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)

Changes in the beta-adrenergic receptor-G protein-adenylate cyclase complex were investigated in an experimental canine model of low-output heart failure produced by chronic rapid ventricular pacing. The contractile response occurring after exposure to the beta-adrenergic agonist dobutamine, measured as peak left ventricular + dP/dt, was decreased after 3 weeks of pacing. To further characterize the diminished functional responsiveness to beta-adrenergic receptor stimulation, beta-adrenergic receptor-adenylate cyclase coupling was investigated using membranes prepared from both control and paced animals. The density of beta-adrenergic receptors was decreased by 40% with a selective downregulation of the beta 1-subtype. The affinity of the receptor for the antagonist radioligand [125I]iodocyanopindolol remained unchanged. A defect in coupling was suggested by a decreased ability of isoproterenol, fluoride, and forskolin to stimulate adenylate cyclase in membranes prepared from failing hearts. Determination of the levels of Gi alpha (the alpha-subunit of Gi) by immunoblotting and pertussis toxin labeling revealed modest increases of approximately 30%. Furthermore, Mn2+ and purified Gs failed to stimulate adenylate cyclase in membranes prepared from failing hearts, indicating an impairment in the catalytic moiety of adenylate cyclase itself or in the ability of adenylate cyclase to couple to Gs. In contrast, complementation assay did not reveal differences in the functional activity of Gs alpha (the alpha-subunit of Gs). Taken together, these data demonstrate a selective decrease in the beta 1-subtype of adrenergic receptors and an increase in a 40-kd G1-like protein in the failing heart. Similar changes have been described in human idiopathic dilated cardiomyopathy. In addition to these changes, we identified a possible defect at the level of the catalytic subunit of adenylate cyclase.
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PMID:Beta-adrenergic receptor-G protein-adenylate cyclase complex in experimental canine congestive heart failure produced by rapid ventricular pacing. 165 3

The positive inotropic effect of an alpha 1-adrenoceptor agonist, such as phenylephrine, is accompanied by an increase in the presumed second messenger, inositol 1,4,5-trisphosphate (1,4,5-IP3) and inositol 1,3,4,5-tetrakisphosphate (1,3,4,5-IP4), which may release calcium from the sarcoplasmic reticulum (SR) and/or facilitate calcium entry from the extracellular space. In addition, phenylephrine sensitizes the contractile proteins for calcium. Alpha 1-adrenergic positive inotropic effects are enhanced in heart muscle preparations from cardiomyopathic hamsters and are reduced in heart muscle preparations from human failing myocardium. How the negative inotropic effects of M-cholinoceptor agonists work in the presence of cAMP-increasing agents in ventricular heart muscle preparations is discussed. It involves cAMP-reduction, an increase in cGMP and activation of phosphatase activity. In a rat model, chronic beta-adrenergic stimulation leads to increased sensitivity of rat ventricular tissue for the negative inotropic effect of the M-cholinoceptor agonist, carbachol. This might be due to facilitated signal transduction via increased Gi proteins. In human ventricular tissue from hearts with end-stage heart failure, due to idiopathic dilated cardiomyopathy (IDC), an increased Gi protein has also been found. However, the negative inotropic effects of carbachol were unchanged. The data indicate that changes in alpha-adrenergic and M-cholinergic responses in the heart may depend on underlying causes that induce changes.
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PMID:The role of alpha 1-adrenergic and muscarinic receptors in cardiac function. 166 57

Beta-blockers were initially given to patients with chronic heart failure due to ischemic heart disease and resting tachycardia. The prompt effect on severe backward heart failure was directly associated with an immediate fall in heart rate. This observation led to long-term administration to patients with idiopathic dilated cardiomyopathy and, later, to patients with ischemic cardiomyopathy and secondary cardiomyopathies as well. Due to marked down-regulation of beta receptors, patients with heart failure are extremely sensitive to beta blockade. A test dose of metoprolol 5 mg b.i.d. for 2 days is recommended to select patients for long-term beta-blockade, followed by careful titration with increment in dose over 6 weeks. One important effect of beta-blockade in the early phase of treatment is a reduction in the myocardial energy demand early after the onset of long-term treatment. After 1 month of treatment with beta-blockers, marked improvement of diastolic function is observed. This effect might be attributed to inhibition of calcium overload. After 3 months of treatment, an increase in ejection fraction can be observed, which might be attributed to upregulation of beta receptors. The withdrawal of long-term treatment was followed by a deterioration of heart function in 61% of patients and improvement was seen after reinstitution of beta-blockade. There was an increase in cardiac index and stroke work index at rest as well as during supine exercise. A marked fall in left ventricular filling pressure at rest and unchanged filling pressure during supine exercise was noted, while exercise capacity increased by 25%. A similar pattern was seen in patients with ischemic cardiomyopathies and other secondary cardiomyopathies. However, the increase in ejection fraction in the ischemic cardiomyopathy group was lower (0.06) compared to the groups with dilated cardiomyopathy and other secondary cardiomyopathies (0.18).
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PMID:Beta-adrenergic blockade in dilated cardiomyopathy, ischemic cardiomyopathy, and other secondary cardiomyopathies. 168 23

Conventional therapy of patients with idiopathic dilated cardiomyopathy is currently directed at the control of heart failure. However, the morbidity and mortality of idiopathic dilated cardiomyopathy remains very high despite such interventions. One promising new approach to therapy of idiopathic dilated cardiomyopathy is beta-blockade. The potential mechanisms for benefit from beta-blockade include protection from catecholamine cardiotoxicity, upregulation of myocardial beta-adrenergic receptors, reduction in sudden death, reduction in heart rate, improved ventricular diastolic function, and reduction in afterload. Several reports have suggested that long-term beta-blockade may improve hemodynamic function, clinical symptoms, and survival in patients with idiopathic dilated cardiomyopathy. However, data from controlled trials are limited and some reports have been negative. This paper will summarize the rationale for the use of beta-blocker therapy in idiopathic dilated cardiomyopathy and review the clinical experience with this therapy.
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PMID:Therapy of idiopathic dilated cardiomyopathy with chronic beta-adrenergic blockade. 168 24

We analyzed our 10-year cumulative experience of 40 consecutive patients with idiopathic dilated cardiomyopathy and associated ventricular tachyarrhythmias, treated with implantable cardioverter defibrillators. Dilated cardiomyopathy was defined as left ventricular ejection fraction (EF) less than or equal to 50% with no defineable etiology. Patient characteristics included: 24 male, mean age 52 years, mean EF = 33%, New York Heart Association Class I-III, presenting syndrome--cardiac arrest (n = 28), syncope/near syncope (n = 12). At 2.5 years mean follow-up, there were 16 deaths: one operative, three sudden, two incessant ventricular tachycardia/ventricular fibrillation (VT/VF), six heart failure, and four noncardiac. The actuarial mortality at 1 and 4 years was 0% and 14% for sudden death, 11% and 34% for cardiac death. The projected mortality was 52% and 78% for same time intervals (P less than 0.01). No useful baseline variable predicted who would or would not receive an ICD shock in follow-up. ICD therapy appears effective in reducing sudden death mortality in this high risk population.
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PMID:Long-term follow-up of patients with nonischemic dilated cardiomyopathy and ventricular tachyarrhythmias treated with implantable cardioverter defibrillators. 172 Nov 97

The present study was performed to compare the effects of the new positive inotropic phosphodiesterase III inhibitors pimobendan, adibendan, and saterinone on the isometric force of contraction in electrically driven ventricular trabeculae carneae isolated from explanted failing (end-stage myocardial failure) with those from nonfailing (prospective organ donors) human hearts. In preparations from nonfailing hearts the phosphodiesterase inhibitors, as well as the beta-adrenoceptor agonist isoprenaline, the cardiac glycoside dihydro-ouabain, and calcium, which were studied for comparison, revealed pronounced positive inotropic effects. The maximal effects of pimobendan, adibendan, and saterinone amounted to 56%, 36% and 45%, respectively, of the maximal effect of calcium. In contrast, in preparations from failing hearts the phosphodiesterase III inhibitors failed to significantly increase the force of contraction and the effect of isoprenaline was markedly reduced. The effects of dihydroouabain and calcium were almost unaltered. The diminished effects of isoprenaline were restored by the concomitant application of phosphodiesterase inhibitors. To elucidate the underlying mechanism of the lack of effect of the phosphodiesterase III inhibitors in the failing heart we also investigated the inhibitory effects of these compounds on the activities of the phosphodiesterase isoenzymes I-III separated by DEAE-cellulose chromatography from both kinds of myocardial tissue. Furthermore, the effects of pimobendan and isoprenaline on the content of cyclic adenosine monophosphate (determined by radioimmunoassays) of intact contracting trabeculae were studied. The lack of effect of the phosphodiesterase inhibitors in failing human hearts could not be explained by an altered phosphodiesterase inhibition, since the properties of the phosphodiesterase isoenzymes I-III and also the inhibitory effects of the phosphodiesterase inhibitors on these isoenzymes did not differ between failing and nonfailing human myocardial tissue. Instead, it may be due to a diminished formation of cyclic adenosine monophosphate in failing hearts, presumably caused mainly by a defect in receptor-adenylate cyclase coupling at least in idiopathic dilated cardiomyopathy. Both the basal and the pimobendan-stimulated or isoprenaline-stimulated contents of cyclic adenosine monophosphate of intact contracting trabeculae from failing hearts were decreased compared with the levels in nonfailing hearts. However, under the combined action of isoprenaline and pimobendan the cyclic adenosine monophosphate level reached values as high as with each compound alone in nonfailing preparations, and in addition the positive inotropic effect of isoprenaline was restored. These findings may have important clinical implications. Along with the elevated levels of circulating catecholamines the positive inotropic effects of the phosphodiesterase inhibitors may be maintained in patients with heart failure.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mechanism underlying the reduced positive inotropic effects of the phosphodiesterase III inhibitors pimobendan, adibendan and saterinone in failing as compared to nonfailing human cardiac muscle preparations. 172 53

Although both asymptomatic ventricular arrhythmias and sudden death are common in patients with chronic heart failure, there is little evidence that patients who have frequent or complex ventricular arrhythmias are at increased risk of sudden death. Two hypotheses may explain the lack of an arrhythmia-sudden death relation in this disorder. First, complex ventricular arrhythmias may be a nonspecific manifestation of a dying left ventricle rather than an indication of a specific arrhythmogenic substrate. In fact, during long-term follow-up, patients with mild heart failure who have nonsustained ventricular tachycardia are more likely to develop clinical progression of the disease rather than sudden death. Second, sudden death may be related to events other than a malignant ventricular arrhythmia. The most common myocardial ischemia, whereas the terminal event in patients with an idiopathic dilated cardiomyopathy is commonly a severe bradyarrhythmia or electromechanical dissociation. Neither outcome can be predicted by a prior history of ventricular arrhythmias on ambulatory electrocardiographic monitoring. If asymptomatic ventricular arrhythmias do not lead to sudden death, then there would appear to be little reason to expect that antiarrhythmic drugs could prevent cardiac arrest in patients with chronic heart failure. This may explain why drugs that suppress ambulatory arrhythmias do not prevent sudden death in these patients, whereas interventions may reduce the risk of unexpected circulatory collapse in this disorder without suppressing ventricular ectopic activity. To make matters more complicated, the desirable actions of antiarrhythmic drugs are attenuated and their negative inotropic and proarrhythmic actions are enhanced in patients with severe cardiac dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Lack of relation between ventricular arrhythmias and sudden death in patients with chronic heart failure. 172 5

Severe cardiac arrhythmias (Lown class IVa), rapid loss of physical capacity and dyspnoea on the slightest exertion occurred in a 55-year-old man with idiopathic dilated cardiomyopathy. In the preceding year he had recurrent diarrhoea and lost 23 kg in weight. He was found to have hypercalcaemia (3-3.2 mmol/l). The heart failure significantly improved under treatment with twice daily 12.5 mg captopril, 100 mg spironolactone daily, furosemide 40 mg twice daily, and digitoxin 0.07 mg daily. The arrhythmia responded to verapamil 80 mg and quinidine 160 mg, both drugs three times daily. Primary hyperparathyroidism was found to be the cause of the hypercalcaemia (parathormone 84 pmol/l). After the parathyroid adenoma had been removed the patient's condition again improved markedly. There were only rare monotopic extrasystoles, cardiac size regressed, and diuretics were no longer necessary. His medication at present is verapamil (80 mg three times daily), captopril (12.5 mg three times daily) and digitoxin (0.07 mg daily). It is concluded that the hypercalcaemia influenced the severity of the cardiomyopathy. It would seem that both intra- and extracellular calcium homoeostasis is of great importance in dilated cardiomyopathy.
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PMID:[The coincidence of rapidly progressing dilated cardiomyopathy and primary hyperparathyroidism. The course before and after the removal of a parathyroid adenoma]. 173 86

Previous studies have suggested that some cases of idiopathic dilated cardiomyopathy (IDC) are due to persistent viral infection following an episode of viral myocarditis. Viral RNA sequences have recently been detected in material from patients with IDC using molecular biological techniques. We tested 40 samples from recipients' hearts explanted at cardiac transplantation for the presence of enteroviral RNA sequences, using a Northern blotting technique. Material from 19 cases of IDC and 21 cases of non-cardiomyopathic cardiac failure was examined together with Coxsackie-virus-infected neonatal mouse heart as a positive control and non-infected adult mouse heart as a negative control. A sharp band of viral RNA was detected in the positive control sample. No hybridization signal attributable to viral RNA was obtained for the negative control or for any of the test samples. We conclude that the role of enteroviruses in the pathogenesis of cardiomyopathy is not fully established and that further study is warranted.
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PMID:Enteroviruses and idiopathic dilated cardiomyopathy. 184 88

The relation between left ventricular (LV) shape and functional mitral regurgitation (MR) was evaluated in 39 patients with congestive heart failure. Heart failure was due to coronary artery disease in 23 patients (group I) and to idiopathic dilated cardiomyopathy in 16 (group II). LV shape was quantitated based on the ratio of LV major-to-minor axis and LV sphericity index calculated at end-systole and end-diastole. In group I, 9 patients had angiographic evidence of MR and 14 did not. In group II, 10 patients had MR and 6 did not. Within each group, there were no differences between patients with and without MR with regard to LV chamber volume and regional segmental wall motion abnormalities. In both groups, however, a significant difference was observed between patients with and without MR with respect to end-systolic and end-diastolic LV shape indexes. In group I, the end-systolic major-to-minor axis ratio was lower in patients with (1.42 +/- 0.04) than without (1.72 +/- 0.05) MR (p less than 0.001). Similar differences were observed in group II (1.41 +/- 0.06 vs 1.69 +/- 0.04) (p less than 0.01). In group I, the end-systolic sphericity index was also greater in patients with (0.32 +/- 0.02) than without (0.25 +/- 0.01) MR (p less than 0.02). Similar differences were observed in group II (0.37 +/- 0.03 vs 0.26 +/- 0.01) (p less than 0.02). These data indicate that in patients with severe heart failure, functional MR is present in those who manifest a more spherical LV cavity.
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PMID:Left ventricular shape as a determinant of functional mitral regurgitation in patients with severe heart failure secondary to either coronary artery disease or idiopathic dilated cardiomyopathy. 185 76


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