been adequately evaluated to allow them to be recommended for use in routine clinical practice.
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PMID:Detection of anthracycline-induced cardiotoxicity. 1044 32

Cardiac hypertrophy in the guinea-pig is not accompanied by a large shift in the expression of the predominant isoform of myosin in the left ventricle; however, in this species, thin filament proteins do change. We examined the relaxation, following laser flash photolysis of the photolabile caged Ca2+ chelator diazo-2, of a skinned trabecular preparation from the left ventricle of guinea-pigs that had undergone abdominal aortic banding. Sham-operated animals were used as controls; no guinea-pigs showed any signs of heart failure. We report that mild cardiac hypertrophy does not affect the relaxation rate of Triton-skinned trabeculae from the guinea-pig. However, there was a 35% reduction in the maximum force generated by trabeculae from the left ventricle of the abdominal aortic-banded animals. Additionally, alterations in key troponin subunits occur in the left ventricle of guinea-pigs with mild hypertrophy. We conclude that the thin filament protein changes do not influence trabecular relaxation rates, even though they probably affect maximal force generation. The cellular membrane systems of the intact guinea-pig heart, which were not a factor in this present study, appear to have an important role in the altered cardiac relaxation rates seen in hypertrophy.
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PMID:Investigating the relaxation rate, following diazo-2 photolysis, of a skinned trabecular preparation from guinea-pig hypertrophied left ventricle. 1059 Oct 64

The regulatory protein troponin (Tn) located on actin filament consists of three subunits: TnT--binds troponin to tropomyosin, TnC--binds divalent calcium ions, and TnI--affects myosin-actin interactions. Tn subunits display several molecular and calcium binding variations. During ontogenetic development of cardiac and skeletal muscles the synthesis of multiple isoforms of Tn subunits was detected. Expression of Tn isoforms and the extent of phosphorylation of both TnT and TnI via protein kinase C or protein kinase A under different pathological situations (e.g. ischemia, congenital heart disease, heart failure) can affect the Ca2+-stimulated contraction function and the myofibrillar ATPase activity of the heart.
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PMID:Isoforms of troponin in normal and diseased myocardium. 1063 75

Alcoholic heart muscle disease is characterized by structural changes which include chamber dilation, ventricular hypertrophy, and myocyte damage. These effects often lead to contractile dysfunction and ultimately to heart failure if alcohol consumption is not terminated. In rat models for heart failure in which heart failure is induced by pressure or volume overload, there is a shift in the myosin heavy chain (MHC) isoforms, from alpha to beta. As a result of this MHC transition, there is typically a decrease in myosin ATPase activity. We utilized a rat model of chronic alcohol consumption in order to determine if alcohol causes a similar shift in MHC isoforms and changes in myosin ATPase activity. A liquid diet containing 9% ethanol (46% of daily calories; 11.8 g/kg/day) was administered to adult rats for a period of 60 or 90 days. This heavy consumption of ethanol resulted in an average blood ethanol content of 150 mg %. The relative abundance of beta-MHC isoform protein increased from a control level of 9.7% to 35.1% in hearts of ethanol-fed rats, following 90 days of ethanol consumption. In a separate set of experiments, the levels of alpha-MHC and beta-MHC mRNA were demonstrated to increase by 150% and 230%, respectively. Following a 60 day treatment, there was a significant reduction in the actomyosin Mg2+ -ATPase activity in the myofibrillar preparations from hearts of ethanol-fed rats compared to hearts from control-fed rats. In addition, the myosin Ca2+ -ATPase activity was decreased 17% and 30% after 60 and 90 days of ethanol consumption, respectively. The present study demonstrates that chronic ethanol consumption induces an increase in the proportion of the total MHC content composed of the beta-isoform. This isoform transition is accompanied by an accumulation of beta-MHC mRNA, suggesting that the switch is organized pretranslationally. A functional consequence of this transition in MHC phenotype is demonstrated by significant decreases in the myofibrillar and myosin ATPase activities.
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PMID:Heavy long-term ethanol consumption induces an alpha- to beta-myosin heavy chain isoform transition in rat. 1065 Nov 60

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

Inotropic responsiveness to beta-adrenergic stimulation is generally found to be impaired in left ventricular (LV) hypertrophy and failure. To investigate the mechanisms by which angiotensin-converting enzyme inhibitor therapy may modulate inotropic responsiveness with long-term pressure overload, we studied the effects of captopril treatment on cardiac gene expression, LV muscle mechanical contraction, and intracellular calcium (Ca(2+)) transients from spontaneously hypertensive rats (SHR). LV papillary muscles from untreated SHR, age-matched normotensive Wistar-Kyoto rats (WKY), and SHR treated with captopril (CAP(Rx) started at 12, 18, and 21 months of age) were studied. All animals were studied at 24 months of age or when heart failure developed. In untreated SHR, alpha-myosin heavy chain (MHC) gene expression and protein were decreased, the Ca(2+) transient (with the bioluminescent indicator aequorin) was prolonged, and abundance of Na(+)/Ca(2+) exchanger mRNA levels increased in comparison to WKY. Active stress development at L(max) and the maximum rate of stress development were depressed and contractile duration prolonged in SHR relative to WKY. Isoproterenol administration further decreased active stress in untreated SHR despite an increase in intracellular Ca(2+) levels. In CAP(Rx) SHR, alpha-MHC gene expression and protein levels were increased, the Ca(2+) transient was not prolonged, Na(+)/Ca(2+) exchanger expression was downregulated, and papillary muscle function demonstrated increased active stress and maximum rate of stress development in response to isoproterenol. The increased abundance of alpha-MHC mRNA in conjunction with an increase in V(1) myosin isozyme suggests that captopril affects transcriptional regulation of cardiac gene expression. Restored LV inotropic responsiveness to beta-adrenergic stimulation in CAP(Rx) SHR appears to be coupled to normalization of Na(+)/Ca(2+) exchanger mRNA expression, upregulation of V(1) myosin isozyme levels, and increased speed of contraction.
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PMID:Altered inotropic responsiveness and gene expression of hypertrophied myocardium with captopril. 1085 64

To investigate the kinetic parameters of the crossbridge cycle that regulate force and shortening in cardiac muscle, we compared the mechanical properties of cardiac trabeculae with either ATP or 2-deoxy-ATP (dATP) as the substrate for contraction. Comparisons were made in trabeculae from untreated rats (predominantly V1 myosin) and those treated with propylthiouracil (PTU; V3 myosin). Steady-state hydrolytic activity of cardiac heavy meromyosin (HMM) showed that PTU treatment resulted in >40% reduction of ATPase activity. dATPase activity was >50% elevated above ATPase activity in HMM from both untreated and PTU-treated rats. V(max) of actin-activated hydrolytic activity was also >50% greater with dATP, whereas the K(m) for dATP was similar to that for ATP. This indicates that dATP increased the rate of crossbridge cycling in cardiac muscle. Increases in hydrolytic activity were paralleled by increases of 30% to 80% in isometric force (F(max)), rate of tension redevelopment (k(tr)), and unloaded shortening velocity (V(u)) in trabeculae from both untreated and PTU-treated rats (at maximal Ca(2+) activation), and F-actin sliding speed in an in vitro motility assay (V(f)). These results contrast with the effect of dATP in rabbit psoas and soleus fibers, where F(max) is unchanged even though k(tr), V(u), and V(f) are increased. The substantial enhancement of mechanical performance with dATP in cardiac muscle suggests that it may be a better substrate for contractility than ATP and warrants exploration of ribonucleotide reductase as a target for therapy in heart failure.
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PMID:2-deoxy-ATP enhances contractility of rat cardiac muscle. 1086 10

The diaphragm as a striated muscle is characterized by the repetition of a single element arranged in series: the sarcomere containing two kinds of myofilaments: a thick one constituted by the myosin, and a thin one primarily composed of actin. The myosin molecule consists of two heads where two myosin heavy chains (MHC) are fixed, a flexible hinge with two light (MLC) chains, and long rod-shaped tails. The diaphragm contains 4 MHC isoforms (MHC-slow, MHC-2A, MHC-2B, MHC-2X) and 6 MLC isoforms (MLC-1f, MLC-3f, MLC-1sa, MLC-1sb, MLC-2f, MLC-2s/v). In humans, the diaphragm contains mainly fibers expressing the isoforms MHC-slow, MHC-2A, and MLC-2f, MLC-2s et MLC-1f. For the mechanical properties of the different isoforms, there is a gradient from the MHC-slow to the MHC-2A, MHC-2B and MHC-2X/2B. According to the circumstances, the diaphragm will adapt towards a slow profile (COPD, cardiac failure and in animals: Duchenne muscular dystrophy, denervation-1 week, age-female, corticosteroids, chronic stimulation), or a fast profile (in animals: chronic hypoxia, denervation-2 weeks, age-males) or a more oxidative profile (in animals: cachexia, obesity). The reasons why the diaphragm adapts towards a slower or a faster muscle are not known. In fact, for a given pathological situation, several factors are able to influence the fiber composition of the diaphragm. Therefore, the net result of the influence of these different factors in terms of MHC and MLC diaphragm adaptation is difficult to predict.
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PMID:[Clinical relevance of myosin isoforms in the diaphragm]. 1093 18


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