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)

Heart failure leading to ventricular arrhythmogenesis is a major cause of clinical mortality and has been associated with a leak of sarcoplasmic reticular Ca(2+) into the cytosol due to increased open probabilities in cardiac ryanodine receptor Ca(2+)-release channels. Caffeine similarly increases such open probabilities, and so we explored its arrhythmogenic effects on intact murine hearts. A clinically established programmed electrical stimulation protocol adapted for studies of isolated intact mouse hearts demonstrated that caffeine (1 mM) increased the frequency of ventricular tachycardia from 0 to 100% yet left electrogram duration and latency unchanged during programmed electrical stimulation, thereby excluding slowed conduction as a cause of arrhythmogenesis. We then used fluorescence measurements of intracellular Ca(2+) concentration in isolated mouse ventricular cells to investigate parallel changes in Ca(2+) homeostasis associated with these arrhythmias. Both caffeine (1 mM) and FK506 (30 microM) reduced electrically evoked cytosolic Ca(2+) transients yet increased the frequency of spontaneous Ca(2+)-release events. Diltiazem (1 microM) but not nifedipine (1 microM) pretreatment suppressed these increases in frequency. Identical concentrations of diltiazem but not nifedipine correspondingly suppressed the arrhythmogenic effects of caffeine in whole hearts. These findings thus directly implicate spontaneous Ca(2+) waves in triggered arrhythmogenesis in intact hearts.
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PMID:Caffeine-induced arrhythmias in murine hearts parallel changes in cellular Ca(2+) homeostasis. 1592 7

Cardiac Na/Ca exchange (NCX, NCX1.1) is critical in cardiac myocyte Ca regulation, and its altered function contributes to inotropic state, systolic dysfunction in heart failure and arrhythmogenesis. Regulation of NCX is multifaceted, but protein kinase A (PKA) effects on NCX function are controversial. Here, we use three different and complementary approaches to compare NCX function +/-1 microM isoproterenol (ISO) in intact rabbit cardiac myocytes (in paired comparisons). First, in field-stimulated intact cells we inferred the cytosolic [Ca] ([Ca](i)) dependence of NCX function from the decay rate of caffeine-induced [Ca](i) transients. Second, we measured caffeine-induced [Ca](i) and inward I(NCX) simultaneously (perforated patch voltage clamp), to measure directly the [Ca](i) dependence of NCX rate. Third, using whole cell ruptured patch with [Ca](i) heavily buffered to 100 nM, [Na](i)=10 mM, and I(Ca), SR Ca release and Na/K pump all blocked, we recorded I(NCX) ramps at 37 degrees C. We find that NCX function is not altered by PKA activation under any of these three protocols, where intracellular conditions ranged from near-physiological to highly controlled. This does not rule out NCX modulation by PKA under all conditions, or in species other than rabbit. However, such effects are likely to be either minor (vs. other PKA actions on myocyte Ca handling) or indirect, such as secondary effects dependent on altered local [Ca](i) and [Na](i).
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PMID:Isoproterenol does not enhance Ca-dependent Na/Ca exchange current in intact rabbit ventricular myocytes. 1624 49

The normally positive force- and Ca2+ -frequency responses (FFR and CaFR) are inverted in heart failure (HF); whether oxidative stress contributes to these abnormalities is unknown. We evaluated the impact of acute and prolonged oxidative stress on contraction and Ca2+ handling in adult rat cardiomyocytes. Acute (30 min) exposure to H2O2 (100 microM) induced a twofold increase (P<0.025) in intracellular oxyradicals together with contractile depression despite preservation of the Ca2+ transient and the FFR and CaFR to 3 Hz, indicating reduced myofilament Ca2+ responsiveness. In contrast, prolonged (24 h) exposure to the copper-zinc superoxide dismutase inhibitor diethyldithiocarbamic acid (DDC, 1 microM) similarly augmented oxyradicals but also increased cell size, and contraction and Ca2+ transient duration (P<0.025). DDC-treated myocytes displayed inverted FFRs and attenuated (though still positive) CaFRs as compared to control, indicating reduced myofilament Ca2+ responsiveness coupled with altered Ca2+ handling. Protein levels of the Na+ -Ca2+ exchanger (NCX), sarcoplasmic reticular (SR) Ca2+ ATPase (SERCA2), and serine-16 phosphorylated phospholamban (pSer16-PLB) were increased (P<0.025), whereas dihydropyridine receptor abundance was decreased. Total PLB and ryanodine receptor protein expression were unchanged. Caffeine-induced Ca2+ release showed increased NCX activity (P<0.025) without changes in total releasable SR Ca2+, suggesting compensatory changes in SERCA2 and pSer16-PLB to maintain SR Ca2+ load. The superoxide scavenger Tiron attenuated these effects. Thus, acute oxyradical exposure rapidly depresses myofibrillar Ca2+ responsiveness. Prolonged oxidative stress further induces alterations in Ca2+ handling that combined with extant reductions in myofibrillar responsiveness invert the FFR. With regard to Ca2+ handling, reduced transsarcolemmal Ca2+ flux rather than reduced SR Ca2+ uptake was the primary determinant of a negative FFR. Analogous changes may be operative in HF, a state characterized by both oxidative stress and Ca2+ dysregulation.
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PMID:Prolonged oxidative stress inverts the cardiac force-frequency relation: role of altered calcium handling and myofilament calcium responsiveness. 1628 76

Duchenne muscular dystrophy (DMD) is a lethal degenerative disease of skeletal muscle, characterized by the absence of the cytoskeletal protein dystrophin. Some DMD patients show a dilated cardiomyopathy leading to heart failure. This study explores the possibility that dystrophin is involved in the regulation of a stretch-activated channel (SAC), which in the absence of dystrophin has increased activity and allows greater Ca(2+) into cardiomyocytes. Because cardiac failure only appears late in the progression of DMD, we examined age-related effects in the mdx mouse, an animal model of DMD. Ca(2+) measurements using a fluorescent Ca(2+)-sensitive dye fluo-4 were performed on single ventricular myocytes from mdx and wild-type mice. Immunoblotting and immunohistochemistry were performed on whole hearts to determine expression levels of key proteins involved in excitation-contraction coupling. Old mdx mice had raised resting intracellular Ca(2+) concentration ([Ca(2+)](i)). Isolated ventricular myocytes from young and old mdx mice displayed abnormal Ca(2+) transients, increased protein expression of the ryanodine receptor, and decreased protein expression of serine-16-phosphorylated phospholamban. Caffeine-induced Ca(2+) transients showed that the Na(+)/Ca(2+) exchanger function was increased in old mdx mice. Two SAC inhibitors streptomycin and GsMTx-4 both reduced resting [Ca(2+)](i) in old mdx mice, suggesting that SACs may be involved in the Ca(2+)-handling abnormalities in these animals. This finding was supported by immunoblotting data, which demonstrated that old mdx mice had increased protein expression of canonical transient receptor potential channel 1, a likely candidate protein for SACs. SACs may play a role in the pathogenesis of the heart failure associated with DMD. Early in the disease process and before the onset of clinical symptoms increased, SAC activity may underlie the abnormal Ca(2+) handling in young mdx mice.
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PMID:Intracellular calcium handling in ventricular myocytes from mdx mice. 1701 53

Different strategies can, at least in certain conditions, prevent or reverse myocardial remodeling due to heart failure and induce myocardial functional improvement. Na+/Ca2+ exchanger (NCX) is considered a major player in the pathophysiology of heart failure but its role in reverse remodeling is unknown. A combination of mechanical unloading by left ventricular assist devices (LVADs) and pharmacological therapy has been shown to induce clinical recovery in a limited number of patients with end-stage heart failure. In myocytes isolated from these patients we found that, after LVAD treatment, NCX1/SERCA2a mRNA was 38% higher than at device implant. We studied the ability of NCX to extrude Ca2+ during caffeine-induced SR Ca2+ release in isolated ventricular myocytes from these patients. The time constant of decline was slower in heart failure. In myocytes from patients with clinical recovery following mechanical and pharmacological treatment, NCX1-mediated Ca2+ extrusion was faster compared with myocytes from patient who, despite identical treatment, did not recover. We propose that increased NCX function may be associated with reverse remodeling in patients and that factors that regulate NCX function (i.e., phosphorylation or intracellular [Na+]) other than NCX expression levels alone, may have detrimental consequences on cardiac function.
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PMID:The role of the cardiac Na+/Ca2+ exchanger in reverse remodeling: relevance for LVAD-recovery. 1744 75

Substance abuse cessation is one of the leading factors in determining the eligibility for the heart transplantation waiting list, as noncompliance with this issue may seriously endanger posttransplantation outcomes. Yet, the prevalence of substance-related disorders among candidates for heart transplantation has not been evaluated enough. Eighty three heart transplantation candidates were assessed for prior or current substance-related disorders through the Structured Clinical Interview for mental disorders according to DSM-IV. A prior history of at least one substance-related disorder was found in 64% of patients, with nicotine dependence as the most prevalent diagnosis (61.4% of the sample). Ten subjects were currently smokers, despite heart failure. A prior history of alcohol abuse and caffeine intoxication was found in 9.6% and 2.4% of patients, respectively. Substance abuse or dependence behaviors should be monitored during all the phases of heart transplantation program. Early identification of current substance-related disorders may allow better allocation of organ resources and proper lifestyle modification programs provision. A prior history of substance-related disorders should alert physicians to assess patients for possible relapse, especially after transplantation. The inclusion of a specialist in the assessment and treatment of substance-related disorders in the heart transplantation unit may reduce the risk of unsuccessful outcomes due to noncompliance with an adequate lifestyle.
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PMID:Prevalence of substance-related disorders in heart transplantation candidates. 1769 68

Isolated diastolic dysfunction is found in almost half of asymptomatic patients with well-controlled diabetes and may precede diastolic heart failure. However, mechanisms that underlie diastolic dysfunction during diabetes are not well understood. We tested the hypothesis that isolated diastolic dysfunction is associated with impaired myocardial Ca(2+) handling during type 1 diabetes. Streptozotocin-induced diabetic rats were compared with age-matched placebo-treated rats. Global left ventricular myocardial performance and systolic function were preserved in diabetic animals. Diabetes-induced diastolic dysfunction was evident on Doppler flow imaging, based on the altered patterns of mitral inflow and pulmonary venous flows. In isolated ventricular myocytes, diabetes resulted in significant prolongation of action potential duration compared with controls, with afterdepolarizations occurring in diabetic myocytes (P < 0.05). Sustained outward K(+) current and peak outward component of the inward rectifier were reduced in diabetic myocytes, while transient outward current was increased. There was no significant change in L-type Ca(2+) current; however, Ca(2+) transient amplitude was reduced and transient decay was prolonged by 38% in diabetic compared with control myocytes (P < 0.05). Sarcoplasmic reticulum Ca(2+) load (estimated by measuring the integral of caffeine-evoked Na(+)-Ca(2+) exchanger current and Ca(2+) transient amplitudes) was reduced by approximately 50% in diabetic myocytes (P < 0.05). In permeabilized myocytes, Ca(2+) spark amplitude and frequency were reduced by 34 and 20%, respectively, in diabetic compared with control myocytes (P < 0.05). Sarco(endo)plasmic reticulum Ca(2+)-ATPase-2a protein levels were decreased during diabetes. These data suggest that in vitro impairment of Ca(2+) reuptake during myocyte relaxation contributes to in vivo diastolic dysfunction, with preserved global systolic function, during diabetes.
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PMID:Mechanisms of impaired calcium handling underlying subclinical diastolic dysfunction in diabetes. 1776 17

In this study, we investigated the role of elevated sarcoplasmic reticulum (SR) Ca(2+) leak through ryanodine receptors (RyR2s) in heart failure (HF)-related abnormalities of intracellular Ca(2+) handling, using a canine model of chronic HF. The cytosolic Ca(2+) transients were reduced in amplitude and slowed in duration in HF myocytes compared with control, changes paralleled by a dramatic reduction in the total SR Ca(2+) content. Direct measurements of [Ca(2+)](SR) in both intact and permeabilized cardiac myocytes demonstrated that SR luminal [Ca(2+)] is markedly lowered in HF, suggesting that alterations in Ca(2+) transport rather than fractional SR volume reduction accounts for the diminished Ca(2+) release capacity of SR in HF. SR Ca(2+) ATPase (SERCA2)-mediated SR Ca(2+) uptake rate was not significantly altered, and Na(+)/Ca(2+) exchange activity was accelerated in HF myocytes. At the same time, SR Ca(2+) leak, measured directly as a loss of [Ca(2+)](SR) after inhibition of SERCA2 by thapsigargin, was markedly enhanced in HF myocytes. Moreover, the reduced [Ca(2+)](SR) in HF myocytes could be nearly completely restored by the RyR2 channel blocker ruthenium red. The effects of HF on cytosolic and SR luminal Ca(2+) signals could be reasonably well mimicked by the RyR2 channel agonist caffeine. Taken together, these results suggest that RyR2-mediated SR Ca(2+) leak is a major factor in the abnormal intracellular Ca(2+) handling that critically contributes to the reduced SR Ca(2+) content of failing cardiomyocytes.
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PMID:Enhanced ryanodine receptor-mediated calcium leak determines reduced sarcoplasmic reticulum calcium content in chronic canine heart failure. 1782 26

Recovery of intracellular Ca transients and fractional shortening during late phase acidosis are suggested to be associated with CaMKII-dependent processes of which phospholamban (PLB) phosphorylation may play an important role. To test whether increased expression levels of CaMKII may further enhance recovery, we investigated myocytes from CaMKIIdelta(C) transgenic (TG) mice (cytosolic localized CaMKII) having heart failure vs. wild-type littermates (WT). Furthermore, mouse and rabbit myocytes overexpressing CaMKIIdelta(C) using adenovirus-mediated gene transfer (vs. LacZ control) were investigated. Fractional shortening (% vs. resting cell length, % RCL) was assessed during control conditions (pH 7.4) and during acidosis (pH 6.5). Ca transients were measured using fluo-3 (DeltaF/F(0), 10 microM). In WT mouse myocytes, fractional shortening clearly recovered by 90% from 4.6+/-0.6 to 7.2+/-0.7% RCL during late acidosis. In parallel, Ca transients increased from 2.01+/-0.11 to 2.33+/-0.15 DeltaF/F(0). When blocking CaMKII (KN-93, 1 microM), recovery of Ca transients and shortening could be completely abolished. In contrast, in CaMKIIdelta(C) TG mouse myocytes shortening recovered only by 32% from 3.4+/-0.6 to 4.4+/-0.5% RCL (P<0.05 vs. WT using ANOVA). In parallel, Ca transients increased only slightly from 1.75+/-0.15 to 1.84+/-0.13 DeltaF/F(0) (P<0.05 vs. WT using ANOVA). In accordance, SR Ca content (measured by caffeine contractures, 10 mM) in WT significantly increased during late acidosis but not in CaMKIIdelta(C) TG mice. In contrast, in mouse and rabbit myocytes overexpressing CaMKIIdelta(C) by means of adenovirus-mediated gene transfer, recovery of fractional shortening and Ca transients was not impaired during late acidosis but even slightly improved vs. LacZ control (P<0.05 vs. CaMKIIdelta(C) using ANOVA for mouse and rabbit myocytes). This was associated with significantly increased SR Ca content during late acidosis in CaMKIIdelta(C) as compared to LacZ. CaMKII-dependent PLB Thr-17 phosphorylation, contributing to increased SR Ca uptake, was significantly increased in CaMKIIdelta(C) transfected rabbit myocytes vs. LacZ in the light of unchanged SR Ca ATPase and PLB protein expression. CaMKII inhibition completely prevented recovery of all parameters in both CaMKIIdelta(C) and LacZ. In summary and in contrast to our initial hypothesis, we showed for the first time that TG CaMKIIdelta(C) overexpression (i.e., chronic overexpression) in mice with heart failure clearly resulted in impaired recovery associated with impaired SR Ca loading during late acidosis vs. WT. This may be due to decreased SR Ca ATPase and PLB expression as reported previously. In contrast, adenovirus-mediated gene transfer of CaMKIIdelta(C) in mouse and rabbit myocytes (i.e., acute overexpression) did not result in impaired but even slightly improved recovery associated with increased SR Ca load during late acidosis as compared to LacZ. This most likely was due to higher PLB Thr-17 phosphorylation in CaMKIIdelta(C) myocytes. In conclusion, possible beneficial effects by therapeutical CaMKIIdelta(C) stimulation on the ability to recover from acidosis may be challenged by altered expression levels of its target proteins and should be carefully considered.
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PMID:Effects on recovery during acidosis in cardiac myocytes overexpressing CaMKII. 1795 Jul 50

1. Previous studies have demonstrated progressive ventricular hypertrophy, dilatation and contractile depression in response to chronic volume overload. Whether this decompensation was related to intrinsic myocyte dysfunction was not clear. The present study evaluated ventricular myocyte function at critical times during the progression of ventricular remodelling induced by volume overload. 2. Chronic volume overload was induced with an infrarenal aortocaval fistula in rats. Myocyte contraction and intracellular Ca(2+) concentrations ([Ca(2+)](i)) were evaluated using a fura-2 fluorescence and edge detection system. Protein levels of sarcoplasmic reticulum (SR) Ca(2+) transporters were determined by western blots. Progressive ventricular dilatation developed following creation of the fistula. Although myocyte function in 5 week fistula rats was comparable to that of the control group, myocytes from rats 10 weeks post-fistula demonstrated significant depression of cell shortening and peak [Ca(2+)](i). Application of isoproterenol (0.1 micromol/L) was not able to compensate for the functional deficiency in myocytes from 10 week fistula rats. Caffeine (10 mmol/L) induced SR Ca(2+) release, as well as protein expression of SR Ca(2+)-ATPase, and ryanodine receptors were reduced in myocytes obtained from the same group of 10 week fistula rats. 3. These data indicate that the transition to heart failure secondary to chronic volume overload is related to depressed myocyte contractility secondary to altered intracellular Ca(2+) homeostasis.
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PMID:Defective intracellular Ca2+ homeostasis contributes to myocyte dysfunction during ventricular remodelling induced by chronic volume overload in rats. 1834 70

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