Relation of iodine-123 metaiodobenzylguanidine myocardial scintigraphy to endomyocardial biopsy findings in patients with dilated cardiomyopathy

Background: Iodine-123 metaiodobenzylguanidine (¹²³I-MIBG) concentrates in adrenergic neurons and has been developed for evaluation of the sympathetic nervous system. Recent studies have demonstrated that the normal heart is clearly visualized by ¹²³I-MIBG cardiac scintigraphy, whereas abnormal ¹²³I-MIBG myocardial uptake and washout have been demonstrated in patients after myocardial infarction and in patients with congestive cardiomyopathy, long QT syndrome, and ventricular tachycardia. Hypothesis: Based on evidence from recent studies, it can be hypothesized that ¹²³I-MIBG uptake is related to histopathologic changes in the myocardium. Methods: The relation of ¹²³I-MIBG uptake to the histologic findings for the heart was studied in 24 patients with dilated cardiomyopathy (DCM). The study group did not include patients with complicating disorders that primarily affect the adrenergic nervous system. The ¹²³I-MIBG uptake was visually assigned one of four grades using the two criteria of the mean score for six regional uptake grades (mean score) and the global score obtained by visual evaluation of the entire image (global score). The ¹²³I-MIBG uptake score was also determined for the region at which the biopsy specimen was obtained (biopsy region score). The histologic findings were evaluated by assigning one of four grades for each of the following five factors: myocyte hypertrophy, myocardial fibrotic change, myocyte degeneration and necrosis, mononuclear cell infiltration, and myocyte disarray. The sum for all grades was defined as the total score, and the global score was also assigned to the overall histologic findings. Results: All of the global, mean, and biopsy region scores for ¹²³I-MIBG uptake correlated significantly with the global and total scores for the histologic findings. Among the histologic factors, myocyte degeneration showed score correlated with all global, mean, and biopsy region scores for the uptake. Myocyte hypertrophy was associated weakly with the ¹²³I-MIBG uptake scores. Conclusion: These results indicate that ¹²³I-MIBG uptake imaging is associated with histopathologic abnormalities in patients with DCM.     

Messenger RNA levels of guanine nucleotide-binding proteins are reduced in the ventricle of cardiomyopathic hamsters

The expression of guanine nucleotide-binding protein (G-protein) genes (Gs alpha, Go alpha, Gi alpha 1, Gi alpha 2, and Gi alpha 3) was examined in the ventricle of cardiomyopathic Syrian hamsters of the Bio14.6 strain (10-35 weeks old). Northern blot analysis of total cellular RNA revealed that all G-protein genes except Gi alpha 1 were expressed in the ventricle of Syrian hamsters. Gs alpha and Gi alpha 2 genes were abundantly expressed. The expression levels of the Gs alpha and Gi alpha 2 messenger RNAs in Bio14.6 ventricles were lower than the levels in ventricles of the F1B hamster strain; the abundance of Go alpha and Gi alpha 3 messenger RNAs did not change markedly. Moreover, the messenger RNA levels of Gs alpha and Gi alpha 2 decreased as the stage of cardiomyopathy progressed. Since G-proteins are linked to adenylate cyclase, these alterations of G-protein messenger RNA levels may be related to reduced contractility of cardiomyopathic heart.     

Molecular mechanism of cardiac hypertrophy and development

Congestive heart failure is a major issues for cardiologists and to fully understand heart failure, it is important to understand the mechanism of the development of cardiac hypertrophy. Hemodynamic overload, namely mechanical stress, is a major cause of cardiac hypertrophy and to dissect the signaling pathways from mechanical stress to cardiac hypertrophy, an in-vitro device by which mechanical stress can be imposed on cardiac myocytes of neonatal rats cultured in serum-free conditions has been developed. Passively stretching cardiac myocytes cultured on silicone membranes induced various hypertrophic responses, such as activation of the phosphorylation cascades of many protein kinases, expression of specific genes and an increase in protein synthesis. During this process, secretion and production of vasoactive peptides, such as angiotensin II and endothelin-1, were increased and they played critical roles in the induction of these hypertrophic responses. Candidates for the 'mechanoreceptor' that receives the mechanical stress and converts it into intracellular biochemical signals have been recently demonstrated. Gene therapy and cell transplantation are hopeful strategies for the treatment of heart failure and require an understanding of how normal cardiac myocytes are differentiated. A key gene that plays a critical role in cardiac development has been isolated. The cardiac homeobox-containing gene Csx is expressed in the heart and the heart progenitor cells from the very early developmental stage, and targeted disruption of the murine Csx results in embryonic lethality because of the abnormal looping morphogenesis of the primary heart tube. With a cardiac zinc finger protein GATA4, Csx induces cardiomyocyte differentiation of teratocarcinoma cells as well as upregulation of cardiac genes. Mutations of human CSX cause various congenital heart diseases including atrial septal defect, ventricular septal defect, tricuspid valve abnormalities and atrioventricular block.     

Generation of CD1+RelB+ dendritic cells and tartrate-resistant acid phosphatase-positive osteoclast-like multinucleated giant cells from human monocytes

We previously showed that granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) stimulate the differentiation of human monocytes into two phenotypically distinct types of macrophages. However, in vivo, not only CSF but also many other cytokines are produced under various conditions. Those cytokines may modulate the differentiation of monocytes by CSFs. In the present study, we showed that CD14+ adherent human monocytes can differentiate into CD1+relB+ dendritic cells (DC) by the combination of GM-CSF plus interleukin-4 (IL-4) and that they differentiate into tartrate-resistant acid phosphatase (TRAP)-positive osteoclast-like multinucleated giant cells (MGC) by the combination of M-CSF plus IL-4. However, the monocyte-derived DC were not terminally differentiated cells; they could still convert to macrophages in response to M-CSF. Tumor necrosis factor-alpha (TNF-alpha) stimulated the terminal differentiation of the DC by downregulating the expression of the M-CSF receptor, cfms mRNA, and aborting the potential to convert to macrophages. In contrast to IL-4, interferon-gamma (IFN-gamma) had no demonstrable effect on the differentiation of monocytes. Rather, IFN- gamma antagonized the effect of IL-4 and suppressed the DC and MGC formation induced by GM-CSF + IL-4 and M-CSF + IL-4, respectively. Taken together, these results provide a new aspect to our knowledge of monocyte differentiation and provide evidence that human monocytes are flexible in their differentiation potential and are precursors not only of macrophages but also of CD1+relB+DC and TRAP-positive MGC. Such a diverse pathway of monocyte differentiation may constitute one of the basic mechanisms of immune regulation.     

Effect of pravastatin on the development of diabetes and adiponectin production

In the West of Scotland Coronary Prevention Study (WOSCOPS), treatment of hypercholesterolemic men with pravastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, reduced their likelihood to progress to diabetes mellitus by 30%. However, the mechanism of this effect of pravastatin has not been investigated. In the current study, we examined the effect of pravastatin on the development of diabetes in obese diabetic mice, and on the insulin-induced glucose uptake and adiponectin production. Pravastatin treatment attenuated the development of diabetes in db/db and high fat/high sucrose diet-fed C57BL/6J mice. An in vivo glucose transport assay showed that pravastatin upregulated glucose uptake in adipose tissue. Insulin-stimulated glucose uptake was enhanced in primary adipocytes isolated from pravastatin-treated mice. Pravastatin treatment increased adiponectin production in 3T3-L1 adipocytes. Plasma adiponectin levels were significantly increased in pravastatin-treated mice. Analyses of plasma samples from the WOSCOPS biobank indicated a significant increase of plasma adiponectin levels with pravastatin treatment (placebo -0.28+/-0.34 microg/ml versus pravastatin +1.47+/-0.33 microg/ml, p=0.0003). Taken together, our findings suggest that pravastatin may have beneficial effects on adipose tissue, which may partly explain the reduction of the development of diabetes by pravastatin treatment.     

Angiotensin II type 1a receptor signals are involved in the progression of heart failure in MLP-deficient mice.

BACKGROUND: Angiotensin II (AT) is implicated in the development of cardiac remodeling, which leads to heart failure, and pharmacological inhibition of the AT type 1 (AT1) receptor has improved mortality and morbidity in patients of heart failure. The aim of this study was to elucidate the role of the AT1 receptor in disease progression in muscle LIM protein (MLP)-deficient mice, which are susceptible to heart failure because of defective function of mechanosensors in cardiomyocytes. METHOD AND RESULTS: Hearts from MLP knockout (MLPKO) mice and MLP-AT1a receptor double knockout (DKO) mice were analyzed. MLPKO hearts showed marked chamber dilatation with cardiac fibrosis and reactivation of the fetal gene program. All of these changes were significantly milder in the DKO hearts. Impaired left ventricular (LV) contractility and filling were alleviated in DKO hearts. However, the impaired relaxation and downregulated expression of sarcoplasmic reticulum calcium-ATPase 2 were unchanged in DKO hearts. CONCLUSIONS: The AT1a receptor is involved in progression of LV remodeling and deterioration of cardiac function in the hearts of MLPKO mice. These results suggest that blockade of the receptor is effective in preventing progression of heart failure in dilated cardiomyopathy.