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 objective of this study was to elucidate the role of the sarcoplasmic reticulum (SR) in the transition from compensated pressure-overload hypertrophy (increased left ventricular [LV] mass, normal LV function, and no pulmonary congestion) to congestive heart failure (increased LV mass, depressed LV function, and pulmonary congestion). To address this issue, the descending thoracic aorta was banded for 4 and 8 weeks in adult guinea pigs, and the changes in isovolumic LV mechanics, SR Ca2+ transport, and SR protein levels were determined and compared with age-matched sham-operated control animals. A subgroup of the 8-week banded animals manifested the congestive heart failure phenotype with diminished developed LV pressure normalized by LV mass, reduced rates of LV pressure development and relaxation, and markedly increased lung weight-to-body weight ratios. The cardiac mechanical and morphometric changes were associated with depressed protein levels of the SR Ca(2+)-ATPase (85% of the control) and phospholamban (65% of the control) assessed by quantitative immunoblotting. Resultant rates of SR Ca2+ uptake (Vmax) and the affinity of SR Ca(2+)-ATPase for Ca2+ (EC50) were significantly depressed [32 +/- 6 nmol Ca2+.min-1.mg-1 and 0.59 +/- 0.12 (mumol/L)/L, respectively] compared with the 8-week sham-operated control animals [40 +/- 1 nmol Ca2+.min-1.mg-1 and 0.40 +/- 0.05 (mumol/L)/L, respectively]. We conclude that this model of pressure overload-induced cardiac failure is associated with (1) diminished LV force development, rates of pressure development, and decay; (2) depressed protein expression of the Ca(2+)-cycling proteins SR Ca(2+)-ATPase and phospholamban; and (3) decreased Vmax and affinity of the SR Ca(2+)-ATPase for Ca2+.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differential changes in cardiac phospholamban and sarcoplasmic reticular Ca(2+)-ATPase protein levels. Effects on Ca2+ transport and mechanics in compensated pressure-overload hypertrophy and congestive heart failure. 755 23

Despite the long history of use of cardiac glycosides, questions persist relating to the very narrow range of therapeutic v toxic levels of the drug, and the factors, including hypokalemia, that predispose a patient to cardiac glycoside toxicity. The therapeutic receptor for cardiac glycosides is believed to be the alpha subunit of sodium pump, Na,K-ATPase. Three isoforms of this subunit are expressed in the heart, and the levels of cardiac sodium pump expression are depressed in heart failure. Which human sodium pump isoform(s) binds cardiac glycosides in the therapeutic range (1-2 nM for digoxin) in the failing heart has not been determined. Hypokalemia can potentially influence cardiac glycoside sensitivity at multiple levels: (1) it directly increases the affinity of cardiac glycosides for sodium pumps by decreasing competition with K+, (2) it decreases cardiac sodium pump expression which can augment or amplify the effects of decreased pump expression and activity due to heart failure itself and cardiac glycoside inhibition; (3) it decreases the expression of skeletal muscle sodium pumps which will influence the relative tissue and plasma distributions of cardiac glycosides. Establishing the therapeutic v toxic targets of cardiac glycosides will enable investigators to design isoform specific inhibitors that would potentially be specific for the therapeutic receptors and independent of plasma potassium levels.
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PMID:Significance of sodium pump isoforms in digitalis therapy. 756 97

In chronic heart failure, the inter-relationship of the renin-angiotensin-aldosterone system (RAAS) and cardiac growth is of primary clinical interest. In the pressure or volume overloaded heart, hypertrophic growth of the myocardium includes the enlargement of cardiac myocytes--an adaptation governed by ventricular loading. Nonmyocyte cell growth involving cardiac fibroblast may also occur but not primarily regulated by the hemodynamic load. Cardiac fibroblast activation is responsible for the accumulation of fibrillar type I and type III collagens within the interstitium and adventitia of intramyocardial coronary arteries. In addition to relaxation abnormalities due to impairment of sarcoplasmic Ca(2+)-ATPase activity, this remodeling of the cardiac interstitium represents a major determinant of pathological hypertrophy in that it accounts for abnormal myocardial stiffness, leading to ventricular diastolic and systolic dysfunction and ultimately the appearance of symptomatic heart failure. In vivo and in vitro studies suggest that the effector hormones, angiotensin II and aldosterone, of the RAAS are primarily involved in regulating the structural remodeling of the myocardial collagen matrix. In cultured adult cardiac fibroblasts, angiotensin II and aldosterone have been shown to stimulate collagen synthesis while angiotensin II additionally inhibits matrix metalloproteinase 1 activity, which is the key enzyme for interstitial collagen degradation in the myocardium. These observations may serve as rationale why angiotensin converting enzyme inhibition or blockade of the RAAS represents such remedial therapy in congestive heart failure in patients with hypertensive heart disease, post-myocardial infarction or with dilated cardiomyopathy.
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PMID:Myocardial collagen matrix remodeling and congestive heart failure. 763 1

Although the interrelationship between the two messengers Ca2+ and cyclic AMP in platelet function is well documented, its mechanism of action still remains to be established. We investigated here the question of the regulation of platelet Ca(2+)-ATPases by cyclic AMP through the phosphorylation of the Rap1 protein using a pathological model. We first found experimental conditions where Ca(2+)-transport by platelet membrane vesicles appeared to be dependent on the phosphorylation of the Rap1 protein. Then, we studied platelets of patients with congestive heart failure for their expression of the potential 97 kDa Ca(2+)-ATPase target of regulation through the Rap1 protein as well as the phosphorylation of the Rap1 protein using the catalytic subunit of the cyclic AMP-dependent protein kinase (C. Sub.). In the first patients studied, we found no significant modification in the expression of the 97 kDa Ca(2+)-ATPase by Western blotting using the PL/IM 430 monoclonal antibody which specifically recognized this isoform. In contrast, the Rap1 protein was differentially phosphorylated when using 15 micrograms/ml of the C. Sub. These results allowed us to use these pathological platelets to study the relationship between the expression of Rap1 protein and the regulation of Ca2+ transport by selecting a patient with severe heart failure. We could show a decrease in the expression as well as in the phosphorylation of Rap1 protein and demonstrate a lower effect of C. Sub. on Ca2+ transport. Finally, by studying a further series of patients, we could confirm that the decrease in Rap1 protein expression in heart failure, whatever its extent, was variable, and could strictly correlate the expression of Rap1 protein with the stimulatory effect of C. Sub. on Ca2+ transport. Besides the evidence for regulation of the expression of the Rap1 protein in platelets from patients with heart failure, these findings constitute a new approach in favour of the regulation of platelet Ca2+ transport through the phosphorylation of the Rap1 protein.
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PMID:Relationship between Rap1 protein phosphorylation and regulation of Ca2+ transport in platelets: a new approach. 765 84

Idiopathic dilated cardiomyopathy is associated with derangement of myocardial sarcoplasmic Ca-homeostasis and energy production. The molecular mechanism for these changes is unknown. Accordingly, we used genetic and experimentally-induced models of canine dilated cardiomyopathy and tested the hypothesis that these metabolic changes resulted from altered gene expression, as indicated by mRNA content. We studied dilated cardiomyopathy occurring naturally (n = 9) in Doberman pinschers, and in dogs subjected to rapid ventricular pacing (n = 5), in comparison with normal dogs (n = 9). We determined content and integrity of mRNA's using Northern and slot blotting, and measured activities of their translated product for the Ca-release channel and Ca-ATPase of sarcoplasmic reticulum, lactate dehydrogenase of glycolysis, citrate synthase of the tricarboxylic acid cycle, and for myoglobin, ATP-synthetase and the adenine nucleotide transporter, which are integral in oxidative phosphorylation. We found that, whereas both mRNA content and enzyme activity for markers of Ca-cycling, glycolysis, and oxidative phosphorylation were downregulated (20-80%) in dilated cardiomyopathy, they were upregulated (10-15%) for tricarboxylic acid cycling and for ribosomal RNA. RNA from cardiomyopathic tissue was up to 50% more degraded than for normal hearts in association with a 150% increase in ribonuclease activity. Downregulation of the Ca-cycle was asymmetric, with the Ca-channel being 65% more affected than the Ca-ATPase. This work supports the general paradigm that transcriptional and translational responses to pathophysiology are major determinants of the metabolic response seen in cardiac failure.
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PMID:Myocardial mRNA content and stability, and enzyme activities of Ca-cycling and aerobic metabolism in canine dilated cardiomyopathies. 777 66

In this work we analyze the renal and systemic factors involved in the sodium retention in two conditions: in extracellular volume depletion and in edema forming states, particularly liver cirrhosis with ascitis. In this paper we accept that the volume loss of body fluids stimulates the "effective arterial blood volume" (VAE). This term results from a decrease in the arterial blood volume secondary to a fall in cardiac output or a peripheral arterial vasodilatation. The reduction in the VAE stimulates: the high pressure baroreceptors (carotid sinus and aortic arch); the intrarrenal mechanisms, such as the yuxtaglomerular apparatus and the renin angiotensin aldosterone system; the sympathetic adrenergic system; the non osmotic release of antidiuretic hormone; prostaglandins (PGE1, Tromboxane) and endothelin; and inhibits the atrial natriuretic peptide. We also describe the sodium transport mechanisms along the nephron during physiological conditions and after volume depletion, and in edema formation states, specially hepatic cirrhosis with ascitis. We speculate that the intrarenal mechanisms are more important and persistent than the systemic mechanisms. It is possible that the sodium retention of these states might be the result of direct stimuli of the tubular sodium transport mechanisms in the different segments of the nephron, mediated by the co and counter transports, ATPase activity or by the second messengers cyclic AMP and cyclic GMP. The clonation and structural characterization of the different sodium transports may help us to establish, more precisely, the intracellular tubular mechanisms responsible for the tendency of the body to retain sodium. The amount of information generated in the future may help us to demonstrate, with more precision, the mechanisms responsible for the sodium retention and excretion in normal and pathological conditions, particularly the edema forming states such as cardiac failure, nephrotic syndrome and hepatic cirrhosis with ascitis.
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PMID:[Renal and extra-renal mechanisms of sodium and water retention in cirrhosis with ascites]. 777 18

GH exerts direct effects on myocardial growth and function. Evidence from laboratory models shows that GH (or IGF-I) induces mRNA expression for specific contractile proteins and myocyte hypertrophy. Furthermore, GH increases the force of contraction and determines myosin phenoconversion toward the low ATPase activity V3 isoform. These data provide plausible explanations for the cardiac abnormalities observed in clinical settings of excessive or defective GH production. In acromegaly, the functional consequences of GH excess initially prevail (hyperkinetic syndrome), followed by alterations of cardiac function when myocardial hypertrophy develops. This involves both ventricles and is purposeless because it occurs without increased wall stress. Hypertrophy also entails proliferation of the myocardial fibrous tissue that leads to interstitial remodeling. The functional consequence is an impaired ventricular relaxation that causes a diastolic dysfunction, followed by impairment of systolic function. In untreated disease, cardiac performance slowly but inexorably deteriorates and heart failure eventually develops. Several lines of evidence support the specificity of heart disease in acromegaly. Particularly demonstrative are the recent studies in which GH production was suppressed by octreotide, with a consequent significant regression of hypertrophy and improvement of cardiac dysfunction. It is not yet established whether full recovery of normal cardiac morphology and function is possible after correction of GH excess. The point is not a minor one since the possibility to revert, albeit partially, myocardial fibrosis is of great relevance to the control of cardiac hypertrophy in general. GHD leads to a reduced mass of both ventricles and to impaired cardiac performance with low heart rate (hypokinetic syndrome). These alterations are particularly evident during physical exercise and might provide an important contribution to the reduced exercise capacity of GHD patients, in addition to the reduced muscle mass and strength. The data also support a role of GH in the maintenance of a normal cardiac structure and performance. The hypokinetic syndrome is well documented in young patients in whom GHD began very early in their childhood. In contrast, the data in adult-onset GHD are less consistent. This suggests that the consequences of GHD are more relevant if the disorder starts during early heart development. As observed with other abnormalities associated with GHD, cardiac dysfunction is also susceptible to marked improvement by hrGH. This observation lends further support to the proposal to treat these patients with replacement therapy.
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PMID:Growth hormone and the heart. 784 68

Heart failure mainly occurs during the last decades of life, and it is important to know if the senescent heart is not an already failing heart. During aging, both contraction and relaxation of papillary muscle are impaired. Such an impairment is compensated in vivo and the cardiac output remains normal. In spite of a loss in myocytes, the heart weight/body weight ratio is unchanged, but the myocytes are bigger. Arrhythmias are permanent and are accompanied by a loss of the normal heart rate variability. Changes in specific mRNAs include: a shift in myosin heavy chain (MHC) isogene expression leading to an increased beta MHC content; decreased densities of Ca2+ ATPase of the sarcoplasmic reticulum, beta 1-adrenergic receptor, and muscarinic receptors; and attenuation of the Na+/Ca2+ exchange activity. Most of these changes, but not all, resemble those observed during cardiac overload and are accompanied by an increased duration of both the action potential and the intracellular calcium transient. However, the senescent heart is still able to further modify its phenotype in response to mechanical overload. The senescent heart is a diseased heart, and the origin of the "disease" is multifactorial and includes the general process of senescence, hormonal changes, and the myocardial consequences of senescence of the vessels.
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PMID:Is the senescent heart overloaded and already failing? 784 94

1. The relevance of a functional sarcoplasmic reticulum (SR) membrane system to the contraction-relaxation cycle and to the force-frequency relationship of guinea-pig atrial tissue was investigated. Cyclopiazonic acid (CPA) was used to inhibit selectively the activity of the SR Ca(2+)-ATPase. IC50 values of 0.2 microM or 1.0 microM were measured in guinea-pig isolated SR membranes in the absence or presence of millimolar ATP, respectively. CPA (0.3-30 microM) did not inhibit the activity of the sarcolemmal Na(+)-Ca(2+)-exchanger as measured in isolated cardiac cell membrane preparations. 2. In guinea-pig isolated left atrium paced at 2.5 Hz (30 degrees C), CPA (1-100 microM) produced a concentration-dependent reduction in developed tension and a fall in the maximum rate of tension increase (+dT/dtmax) and decrease (-dT/dtmax). The twitch duration was markedly increased due to a prolongation of the time to peak tension, and in particular, the relaxation phase. 3. The contraction-relaxation cycle of the left atrium showed a marked dependence on the frequency of stimulation. The developed tension and +dT/dtmax showed a progressive increase from 0.5 Hz, reaching peak values at a stimulation rate of 1.5-2.5 Hz, the positive staircase phenomenon. Higher frequencies of stimulation caused a fall in these parameters. Resting tension was unaffected. The time-course of the contraction-relaxation cycle was also frequency-dependent, with both time to peak tension and relaxation time showing a progressive fall from 2.0-3.5 Hz. 4. The addition of CPA (30 microM) caused marked alterations in the frequency-dependence of the contraction-relaxation cycle. The frequency-dependence of developed tension, + dr/dtmax and dT/dt max was shifted downwards, particularly at higher frequencies, and the frequency at which peak values of+ dT/dtmax and - dT/dtmax were reached was shifted leftwards. The resting tension of the tissues in the presence of 30 micro M CPA was increased markedly at frequencies greater than 2 Hz. The time-course of the contraction-relaxation cycle was markedly prolonged between 1.0 and 3.5 Hz, due to an effect on both time to peak tension and relaxation time.5. In conclusion, these results show that CPA is a highly selective inhibitor of the cardiac SR Ca2+-ATPase, without effect on the sarcolemmal Na+-Ca2+-exchanger, and suggest that a functional SR Ca2+-ATPase is necessary for the normal contraction-relaxation cycle of guinea-pig cardiac tissue.Additionally, the results suggest an increasing dependence of tension development on SR Ca2+-ATPase with increasing frequency, which may reflect either a frequency-dependent activation of this enzyme or the diminished contribution of the Na+-Ca2+ exchanger. These results also provide novel support for the mechanism of the depressed force-frequency relation found in cardiac tissue of heart failure patients, in which there is a reduced expression of Ca2+-ATPase.
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PMID:Effect of cyclopiazonic acid, an inhibitor of sarcoplasmic reticulum Ca(2+)-ATPase, on the frequency-dependence of the contraction-relaxation cycle of the guinea-pig isolated atrium. 785 41

Whether sarcolemmal (SL) calcium handling is altered in endstage heart failure produced by chronic rapid pacing is not known. To investigate this we paced 7 rabbits at a rate of 400 beats/min for 35 +/- 11 days. 6 animals served as non-paced controls. Purified left ventricular SL membranes were then prepared and tested for [3H]-nitrendipine binding and (Ca(2+) + Mg2+)-dependent ATPase (Ca(2+)-pump) activity. Results show a 50% reduction in calcium channel antagonist binding sites with Bmax values reduced from 450 +/- 40 to 230 +/- 8 fmoles/mg protein in response to chronic rapid pacing (P < 0.01). This change was accompanied by a modest decrease in Kd from 0.29 +/- 0.09 to 0.22 +/- 0.03 nM (not significant). Vmax values for the SL Ca(2+)-pump ATPase were decreased from 387 to 164 nmoles/mg protein/min (P < 0.01) with KCa2+ values reduced from 0.91 to 0.28 microM Ca2+ (P < 0.05) in response to tachycardia induced failure as compared to controls. ATPase activity in both groups was very sensitive to 25 microM calmidazolium and 5 microM vanadate. Results from this study indicate that both a reduction in SL calcium channel density and decrease in SL Ca(2+)-pump ATPase activity are evident in tachycardia heart failure. We conclude that sarcolemmal calcium handling is altered in heart failure induced by chronic rapid pacing and that such changes may contribute to systolic dysfunction associated with this model to heart failure.
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PMID:Altered sarcolemmal calcium channel density and Ca(2+)-pump ATPase activity in tachycardia heart failure. 785 49

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