Enhanced myocardial glucose use in patients with a deficiency in long-chain fatty acid transport (CD36 deficiency).
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CD36 is a multifunctional, 88 kDa glycoprotein that is expressed on platelets and monocytes/macrophages. CD36 also has high homology with the long-chain fatty acid (LFA) transporter in the myocardium. Although platelet and monocyte CD36 levels can indicate a CD36 deficiency, they cannot predict specific clinical manifestations in the myocardium of a given person. We examined the hypothesis that a deficiency in LFA transport augments myocardial glucose uptake in patients with a type I CD36 deficiency. METHODS: Seven fasting patients with a type I CD36 deficiency and 9 controls were assessed by cardiac radionuclide imaging using beta-methyl-p-iodophenyl-pentadecanoic acid (BMIPP) as a LFA tracer and by PET with 18F-fluorodeoxyglucose (FDG). RESULTS: None of the patients with a CD36 deficiency showed myocardial uptake of BMIPP. The percentage dose uptake of BMIPP in these subjects was significantly lower than that in normal controls (1.31+/-0.24 versus 2.90+/-0.2; P < 0.005). PET studies revealed that myocardial FDG accumulation was substantially increased in patients with a CD36 deficiency. Quantitative analysis showed that the percentage dose uptake of FDG in patients with a CD36 deficiency was significantly higher than that in normal controls (1.28+/-0.35 versus 0.43+/-0.22; P< 0.01). CONCLUSION: CD36 functions as a major myocardial LFA transporter and its absence may cause a compensatory upregulation of myocardial glucose uptake. (+info)
A novel interaction mechanism accounting for different acylphosphatase effects on cardiac and fast twitch skeletal muscle sarcoplasmic reticulum calcium pumps.
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In cardiac and skeletal muscle Ca2+ translocation from cytoplasm into sarcoplasmic reticulum (SR) is accomplished by different Ca2+-ATPases whose functioning involves the formation and decomposition of an acylphosphorylated phosphoenzyme intermediate (EP). In this study we found that acylphosphatase, an enzyme well represented in muscular tissues and which actively hydrolyzes EP, had different effects on heart (SERCA2a) and fast twitch skeletal muscle SR Ca2+-ATPase (SERCA1). With physiological acylphosphatase concentrations SERCA2a exhibited a parallel increase in the rates of both ATP hydrolysis and Ca2+ transport; in contrast, SERCA1 appeared to be uncoupled since the stimulation of ATP hydrolysis matched an inhibition of Ca2+ pump. These different effects probably depend on phospholamban, which is associated with SERCA2a but not SERCA1. Consistent with this view, the present study suggests that acylphosphatase-induced stimulation of SERCA2a, in addition to an enhanced EP hydrolysis, may be due to a displacement of phospholamban, thus to a removal of its inhibitory effect. (+info)
Molecular cloning and characterization of a novel angiopoietin family protein, angiopoietin-3.
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Using homology-based PCR, we have isolated cDNA encoding a novel member (491 amino acids) of the angiopoietin (Ang) family from human adult heart cDNA and have designated it angiopoietin-3 (Ang3). The NH2-terminal and COOH-terminal portions of Ang-3 contain the characteristic coiled-coil domain and fibrinogen-like domain that are conserved in other known Angs. Ang3 has a highly hydrophobic region at the N-terminus (approximately 21 amino acids) that is typical of a signal sequence for protein secretion. Ang3 mRNA is most abundant in adrenal gland, placenta, thyroid gland, heart and small intestine in human adult tissues. Additionally, Ang3 is a secretory protein, but is not a mitogen in endothelial cells. (+info)
Regional patterns of myocardial sympathetic denervation in dilated cardiomyopathy: an analysis using carbon-11 hydroxyephedrine and positron emission tomography.
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OBJECTIVE: To assess presynaptic function of cardiac autonomic innervation in patients with advanced congestive heart failure using positron emission tomography (PET) and the recently developed radiolabelled catecholamine analogue carbon-11 hydroxyephedrine (HED) as a marker for neuronal catecholamine uptake function. DESIGN AND PATIENTS: 29 patients suffering from dilated cardiomyopathy with moderate to severe heart failure were compared with eight healthy controls. Perfusion scan was followed by HED dynamic PET imaging of cardiac sympathetic innervation. The scintigraphic results were compared with markers of disease severity and the degree of sympathetic dysfunction assessed by means of heart rate variability. RESULTS: In contrast to nearly normal perfusions, mean (SD) HED retention in dilated cardiomyopathy patients was abnormal in 64 (32)% of the left ventricle. Absolute myocardial HED retention was 10.7 (1.0)%/min in controls v 6.2 (1.6)%/min in dilated cardiomyopathy patients (p < 0.001). Moreover, significant regional reduction of HED retention was demonstrated in apical and inferoapical segments. HED retention was significantly correlated with New York Heart Association functional class (r = -0.55, p = 0. 002) and ejection fraction (r = 0.63, p < 0.001), but not, however, with plasma noradrenaline concentrations as well as parameters of heart rate variability. CONCLUSIONS: In this study, using PET in combination with HED in patients with dilated cardiomyopathy, not only global reduction but also regional abnormalities of cardiac sympathetic tracer uptake were demonstrated. The degree of abnormality was positively correlated to markers of severity of heart failure. The pathogenetic mechanisms leading to the regional differences of neuronal damage as well as the prognostic significance of these findings remain to be defined. (+info)
The posterior nasal nerve plays an important role on cardiopulmonary reflexes to nasal application of capsaicin, distilled water and l-menthol in anesthetized dogs.
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The sensory innervation of the cardiopulmonary reflexes to nasal application of capsaicin (CAPS), distilled water (DW) and l-menthol (LM) was studied in anesthetized dogs breathing through tracheostomy. A marked cardiopulmonary reflex was observed by CAPS and DW into the nasal cavity, while a prolongation of expiration was induced by LM. All these reflexes were significantly decreased by bilateral section of the posterior nasal nerve (PNN) and completely abolished by topical nasal anesthesia with lidocaine. Responses of the whole nerve activity of the PNN to these substances corresponded to the magnitude of the reflexes. These results indicate that PNN afferents play an important role on the reflex elicitation of the noxious, water and cold stimuli from the nasal cavity. (+info)
Enteroviral RNA replication in the myocardium of patients with left ventricular dysfunction and clinically suspected myocarditis.
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BACKGROUND: Previous studies dealing with the detection of enteroviral RNA in human endomyocardial biopsies have not differentiated between latent persistence of the enteroviral genome and active viral replication. Enteroviruses that are considered important factors for the development of myocarditis have a single-strand RNA genome of positive polarity that is transcribed by a virus-encoded RNA polymerase into a minus-strand mRNA during active viral replication. The synthesis of multiple copies of minus-strand enteroviral RNA therefore occurs only at sites of active viral replication but not in tissues with mere persistence of the viral genome. METHODS AND RESULTS: We investigated enteroviral RNA replication versus enteroviral RNA persistence in endomyocardial biopsies of 45 patients with left ventricular dysfunction and clinically suspected myocarditis. Using reverse-transcriptase polymerase chain reaction in conjunction with Southern blot hybridization, we established a highly sensitive assay to specifically detect plus-strand versus minus-strand enteroviral RNA in the biopsies. Plus-strand enteroviral RNA was detected in endomyocardial biopsies of 18 (40%) of 45 patients, whereas minus-strand RNA as an indication of active enteroviral RNA replication was detected in only 10 (56%) of these 18 plus-strand-positive patients. Enteroviral RNA was not found in biopsies of the control group (n=26). CONCLUSIONS: These data demonstrate that a significant fraction of patients with left ventricular dysfunction and clinically suspected myocarditis had active enteroviral RNA replication in their myocardium (22%). Differentiation between patients with active viral replication and latent viral persistence should be particularly important in future studies evaluating different therapeutic strategies. In addition, molecular genetic detection of enteroviral genome and differentiation between replicating versus persistent viruses is possible in a single endomyocardial biopsy. (+info)
Differential effects of a segment of slow conduction on reentrant ventricular tachycardia in the rabbit heart.
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BACKGROUND: The purpose of this study was to compare differential effects of a segment of slow conduction during ventricular tachycardia (VT) due to depression of the action potential and electrical uncoupling. METHODS AND RESULTS: In 33 Langendorff-perfused rabbit hearts, a ring of anisotropic left ventricular subepicardium was created by a cryoprocedure. Reentrant VT was produced by incremental pacing. Slow conduction in a segment of the ring was created by selective perfusion of the LAD with 10 mmol/L potassium or 0.75 mmol/L heptanol. As a result, VT cycle length increased from 193+/-34 to 235+/-37 ms (potassium) and 227+/-42 ms (heptanol). Reset curves were made by applying premature stimuli proximal to the area of depressed conduction. In a ring of uniform anisotropic tissue, the reset curve was almost completely flat. Electrical uncoupling of part of the ring (nonuniform anisotropy) resulted in a mixed reset curve. In both substrates, early premature beats failed to terminate VT. Depression of part of the ring by increasing K+ resulted in a completely sloped reset curve, indicating a gap of partial excitability. Under these conditions, in 19 of 24 hearts, premature beats terminated VT by conduction block in the high K+ area. CONCLUSIONS: The nature of the area of slow conduction determines the type of reset response and the ability to terminate VT. (+info)
Bradykinin promotes ischemic norepinephrine release in guinea pig and human hearts.
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We previously reported that bradykinin (BK; 1-1000 nM) facilitates norepinephrine (NE) release from cardiac sympathetic nerves. Because BK production increases in myocardial ischemia, endogenous BK could foster NE release and associated arrhythmias. We tested this hypothesis in guinea pig and human myocardial ischemia models. BK administration (100 nM) markedly enhanced exocytotic and carrier-mediated NE overflow from guinea pig hearts subjected to 10- and 20-min ischemia/reperfusion, respectively. Ventricular fibrillation invariably occurred after 20-min global ischemia; BK prolonged its duration 3-fold. The BK B2 receptor antagonist HOE140 (30 nM) blocked the effects of BK, whereas the B1 receptor antagonist des-Arg9-Leu8-BK (1 microM; i.e., 2.5 x pA2) did not. When serine proteinase inhibitors (500 KIU/ml aprotinin and 100 microg/ml soybean trypsin inhibitor) were used to prevent the formation of endogenous BK, NE overflow and reperfusion arrhythmias were diminished. In contrast, when kininase I and II inhibitors (DL-2-mercaptomethyl-3-guanidinoethylthiopropanoic acid and enalaprilat, each 1 microM) were used to prevent the degradation of endogenous BK, NE overflow and reperfusion arrhythmias were enhanced. B2 receptor blockade abolished these effects but was ineffective if kininases were not inhibited. B2 receptor stimulation, by either exogenous or endogenous BK, also markedly enhanced carrier-mediated NE release in the human myocardial ischemia model; conversely, inhibition of BK biosynthesis diminished ischemic NE release. Because atherosclerotic heart disease impairs endothelial BK production, in myocardial ischemia BK could accumulate at sympathetic nerve endings, thus augmenting exocytotic and carrier-mediated NE release and favoring coronary vasoconstriction and arrhythmias. (+info)