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)

Alterations in the beta-adrenergic receptor adenylyl cyclase pathway are well known in heart failure. To determine if an alteration in this pathway occurs during the reversible phase of cardiac allograft rejection, we used a rat heterotopic heart transplant model. Lewis rats received either isografts or Lewis Brown Norway allografts. Cardiac grafts and native hearts were explanted 4, 5, or 6 days later. Receptor-mediated modulation of adenylyl cyclase activity was investigated using isoproterenol, forskolin, and the muscarinic and adenosine receptor agonists carbachol and R-N6-(C2-phenyl-isopropyl)-adenosine (R-PIA), respectively. Allografts demonstrated evidence of histological rejection and a significantly impaired response to forskolin and isoproterenol on all days: [table: see text] (% increase in cAMP in response to forskolin or isoproterenol +/- standard error. All results P less than 0.03 except Day 4 forskolin and Day 5 isoproterenol.) No significant difference was noted between isografts and allografts stimulated with carbachol and R-PIA. These data suggest that a primary alteration in adenylyl cyclase activity may be a component of the molecular basis of reversible contractile dysfunction in cardiac allograft rejection.
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PMID:Molecular mechanism of contractile dysfunction in cardiac allograft rejection. 161 16

Brown adipose tissue (BAT) is an important source of non-shivering thermogenesis. Increased BAT amounts have been reported to occur in association with several diseases, including congestive heart failure. The objective of the present study was to determine whether BAT accumulation occurs in patients with Chagas disease. Histological sections of peri-adrenal tissue obtained at autopsy from 259 patients were examined. Of these patients, 58 had the digestive form of Chagas disease, 50 had the cardiac form without heart failure and 201 had the cardiac form with heart failure. All cases were investigated in terms of nutritional status and classified as malnourished, normotrophic or obese according to the Quetelet index. The results showed no correlation between BAT and the patients' nutritional status, and more BAT accumulation in patients with the cardiac form of Chagas disease compared to patients with the digestive form. Similarly, a history of heart failure was correlated with greater BAT accumulation. On the basis of the present data and of information reported in the literature, we propose that chronic hypoxia may be the cause of BAT accumulation in Chagas disease patients with heart failure.
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PMID:Accumulation of brown adipose tissue in patients with Chagas heart disease. 178 Sep 87

Rejection of the cardiac allograft is often associated with reversible myocardial failure, the mechanism of which is not understood. We have examined this phenomenon in a small animal model that provides the opportunity for multimodality study of the rejection process. Heterotopic cardiac transplantation was performed in the Lewis rat with Lewis X Brown-Norway (allografts) or Lewis (isografts) donors. Without immunosuppression, allografts are completely rejected in 6 to 8 days. At 3 days cardiac grafts were explanted and mounted on a modified Langendorff apparatus for functional measurements or submitted for pathologic examination and biochemical determination of high-energy phosphates. Three-day isografts (n = 9) had minimal histologic changes. Pathologic examination of 3-day allografts (n = 13) showed lymphocytic infiltrate and myocyte necrosis, histologic features for which antirejection treatment is usually given clinically. For grafts subjected to functional studies (n = 11), heart rate, cardiac output, coronary flow, and stroke work were determined at baseline and in response to isoproterenol (3 x 10(-8) mol/ml). Three-day allografts (n = 6) and isografts (n = 5) had similar baseline function. The chronotropic response to isoproterenol was similar in allografts and isografts, but allografts had diminished cardiac output and stroke work after isoproterenol. Adenosine triphosphate levels were normal (41.9 nmol/mg) in 3-day allografts (n = 4). We have evaluated functional, biochemical, and pathologic changes associated with myocardial dysfunction during heterotopic cardiac transplant rejection in a small animal. This model reproducibly demonstrates diminished contractile reserve in 3-day allografts with normal baseline function and high-energy stores but histologically significant rejection.
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PMID:The mechanism of heart failure caused by cardiac allograft rejection. 199 37

Alterations in the beta-adrenergic receptor adenylylcyclase (AC) pathway are well known in heart failure. Previous studies by our group have demonstrated impaired function of the AC pathway and contractile reserve when stimulated with isoproterenol (ISO) or forskolin (F) in cardiac allografts with moderate or severe rejection. To determine if recovery of the AC pathway occurs when rejection is reversed, we used a rat heterotopic heart transplant model. Lewis (L) rats received either isografts or Lewis-Brown Norway (LBN) allografts (ALLO). The hearts were explanted on Day 4 and reimplanted into a recipient syngeneic with the original donor (L to L, LBN to LBN). Grafts were harvested 2 days later and analyzed. Receptor-mediated modulation of AC activity was investigated using ISO, F, and the metabolic inhibitor of AC, R-N6-(2-phenylisopropyl)-adenosine (R-PIA). ISO- and F-mediated stimulation of AC were significantly impaired in ALLO (see Table). CARB and R-PIA remained unchanged. [table: see text] Reimplanted hearts had no histologic evidence of rejection and had normal cAMP production in response to ISO and F. In conclusion, AC alterations are concordant with histologic changes in this reversible model of heart failure. Such alterations may be a component in the contractile dysfunction associated with rejection.
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PMID:Reversible contractile dysfunction in reversible experimental cardiac allograft rejection: alterations in the beta-receptor-stimulated adenylylcyclase pathway. 841 72

Using Brown Norway Katholiek (BNK) rats, which are deficient in kininogen (kinin precursor) due to a mutation in the kininogen gene, we examined the role of endogenous kinins in 1) normal cardiac function; 2) myocardial infarction (MI) caused by coronary artery ligation; 3) cardiac remodeling in the development of heart failure (HF) after MI; and 4) the cardioprotective effect of angiotensin-converting enzyme inhibitors (ACEI) on HF after MI. Two months after MI, rats were randomly treated with vehicle or the ACEI ramipril for 2 mo. Brown Norway rats (BN), which have normal kininogen, were used as controls. Left ventricular (LV) end-diastolic volume (EDV), end-systolic volume (ESV), end-diastolic pressure (EDP), and ejection fraction (EF) as well as myocardial infarct size (IS), interstitial collagen fraction (ICF), cardiomyocyte cross-sectional area (MCA), and oxygen diffusion distance (ODD) were measured. We found that 1) cardiac hemodynamics, function, and histology were the same in sham-ligated BN and BNK rats; 2) IS was similar in BN and BNK; 3) in rats with HF treated with vehicle, the decrease in LVEF and the increase in LVEDV, LVESV, LVEDP, ICF, MCA, and ODD did not differ between BNK and BN; and 4) ACEI increased EF, decreased LVEDV and LVESV, and improved cardiac remodeling in BN-HF rats, and these effects were partially blocked by the bradykinin B(2) receptor antagonist icatibant (HOE-140). In BNK-HF rats, ACEI failed to produce these beneficial cardiac effects. We concluded that in rats, lack of kinins does not influence regulation of normal cardiac function, myocardial infarct size, or development of HF; however, kinins appear to play an important role in the cardioprotective effect of ACEI, since 1) this effect was significantly diminished in kininogen-deficient rats and 2) it was blocked by a B(2) kinin receptor antagonist in BN rats.
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PMID:Role of kinins in chronic heart failure and in the therapeutic effect of ACE inhibitors in kininogen-deficient rats. 1066 82

Since its first description in 1979 (Brown et al., 1979. Nature 280, 235-236), extensive work on the I(f) current has amply demonstrated its role in the generation and neurotransmitter-induced modulation of pacemaker activity in heart (DiFrancesco, 1993. Annual Review of Physiology 55, 455-472). At pacemaker voltages, I(f) is an inward current activated by negative voltage and by intracellular cAMP. Moderate beta-receptor stimulation accelerates, and vagal stimulation slows, cardiac rate by increasing and decreasing, respectively, I(f) at diastolic potentials via changes in cAMP level. Cloning of four isoforms of hyperpolarization-activated, cyclic-nucleotide-gated (HCN) channels in the late 1990s has shown their correlation to native f-channels. Comparison of the properties of native pacemaker channels with those of HCN channels has provided information concerning the composition and molecular features of native channels in different cardiac regions. The relevance of I(f) to pacemaker generation and modulation makes f-channels a natural target of drugs aiming to control pharmacologically heart rate. Agents selectively reducing heart rate have been developed which act by specific inhibition of I(f), such as ivabradine; these drugs have a high potential for treatment of diseases where heart rate reduction is beneficial, such as angina and heart failure. Knowledge of the molecular properties of HCN clones will help the development of drugs specifically interacting with cardiac, rather than neuronal pacemaker channels. Devices able to replace electronic pacemakers and based on the delivery of a cellular source of pacemaker channels to non-pacing tissue (biological pacemakers) are likely to be developed in the near future for use in therapies for diseases of heart rhythm.
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PMID:Serious workings of the funny current. 1597 37

"Funny" (f) channels underlie the cardiac "pacemaker"I(f) current, originally described as an inward current activated on hyperpolarization to the diastolic range of voltages in sino-atrial node myocytes [Brown, HF, DiFrancesco, D, Noble, SJ. How does adrenaline accelerate the heart? Nature 1979;280:235-236]. The involvement of funny channels in the generation and modulation of cardiac pacemaker activity has been amply demonstrated by thorough analysis since its discovery. The degree of funny current activation upon termination of an action potential determines the slope of diastolic depolarization, and hence pacemaker frequency; furthermore, I(f) is under cAMP-mediated control by beta-adrenergic and muscarinic stimulation and underlies the modulation of cardiac rate by the autonomous nervous system: it therefore represents a mechanism of fundamental physiological relevance. Their function in pacemaking makes funny channels an obvious target for drugs aiming at regulation of spontaneous activity and cardiac rate. This explains the recent development of "heart rate-reducing" drugs which act as selective f-channel inhibitors, and as such are capable of specifically slow cardiac frequency by decreasing the rate of diastolic depolarization. These substances will be useful in treating diseases such as chronic angina and heart failure. Furthermore, in situ delivery of funny channels, or of a cellular source of funny channels, is a promising new technique for the development of biological pacemakers which may in a near future replace electronic devices. Finally, a channel mutation responsible for one type of a relatively common rhythm disturbance, sinus bradycardia, has been recently identified, highlighting the clinical relevance of funny channels in the pacemaker function.
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PMID:Funny channels in the control of cardiac rhythm and mode of action of selective blockers. 1663 40

Aging is associated with left ventricular hypertrophy, dilatation, and fibrosis of the heart. The Fischer 344/Brown Norway F1 (F344/BNF1) rat is recommended for age-related studies by the National Institutes on Aging because this hybrid rat lives longer and has a lower rate of pathological conditions than inbred rats. However, little is known about age-associated changes in cardiac and aortic function and structure in this model. This study evaluated age-related cardiac changes in male F344/BNF1 rats using ECHO, gross, and microscopic examinations. Rats aged 6-, 30-, and 36-mo were anesthetized and two-dimensional ECHO measurements, two-dimensional guided M-mode, Doppler M-mode, and other recordings from parasternal long- and short-axis views were obtained using a Phillips 5500 ECHO system with a 12 megahertz transducer. Hearts and aortas from sacrificed rats were evaluated grossly and microscopically. The ECHO studies revealed persistent cardiac arrhythmias (chiefly PVCs) in 72% (13/18) of 36-mo rats, 10% (1/10) of 30-mo rats, and none in 6-mo rats (0/16). Gross and microscopic studies showed left ventricular (LV) dilatation, borderline to mild hypertrophy, and areas of fibrosis that were common in 36-mo rats, less evident in 30-mo rats, and absent in 6-mo rats. Aging was associated with mild to moderate decreases of LV diastolic and systolic function. Thus, male F344/BN F1 rats demonstrated progressive age-related (a) decline in cardiac function (diastolic and systolic indices), (b) LV structural changes (chamber dimensions, volumes, and wall thicknesses), and (c) persistent arrhythmias. These changes are consistent with those in humans. The noninvasive ECHO technique offers a means to monitor serial age-related cardiac failure and therapeutic responses in the same rats over designated time intervals.
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PMID:Age-associated changes in hearts of male Fischer 344/Brown Norway F1 rats. 1712 29

The small G-protein RhoA regulates the actin cytoskeleton, and its involvement in cell proliferation has also been established. In contrast, little is known about whether RhoA participates in cell survival or apoptosis. In cardiomyocytes in vitro, RhoA induces hypertrophic cell growth and gene expression. In vivo, however, RhoA expression leads to development of heart failure (Sah, V. P., Minamisawa, S., Tam, S. P., Wu, T. H., Dorn, G. W., Ross, J. Jr., Chien, K. R., and Brown, J. H. (1999) J. Clin. Investig. 103, 1627-1634), a condition widely associated with cardiomyocyte apoptosis. We demonstrate here that adenoviral overexpression of activated RhoA in cardiomyocytes induces hypertrophy, which transitions over time to apoptosis, as evidenced by caspase activation and nucleosomal DNA fragmentation. The Rho kinase inhibitors Y-27632 and HA-1077 and expression of a dominant negative Rho kinase block these responses. Caspase-9, but not caspase-8, is activated, and its inhibition prevents DNA fragmentation, consistent with involvement of a mitochondrial death pathway. Interestingly, RhoA expression induces a 3-4-fold up-regulation of the proapoptotic Bcl-2 family protein Bax. RhoA also increases levels of activated Bax and the amount of Bax protein localized at mitochondria. Bax mRNA is increased by RhoA, indicating transcriptional regulation, and the ability of a dominant negative p53 mutant to block Bax up-regulation implicates p53 in this response. The involvement of Bax in RhoA-induced apoptosis was examined by treatment with a Bax-inhibitory peptide, which was found to significantly attenuate DNA fragmentation and caspase-9 and -3 activation. The dominant negative p53 also prevents RhoA-induced apoptosis. We conclude that RhoA/Rho kinase activation up-regulates Bax through p53 to induce a mitochondrial death pathway and cardiomyocyte apoptosis.
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PMID:RhoA/Rho kinase up-regulate Bax to activate a mitochondrial death pathway and induce cardiomyocyte apoptosis. 1723 27

Decreases in the expression of connexin 43 and the integrity of gap junctions in cardiac muscle, induced by the constitutive activation of the c-Jun N-terminal kinase (JNK) signaling pathway, have been linked to conduction defects and sudden cardiac failure in mice [Petrich BG, Gong X , Lerner DL , Wang X , Brown JH , Saffitz JE , Wang Y. c-Jun N-terminal kinase activation mediates downregulation of connexin 43 in cardiomyocytes. Circ Res. 91 (2002) 640-647; B.G. Petrich, B.C. Eloff, D.L. Lerner, A. Kovacs, J.E. Saffitz, D.S. Rosenbaum, Y. Wang, Targeted activation of c-Jun N-terminal kinase in vivo induces restrictive cardiomyopathy and conduction defects. J. Biol. Chem. 2004;279: 15330-15338]. We examined the membrane cytoskeletal protein, alphaII-spectrin, which associates with connexin 43, to learn if changes in its association with connexin 43 are linked to the instability of gap junctions. Several forms of alphaII-spectrin are expressed in the heart, including one, termed alphaII-SH3i, which contains a 20-amino-acid sequence next to the SH3 domain of repeat 10. In adult mouse heart, antibodies to all forms of alphaII-spectrin labeled the sarcolemma, transverse ("t-") tubules and intercalated disks of cardiomyocytes. In contrast, antibodies specific for alphaII-SH3i labeled only gap junctions and transverse tubules. In transgenic hearts, in which the JNK pathway was constitutively activated, alphaII-SH3i was lost specifically from gap junctions but not from t-tubules while other isoforms of alphaII-spectrin were retained at intercalated disks. Immunoprecipitations confirmed the decreased association of alphaII-SH3i with connexin 43 in transgenic hearts compared to controls. Furthermore, activation of JNK in neonatal myocytes blocked the formation of gap junctions by exogenously expressed Cx43-GFP fusion protein. Similarly, overexpression of the SH3i fragment in the context of repeats 9-11 of alphaII-spectrin specifically caused the accumulation of Cx43-GFP in the perinuclear region and inhibited its accumulation at gap junctions. These results support a critical role for the alphaII-SH3i isoform of spectrin in intracellular targeting of Cx43 to gap junctions and implicates alphaII-SH3i as a potential target for stress signaling pathways that modulate intercellular communication.
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PMID:Role of an alternatively spliced form of alphaII-spectrin in localization of connexin 43 in cardiomyocytes and regulation by stress-activated protein kinase. 1727 56


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