Development Of Left Ventricular Fibrosis Research Articles

The role of fibrosis on the postoperative LV function in severe aortic regurgitation

In asymptomatic patients with severe aortic regurgitation (AR), the degree of left ventricular (LV) remodelling is a determinant of the postoperative function and survival. The development of LV fibrosis may be assessed by extracellular volume (ECV) determined by cMR-T1 mapping. The aim of the study was to evaluate the impact of the LV fibrosis on the postoperative LV function. Between January 2012 and May 2017, 42 patients (age = 47 ± 13 years, 95% men) with severe AR underwent evaluation of fibrosis by ECV preoperatively and 6 months postoperatively. LV biopsies were performed at the time of surgery and stained with Sirius red. The amount of fibrosis quantified by biopsy was 4.95 ± 1.85% [0.97; 8.50], while ECV was 27.46 ± 4.29% [20.67; 37.13] (values are presented as mean ± SD [min; max]). Postoperative ejection fraction was 57% ± 7%. Multivariate regression analysis showed that preoperative EF and histological fibrosis are predictor factors of postoperative EF. LV fibrosis is a major predictor of postoperative LV EF. It may be assessed by ECV and help to determine the right time for surgery in asymptomatic patients with severe AR.

Dynamic Obstruction is Associated With Abnormal Myocardial Mechanics in Hypertrophic Cardiomyopathy

Introduction: Dilated cardiomyopathy (DCM) is a progressive disease characterised by ventricular dilatation, impaired systolic function and diffuse interstitial fibrosis. Recently in the setting of mineralocorticoid-induced cardiac fibrosis, we demonstrated that activation of the SDF-1:CXCR4 axis was central to the development of cardiac fibrosis. In this study we tested the hypothesis that the SDF-1:CXCR4 axis is implicated in the pathogenesis of fibrosis in DCM. Methods and results: A transgenic mouse model (Mst1) of DCM and fibrosis was used. The effect of the CXCR4 antagonist (AMD3100, 6mg/kg/d) on cardiac fibrosis (quantitative Masson’s stain) was examined. After 12wks, blood pressure and left ventricular morphology was analysed. As indicated in the Table, Mst1 mice demonstrated ventricular dilatation and significant cardiac fibrosis. AMD3100 significantly attenuated the development of left ventricular fibrosis (p< 0.01). Conclusion: CXCR4/SDF-1 signalling pathway plays a central role in thepathogenesis of cardiac fibrosis inDCM.

Effects of Captopril and Telmisartan on Matrix Metalloproteinase-2 and -9 Expressions and Development of Left Ventricular Fibrosis Induced by Isoprenaline in Rats

The aim of this study was to clarify the effects of renin-angiotensin system (RAS) blockade by captopril, an angiotensin converting enzyme inhibitor, and telmisartan, an angiotensin II type 1 receptor antagonist, on matrix metalloproteinase (MMP)-2 and MMP-9 expressions and development of left ventricular (LV) fibrosis induced by isoprenaline in rats. Rats were treated with subcutaneous injection of isoprenaline (5 mg/kg/d) and with oral administration of captopril (30 mg/kg/d) or telmisartan (3 mg/kg/d) for 1 or 7 d. Hearts were excised at the day 2 and day 8. Degree of fibrosis was evaluated by Azan staining. MMP-2 and MMP-9 expressions were analyzed by Western blotting. Localization of MMP-9 expression in LV section was detected by immunohistochemical staining. At the day 8, myocardial fibrosis was observed in LV section from isoprenaline-treated rats. Captopril but not telmisartan significantly enhanced the isoprenaline-induced myocardial fibrosis. MMP-9 expression at the day 2 and MMP-2 expression at the day 8 increased significantly in LV from isoprenaline-treated rats. Captopril had no influence on the MMP-2 expression, but significantly augmented the isoprenaline-induced MMP-9 expression. Telmisartan had no effect on the isoprenaline-induced MMP-2 and MMP-9 expressions. In immunohistochemical staining, MMP-9 positive-interstitial cells were extensively observed in LV sections from isoprenaline + captopril-treated rats at the day 2. The present study reveals that RAS blockade by captopril and telmisartan does not have suppressive effects on isoprenaline-induced MMP-2 and MMP-9 expressions as well as LV fibrosis. Furthermore, captopril may enhance LV fibrosis through promoting isoprenaline-induced MMP-9 expression in cardiac interstitial cells.

Melatonin prevents fibrosis but not hypertrophy development in the left ventricle of NG-nitro-L-arginine-methyl ester hypertensive rats

Melatonin was shown to reduce blood pressure, enhance nitric oxide availability and scavenge free radicals. There is, however, a shortage of data with respect to the effect of melatonin on pathological left ventricular remodelling associated with haemodynamic overload. We investigated whether melatonin was able to prevent left ventricular hypertrophy (LVH) and fibrosis associated with N(G)-nitro-L-arginine-methyl ester (L-NAME)-induced hypertension. Four groups of male Wistar rats were investigated: control, L-NAME (50 mg/kg per day), melatonin (10 mg/kg per day) and L-NAME plus melatonin. Blood pressure was measured non-invasively each week. After 5 weeks of treatment the animals were killed and nitric oxide synthase (NOS) activity, endothelial and inducible NOS expression, the level of collagenous proteins, hydroxyproline and conjugated dienes in the left ventricle were determined. The administration of L-NAME inhibited NOS activity, increased conjugated dienes concentration, elevated blood pressure and induced LVH and fibrosis (indicated by increased collagenous proteins and hydroxyproline levels). The addition of melatonin to L-NAME treatment failed to prevent the attenuation of NOS activity and the development of LVH and prevented hypertension only partly. The administration of melatonin, however, completely prevented the increase in conjugated dienes concentration and the development of left ventricular fibrosis. NOS expression was not different among experimental groups. Melatonin prevented the development of left ventricular fibrosis and the increase in oxidative load in rats with L-NAME-induced hypertension. The antifibrotic effect of melatonin seems to be independent of its effects on NOS activity and might be linked to its antioxidant properties.

Long-term administration of nifedipine attenuates cardiac remodeling and diastolic heart failure in hypertensive rats

The Ca 2+ channel blocker nifedipine has been reported to reduce the rate of new overt heart failure. We investigated the effects of nifedipine on left ventricular remodeling, oxidative stress, and gene expression in the failing heart of Dahl salt-sensitive (DS) rats. DS rats fed a high-salt diet from 7 weeks of age were treated with a non-antihypertensive (1 mg/kg per day, Nif-L) or mild-antihypertensive dose of nifedipine (3 mg/kg per day, Nif-H) or with vehicle (Vehicle) from 12 to 19 weeks. Marked left ventricular hypertrophy and fibrosis were apparent and the ratio of collagen type I to type III mRNA levels and the activity of matrix metalloproteinase (MMP)-2 and its mRNA expression in the myocardium were increased in Vehicle at 19 weeks in comparison with Control. Load-induced left ventricular hypertrophy was reduced in Nif-H, but not in Nif-L, relative to that in Vehicle. Treatment with either dose of nifedipine reduced the extent of fibrosis, the collagen type I to type III mRNA ratio, and MMP-2 activity and its mRNA expression compared with those in Vehicle. The decrease in the ratio of reduced to oxidized glutathione and the increase in NADPH oxidase activity apparent in the left ventricle of Vehicle were also inhibited by nifedipine at both doses. Nifedipine thus inhibited the development of left ventricular fibrosis and diastolic heart failure in DS rats, independently of its antihypertensive effect. The overall protective action of nifedipine is likely attributable to its antioxidant effect as well as to its antihypertensive action.

Calcineurin inhibitor attenuates left ventricular hypertrophy, leading to prevention of heart failure in hypertensive rats.

There is controversy regarding the contribution of calcineurin activation to the development of pressure-overload left ventricular (LV) hypertrophy and heart failure. The aim of this study was to explore whether the inhibition of calcineurin may prevent the transition to heart failure in hypertensive rats and, if so, to clarify in which developmental stage of LV hypertrophy calcineurin plays a key role. Dahl salt-sensitive rats placed on an 8% NaCl diet from the age of 7 weeks (hypertensive rats) were randomized to no treatment (n=6) or treatment with the calcineurin inhibitor FK506 (1 mg x kg(-1) x d(-1)) from 8 weeks (FKE, n=7) or from 17 weeks (FKL, n=7). Rats placed on a 0.3% NaCl diet were defined as control rats (n=6). The administration of FK506 from 8 weeks attenuated, although it did not block, LV hypertrophy observed in the untreated rats and prevented the transition to heart failure. The development of LV fibrosis, however, was not attenuated by the administration of FK506 from 8 weeks. The administration of FK506 from 17 weeks brought no benefit for cardiac remodeling or LV function and failed to prevent heart failure. Calcineurin inhibition, if started from the initial stage of pressure overload, attenuated the development of LV hypertrophy without any effect on LV fibrosis and prevented the transition to heart failure. The activation of calcineurin is involved in the development of LV hypertrophy but not of LV fibrosis, and this involvement may be crucial at the initial stage.