Mechanisms of Cardiac Fibrosis in Hypertension
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Abstract:
Changes in the composition of cardiac tissue develop in hypertensive patients with left ventricular hypertrophy (ie, hypertensive heart disease) and lead to structural remodeling of the myocardium. One of these changes is related to the disruption of the equilibrium between the synthesis and degradation of collagen types I and III molecules, which results in an excessive accumulation of collagen types I and III fibers within the myocardium. Myocardial fibrosis is the consequence of a number of pathologic processes mediated by mechanical, neurohormonal, and cytokine routes. The clinical relevance of fibrosis is that it may contribute to heart failure and other cardiac complications in patients with hypertensive heart disease. This brief review focuses on the mechanisms of hypertensive myocardial fibrosis.Keywords:
Hypertensive heart disease
Myocardial fibrosis
Cardiac Fibrosis
Clinical Significance
Myocardial fibrosis is one of the histologic constituents of myocardial remodeling present in hypertensive patients with hypertensive heart disease. In fact, an exaggerated interstitial and perivascular accumulation of fibrillar collagens type I and type III has been found in the myocardium of patients with arterial hypertension and left ventricular hypertrophy. Hypertensive myocardial fibrosis has been shown to facilitate abnormalities of cardiac function, coronary reserve, and electrical activity that adversely affect the clinical outcome of hypertensive patients. Therefore, development of noninvasive tools for the monitoring of myocardial fibrosis and pharmacological strategies aimed to promote the regression of fibrosis could be of particular relevance in the clinical treatment of patients with hypertensive heart disease.
Hypertensive heart disease
Myocardial fibrosis
Clinical Significance
Myocardial hypertrophy
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Abstract Background: Endothelial-to-mesenchymal transition (Endo-MT) is associated with myocardial fibrosis in dilated cardiomyopathy (DCM). Endothelial-to-mesenchymal transition (Endo-MT) is induced by coxsackievirus B3 (CVB3) in cardiac microvascular endothelial cells (CMVECs). Bone morphogenetic protein 7 (BMP7) significantly inhibits Endo-MT and the progression of cardiac fibrosis. The study was aimed to investigate the effect and the underlying mechanism of BMP7 on Endo-MT in myocardial fibrosis induce by CVB3 infection in vivo. Methods: BALB/c mice were intraperitoneally injected by CVB3 to induce viral myocarditis (VMC). Mice were treated with BMP7 after CVB3 infection. Subsequently, all groups of mice were determined by echocardiography, histopathologic and molecular detection. Results: We found that the ratio of BMP7/TGF-β1 in mRNA levels was decreased obviously at different time points after CVB3 injection. BMP7 facilitated the recovery of cardiac function after CVB3 infection via inhibition of myocardial damage, collagen deposition. Double immunofluorescence staining indicated that Endo-MT was implicated in CVB3-induced myocardial fibrosis, which was attenuated by BMP7. The protein levels of pSmad3 and Smad4 were significantly upregulated in VMC group, as well as Wnt/β-catenin and the transcription factor snail. BMP7 treatment reversed the changes of these protein levels. Moreover, CO-IP demonstrated the crosstalk between β-catenin and Smad3 in VMC mice, which was downregulated by BMP7 treatment. Conclusions: These results indicated that BMP7 obviously ameliorated myocardial fibrosis in CVB3-infected mice via Endo-MT, which was involved in the TGF-β/Smad and Wnt/β-catenin pathway. β-Catenin/Smad3 interaction may be associated with Endo-MT in the development of viral myocardial fibrosis.
Myocardial fibrosis
Cardiac Fibrosis
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Hypertensive heart disease
Fabry's disease
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Background: Although few microRNAs (miRNAs) have been involved in the regulation of post-ischemic cardiac fibrosis, the exact effect and underlying mechanism of miRNAs in cardiac fibrosis remains unclear. Here, we sought to investigate whether microRNA-34 (miR-34) plays a role in the pathogenic development of myocardial fibrosis.Methods: The myocardial infarction (MI) mice model was induced and cardiac fibroblasts were cultured. Histological analyses, quantitative real-time polymerase chain reaction and Western blotting analysis were used.Results: We found that the miR-34 cluster, especially miR-34a, was upregulated in the MI heart. In vivo, inhibition of miR-34a reduces the severity of experimental cardiac fibrosis in mice. TGF-β1 increased miR-34a expression in cardiac fibroblasts. Overexpressing miR-34a levels increased the profibrogenic activity of TGF-β1 in cardiac fibroblast, whereas inhibition miR-34a levels weakened the activity. Finally, we showed that miR-34a's underlying mechanism during cardiac fibrosis occurs through the targeting of Smad4 expression.Conclusions: Our findings provide evidence that miR-34a plays a critical role in the progression of cardiac tissue fibrosis by directly targeting Smad4, which suggests that miR-34a may be new marker for cardiac fibrosis progression and that inhibition of miR-34a may be a promising strategy in the treatment of cardiac fibrosis.
Cardiac Fibrosis
Myocardial fibrosis
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In previous studies performed in spontaneously hypertensive rats and patients with essential hypertension we have reported that the serum concentration of carboxy-terminal propeptide of procollagen type I (PIP) provides indirect diagnostic information on both the extent of myocardial fibrosis and the ability of antihypertensive drugs to regress myocardial fibrosis. The current work has been designed to evaluate the diagnostic usefullness of PIP in patients with heart failure (HF) secondary to hypertensive heart disease (HHD). The study was performed in 25 patients with HF and 15 patients with HHD and no echocardiographic evidence of cardiac dysfunction. Myocardial biopsies of the interventricular septum were obtained to quantify the collagen volume fraction (CVF), using the Picrosirius Red staining followed by image analysis. Serum samples were obtained for the determination of PIP, from peripheral blood in the two groups of patients, and from the coronary sinus in the group of patients with HF. PIP concentration was measured by specific radioimmunoassay. The results show that CVF as well as PIP concentration in peripheral blood were increased (P<0.01) in patients with HF compared with patients with HHD. A direct correlation was found between CVF and PIP concentration in peripheral blood (r = 0.844, P<0.001) in all patients. The concentration of PIP was higher in coronary sinus (P<0.05) than in peripheral blood in patients with HF. Besides, PIP concentration in peripheral blood correlated with PIP concentration in coronary sinus (r = 0.799, P<0.001) in these patients. These data suggest that: 1) the development of heart failure in patients with hypertensive heart disease is associated with an increase in myocardial fibrosis, likely due to an increase in the myocardial synthesis of fibrillar collagen type I, 2) PIP measured in peripheral blood is a good marker of myocardial fibrosis in hypertensive patients with heart failure, and 3) PIP measured in peripheral blood in these patients is essentially of cardiac origin.
Myocardial fibrosis
Hypertensive heart disease
Interventricular septum
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It is time to recognize that the quality, not quantity, of myocardium in hypertensive heart disease is responsible for adverse cardiovascular events. Experimental and clinical available data indicate that myocardial fibrosis due to the exaggerated accumulation of collagen type I and type III fibers predisposes to an enhanced risk of diastolic and/or systolic ventricular dysfunction, symptomatic heart failure, ischemic heart disease, and arrhythmias in patients with hypertensive heart disease. Thus, management of these patients must not only focus on detection and regression of left ventricular hypertrophy. Far more sensible are interventions aimed to detect and target hypertensive myocardial fibrosis. The available data on the use of biochemical and/or imaging methodologies to address excessive accumulation of collagen fibers in the myocardium of hypertensive patients are promising. On the other hand, preliminary data suggest that the goal of reducing myocardial fibrosis is achievable in patients with hypertensive heart disease treated with specific antihypertensive agents. Collectively, these findings set the stage for larger trials where-in noninvasive measures and reparative strategies of myocardial fibrosis to prevent heart failure could prove useful. Keywords: Collagen, fibrosis, heart failure, hypertensive heart disease
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Although hypertensive heart disease (HHD) is clinically characterized by development of left ventricular hypertrophy in the absence of a cause other than arterial hypertension, changes in the composition of myocardial tissue also develop in arterial hypertension, leading to structural remodeling of the myocardium (eg, fibrosis). Myocardial fibrosis is the major determinant of diastolic dysfunction/failure in patients with HHD. Recent available data on the determination of serum concentrations of collagen-derived serum peptides, as well as quantitative analysis of echoreflectivity to address the presence of fibrosis in the myocardium of hypertensive patients, are promising. In addition, preliminary data suggest that the goal of reducing myocardial fibrosis is achievable using specific pharmacological agents in patients with HHD. (Circ J 2008; Suppl A: A-8 - A-12)
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Myocardial fibrosis
Myocardial hypertrophy
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Cardiac fibrosis stiffens the ventricular wall, predisposes to cardiac arrhythmias and contributes to the development of heart failure. In the present study, our aim was to identify novel miRNAs that regulate the development of cardiac fibrosis and could serve as potential therapeutic targets for myocardial fibrosis.Analysis for cardiac samples from sudden cardiac death victims with extensive myocardial fibrosis as the primary cause of death identified dysregulation of miR-185-5p. Analysis of resident cardiac cells from mice subjected to experimental cardiac fibrosis model showed induction of miR-185-5p expression specifically in cardiac fibroblasts. In vitro, augmenting miR-185-5p induced collagen production and profibrotic activation in cardiac fibroblasts, whereas inhibition of miR-185-5p attenuated collagen production. In vivo, targeting miR-185-5p in mice abolished pressure overload induced cardiac interstitial fibrosis. Mechanistically, miR-185-5p targets apelin receptor and inhibits the anti-fibrotic effects of apelin. Finally, analysis of left ventricular tissue from patients with severe cardiomyopathy showed an increase in miR-185-5p expression together with pro-fibrotic TGF-β1 and collagen I.Our data show that miR-185-5p targets apelin receptor and promotes myocardial fibrosis.
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Myocardial fibrosis
Apelin
Pressure overload
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This chapter contains sections titled: Introduction Structural and functional alterations in HHD Contribution of Ang II cardiac effects to HHD Cardiomyocyte hypertrophy Coronary insufficiency Ventricular fibrosis Diastolic dysfunction Cardiac RAS in development of HHD: experimental and clinical evidence Pharmacological blockade of cardiac RAS Acknowledgments References
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Hypertensive disease
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Myocardial fibrosis
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This study was designed to investigate whether the serum concentration of the carboxy-terminal propeptide of procollagen type I (PIP), a marker of collagen type I synthesis, is related to myocardial fibrosis in hypertensive patients.The study was performed in 26 patients with essential hypertension in which ischemic cardiomyopathy was excluded after a complete medical workup. Right septal endomyocardial biopsies were performed in hypertensive patients to quantify collagen content. Collagen volume fraction (CVF) was determined on picrosirius red-stained sections with an automated image analysis system. The serum concentration of PIP was measured by specific radioimmunoassay. Compared with normotensives, both serum PIP and CVF were increased (P<0.001) in hypertensives. A direct correlation was found between CVF and serum PIP (r=0.471, P<0.02) in all hypertensives. Histological analysis revealed the presence of 2 subgroups of patients: 8 with severe fibrosis and 18 with nonsevere fibrosis. Serum PIP was higher (P<0.05) in patients with severe fibrosis than in patients with nonsevere fibrosis. Using receiver operating characteristic curves, we observed that a cutoff of 127 microg/L for PIP provided 78% specificity and 75% sensitivity for predicting severe fibrosis with a relative risk of 4.80 (95% CI, 1.19 to 19.30).These results show a strong correlation between myocardial collagen content and the serum concentration of PIP in essential hypertension. Although preliminary, these findings suggest that the determination of PIP may be an easy and reliable method for the screening and diagnosis of severe myocardial fibrosis associated with arterial hypertension.
Myocardial fibrosis
Hypertensive heart disease
Procollagen peptidase
Type I collagen
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