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)

The common underlying heart diseases were ischemic heart disease (39%), valvular heart disease (27%), hypertensive heart disease (10%) in 104 patients (mean age 79 yrs) with congestive heart failure (CHF). Cardiomyopathy (5%) and congenital heart disease (2%) such as atrial septal defect were less common. In addition, many extracardiac diseases including anemia, hypothyroidism, renal failure and pulmonary disease contributed to the etiology of CHF in the elderly. Cardiac amyloidosis should be considered as an uncommon cause of refractory CHF. While the precipitating factor was not found in half of the 104 patients with CHF, the most common factors were respiratory infection, myocardial ischemia and arrhythmia. In addition, inappropriate drug usage including poor drug compliance, the use of beta-blockers and excessive intake of sodium and fluid precipitated or exacerbated heart failure. Renal failure was a most important complication and predisposed to refractory CHF. Aged patients with mild CHF (NYHA class II) showed an insufficient production of cyclic AMP and GMP in proportion to the increases of norepinephrine and atrial natriuretic peptide in comparison with health aged subjects after the submaximal treadmill exercise test. This finding may suggest that an inadequate compensation of neurohumoral factors is prone to cause CHF in the elderly. Appropriate management of acute CHF in the elderly begins with recognition of the underlying heart disease, complications and the severity of cardiac function. In addition to medical management including loop diuretics, vasodilator, beta-receptor agonist and phosphodiesterase inhibitor, cases associated with respiratory and renal failure require mechanical ventilation and continuous hemofiltration.
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PMID:[The etiology and management of congestive heart failure in the elderly]. 820 67

1. The purpose of this study was to elucidate the cellular mechanism of the positive inotropic effect of hydralazine, a vasodilator widely used for afterload reduction in patients with heart failure that has also been reported to have positive inotropic effects on the heart. After isolation, right ventricular papillary muscles from the ferret were maintained in bicarbonate-buffered salt solution (30 degrees C). A concentration-response relationship was obtained for hydralazine (10(-6) to 10(-3) M). In order to mimic different levels of catecholamine release found in heart failure, we utilized two methods of stimulation: (a) threshold punctate pulses and (b) suprathreshold punctate stimulation with voltage approximately 10% above threshold. 2. In a first group of muscles (n = 16), a maximally effective concentration of hydralazine (10(-3) M) increased peak isometric tension by 39 +/- 9% (P < 0.05). Doses lower than 10(-5) M had no significant effect. The bioluminescent Ca2+ indicator, aequorin, was loaded into a subset of these muscles (n = 7). A significant increase in peak light (i.e., intracellular Ca2+) developed, concurrently with an increase in peak tension (38 +/- 5% to 66 +/- 8%). This inotropic response was associated with a decrease in time to peak tension (ms), 221 +/- 7 to 186 +/- 5 (P < 0.05), and time to peak light, 65 +/- 4 to 52 +/- 2 (P < 0.05). These effects were markedly attenuated by pretreatment with autonomic blocking agents. 3. In a second group of muscles (n = 12), histamine was used to stimulate cyclic AMP production in the presence of propranolol. Hydralazine (3 x 10-4 M) led to a shift in the pD2 (i.e. the negative log of the concentration of histamine producing 50% of the maximal response) from 6.1 +/- 0.1 to 5.9 +/- 0.1(P <0.05), thus increasing the sensitivity of the muscles to histamine. Hydralazine also increased maximum tension from 160 +/- 77% to 195 +/- 57% (P <0.05) above baseline. Thus, hydralazine altered the potency and efficacy of histamine despite the presence of beta-adrenoceptor blockade.4. A third group of muscles were chemically skinned to examine the effects of hydralazine on myofilament Ca2+ responsiveness. Pretreatment of ferret papillary muscles with hydralazine (10-3 M)before skinning did not shift the force-pCa curve after skinning (n = 16). However, hydralazine added to previously skinned fibres desensitized the myofilaments, as indicated by a rightward shift of the force-pCa curve (n = 12). Maximum tension development was not changed.5. The pharmacological effects of hydralazine are characteristic of inotropic drugs that act mainly via cyclic AMP; however, the increase in peak tension demonstrated with histamine in the presence of hydralazine also suggests an effect on cyclic AMP-independent second messenger pathways. These data are consistent with reports that large doses of hydralazine may increase cellular levels of cyclic AMP, as well as other second messengers, by direct cardiac and indirect neuronal mechanisms.
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PMID:Cellular mechanism of the positive inotropic effect of hydralazine in mammalian myocardium. 835 64

The receptor systems through which serotonin (5-HT), histamine, angiotensin II and endothelin increase the force of contraction were studied in isolated right atria from patients without apparent heart failure. All agonists increased the atrial force of contraction in a concentration-dependent manner; maximal effects, however, were significantly less than those evoked by isoprenaline or Ca2+. 5-HT and histamine, but not angiotensin II and endothelin, activated adenylate cyclase, whereas endothelin and angiotensin II stimulated inositol phosphate generation. Experiments with subtype-selective antagonists revealed that histamine effects were mediated by H2-receptors (sensitive to ranitidine), 5-HT-effects by 5-HT4-receptors (sensitive to SDZ 205-557) and angiotensin II effects by AT1-receptors (sensitive to losartan). We conclude that in human right atria the force of contraction can be increased by cyclic AMP-dependent (histamine, 5-HT) and -independent (angiotensin II, endothelin) pathways. Compared to beta-adrenoceptors, however, all other receptor systems increase the force of contraction only submaximally indicating that the beta-adrenoceptor pathway is the most important physiological mechanism to regulate force of contraction and/or heart rate in the human heart.
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PMID:Comparison of the positive inotropic effects of serotonin, histamine, angiotensin II, endothelin and isoprenaline in the isolated human right atrium. 838 86

Isolation of calcitonin mRNA initiated studies on the multigene complex encoding a family of peptides: calcitonin, its terminal flanking peptides, calcitonin gene-related peptide (CGRP), and amylin. CGRP is expressed in alpha- and beta-forms that vary by one and three amino acids in rat and humans, respectively. Both alpha- and beta-CGRP are very similar in their biologic activities, therefore the role of duplicating the calcitonin/CGRP gene is unclear. CGRP behaves principally as a regulatory neuropeptide acting locally through interaction with target organ receptors that are either cyclic-AMP dependent, or capable of activating KATP channels of vascular smooth muscle. The dense distribution of CGRP-rich structures and the expression of mRNA in the central nervous system suggests that CGRP has a neuromodulator or neurotransmitter role not limited to vasoregulatory effects only, but like calcitonin, extends its action to physiologic, metabolic, and behavioral functions. Activation of perivascular sensory nerves stimulates the release of neuropeptides, including CGRP, which exerts a potent vasodilatory effect on venous and arterial vasculature. The increased levels of CGRP-like immunoreactivity were observed in volume overload states, in heart failure and myocardial infarction, and in some forms of hypertension. The beneficial effect of CGRP infusions was demonstrated in patients with congestive heart failure and also in subjects with neurological deficits after surgical treatment of subarachnoid hemorrhage. On the other hand, there are experimental studies on the inhibition of increased CGRP activity, in septic and shock conditions, in which the vascular hyperrelaxation could have deleterious effects.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Calcitonin gene-related peptide and regulation of human cardiovascular homeostasis. 839 Feb 69

Myocardial cells are able to adapt the cardiac pump function rapidly and widely to the changing requirements of vital organs through intrinsic and extrinsic regulatory mechanisms. This regulation is achieved by alteration of [Ca2+]i mobilization, Ca2+ sensitivity of myofibrils or both. Frank-Starling's mechanism achieved by alteration of Ca2+ sensitivity and force-frequency relation, primarily due to modulation of [Ca2+]i mobilization, are important intrinsic mechanisms. As extrinsic mechanisms, catecholamines play a crucial role by activation of both beta- and alpha 1-adrenoceptors through cyclic AMP, and products of phosphoinositide hydrolysis, as messengers, respectively. Adenosine and ACh act via similar transduction processes, including Gi or Gk proteins coupled to inhibition of adenylate cyclase, or activation of K+ channels. Most of these regulations are modulated and constitute crucial pathophysiological mechanisms in chronic heart failure.
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PMID:[Signal transduction in regulation of myocardial contractility]. 839 32

An impaired function of the myocardial beta-adrenergic receptor system has been reported in patients with end-stage heart failure and this impairment has been postulated to be a factor in further deterioration of cardiac contractile function. As ventricular dysfunction is often associated with prolonged alcohol abuse, we investigated whether or not chronic administration of ethanol could induce alterations in the beta-adrenergic receptor adenylate-cyclase system in rats. Male Wistar rats of 8 weeks of age received 33% ethanol in drinking water for 3 months. As compared with control rats drinking water, the ethanol-treated rats showed weight loss and an increase in the heart/body weight ratio. Chronic ethanol increased myocardial contents of norepinephrine and epinephrine, possibly resulting from sympathoadrenal activation. The beta-adrenergic receptor density (Bmax) of the myocardial membrane was significantly decreased in the ethanol-treated rats (27.7 +/- 9.9 vs 39.0 +/- 6.0 fmol/mg protein, p < 0.01), while the affinity (Kd) did not differ between the two groups. The myocardial content of cyclic-AMP was also reduced in the ethanol rats (865 +/- 59 vs 1055 +/- 83 pmol/g w.w., p < 0.01). These observations indicate that chronic ethanol administration depresses the function of the beta-adrenergic receptor adenylate-cyclase system. The decreased beta-adrenergic receptor density was partly attributed to down-regulation due to increased sympathetic stimulation. This impaired function may contribute to the cardiac contractile dysfunction observed in chronic alcoholics.
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PMID:Alterations in beta-adrenergic receptor density and cyclic-AMP level in the myocardium of rats chronically treated with alcohol. 839 53

Chronic activation of the sympathetic nervous system in human heart failure is believed to cause cardiac beta-adrenoceptor desensitisation. We have investigated the relationship between beta-adrenoceptor desensitisation and cyclic AMP levels in cardiac myocytes isolated from the ventricle of guinea-pigs chronically infused with noradrenaline hydrochloride for 7 days. Functional beta-adrenoceptor desensitisation was confirmed by a significant decrease in the maximum isoprenaline-stimulated contraction amplitude and an increased EC50 for isoprenaline. In the absence of beta-adrenoceptor stimulation, basal cyclic AMP levels were significantly depressed in populations of myocytes from noradrenaline-treated animals compared to sham-operated controls, and this was not accounted for by myocyte hypertrophy or necrosis. Similarly, there was a significant decrease in cyclic AMP levels at maximally inotropic isoprenaline concentrations. Threshold and maximum inotropic concentrations of the phosphodiesterase inhibitor, 3-isobutyl-l-methylxanthine (IBMX), restored isoprenaline-stimulated cyclic AMP levels in noradrenaline-treated guinea-pig cardiac myocytes, although we have previously reported no increase in maximum inotropic effect of isoprenaline with these compounds.
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PMID:Cyclic AMP levels in ventricular myocytes from noradrenaline-treated guinea-pigs. 888 22

To better characterize the role of skeletal muscle in chronic heart failure we studied energetic charge, metabolites and enzyme activity in the energy production pathway. We selected 15 males with severe chronic heart failure (NYHA class III, stable clinical conditions and in normal nutritional status) and seven controls. Controls and patients were submitted to biopsy of the vastus lateralis muscle in resting and fasting conditions. Hormone profiles were also evaluated. Our results showed near normal ATP, ADP and AMP concentrations, but there were substantially more reductions in glycogen (46 +/- 5 vs 77 +/- 6 mumoles glycosidic units.g-1 fresh tissue) and creatine phosphate (5 +/- 1 vs 13 +/- 1 mumoles.g-1 fresh tissue) in patients than in controls. We also found a reduction in glycolytic activity (pyruvate kinase 1009 +/- 79 vs 1625 +/- 26 nmoles. min-1.mg protein-1), despite normal tricarboxylic acid cycle velocity, an increase in alanine amino-transferase (964 +/- 79 vs 425 +/- 34 nmoles. min-1.mg protein-1) and in aspartate aminotransferase (515 +/- 44 vs 291 +/- 56 nmoles.min-1.mg protein-1). An increase was also observed in total NADH cytochrome c reductase (128 +/- 14 vs 68 +/- 5 nmoles.min-1.mg protein-1), while cytochrome oxidase activity was normal. The cortisol/insulin ratio was slightly elevated (77 +/- 4 vs 32 +/- 12). In conclusion, normonutritive patients with severe heart failure show an imbalance in the energy production/utilization ratio. The impairment is probably due both to a decrease in production and an increase in consumption of energy owing to greater cellular workload and/or a hypercatabolic state.
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PMID:Biochemical analysis of muscle biopsy in overnight fasting patients with severe chronic heart failure. 892 17

We studied peripheral skeletal muscle metabolism in monocrotaline-treated rats. Two distinct groups emerged: a percentage of the animals developed ventricular hypertrophy, with no signs of heart failure (compensated group), whilst others, besides ventricular hypertrophy, developed the syndrome of congestive heart failure (CFH group). Oxidative metabolism and redox cellular state were expressed in terms of creatine phosphate, purine (ATP, ADP and AMP) and pyridine (NAD and NADH) nucleotides tissue content. Skeletal muscles with different metabolism were studied: (a) Soleus (oxidative), (b) extensor digitorium longus (glycolytic) and tibialis anterior (oxidative and glycolytic). The results showed that in CFH animals a decreased high-energy phosphates content occurs in the soleus and extensor digitorum longus, but not in the tibialis anterior. In the soleus. ATP declined from 20.31 +/- 2.5 of control group to 9.55 +/- 0.61 mumol/g dry wt. while in the extensor digitorum longus ATP declined from 30.92 +/- 2.68 to 22.7 +/- 1.54 mumol/g dry wt. In both these muscles, a shift of NAD/NADH couple towards oxidation was also observed (from 26.58 +/- 3.34 to 6.95 +/- 0.97 and from 18.88 +/- 3.43 to 10.57 +/- 1.61, respectively). These alterations were more evident in the aerobic soleus muscle. On the contrary, no major changes occurred in skeletal muscle metabolism of compensated animals. The results show that: (1) a decrease in muscle high-energy phosphates occurs in CFH; (2) this is accompanied by a decrease of NAD/NADH couple suggesting an impairment in oxygen utilization or availability.
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PMID:Skeletal muscle metabolism in experimental heart failure. 893 80

Deficient myocardial cyclic AMP concentrations contribute to abnormal Ca2+ handling and systolic and diastolic dysfunction in chronic heart failure (CHF). We tested the hypothesis that decreased cyclic AMP in skeletal muscle of animals with failure may contribute to the weakness and easy fatiguability also common in patients with CHF. We compared intracellular Ca2+ signaling and contractility in skeletal muscle preparations from rats 6 weeks after myocardial infarction-induced CHF versus sham-operated controls. Bundles of 100 to 200 cells were dissected from the extensor digitorum longus (EDL) muscle of control and CHF rats. Muscles from CHF rats exhibited depressed tension development compared with control muscles during twitches. Treatment with 2mM dibutyryl cyclic AMP returned tension and Ca2+ towards normal levels. There was no evidence of cellular atrophy in the CHF rats. In conclusion, EDL skeletal muscle from rats with CHF had intrinsic abnormalities in excitation-contraction coupling that could be reversed with cyclic AMP supplementation as previously reported for the heart. This suggests that deficient cyclic AMP levels may contribute to both cardiac and skeletal muscle dysfunction in CHF.
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PMID:Deficient cellular cyclic AMP may cause both cardiac and skeletal muscle dysfunction in heart failure. 895 67


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