Interstitial Collagen Volume Fraction Research Articles

ХАРАКТЕРИСТИКА СОСТОЯНИЯ МИОКАРДА И ПРОФИБРОТИЧЕСКИХ ФАКТОРОВ ПРИ РАЗВИТИИ ГИПЕРТОНИЧЕСКОГО СЕРДЦА

Introduction. Myocardial damage caused by arterial hypertension is manifested by changes in myocardial geometry and mass, as well as increased content of collagen and fibrous tissue in the myocardium. Excessive accumulation of collagen in myocardium is the result of imbalance between proteolytic enzymes such as matrix metalloproteinases 1 (MMP-1) and tissue inhibitors of matrix metalloproteinase 1 (TIMMP-1), high content of transforming growth factor β1 (TFG-β1), which was found in fibroblasts and macrophages. Aim. The aim of the study was to investigate the role of MMP-1 activation, its tissue inhibitor TIMMP-1 and TGF-β1 in blood in the development of myocardial fibrosis in locomotive train workers with arterial hypertension. Material and methods. 82 patients with arterial hypertension and 20 virtually healthy control subjects were examined. The patients of the analyzed groups underwent evaluation of the data of daily blood pressure monitoring, echocardiographic examination, based on which the types of left ventricular remodeling, the content of matrix metalloproteinase 1 and its tissue inhibitor activity, the level of transforming growth factor β1 in blood serum were identified. Calculation of the volume fraction of interstitial collagen was performed. Results and discussion. The study established statistically significant signs of structural changes in the left ventricular myocardium, which primarily indicated its marked left ventricular hypertrophy against the background of arterial hypertension due to chronic pressure overload. Statistically significant increase of all levels of serum markers of collagen metabolism was revealed in patients with arterial hypertension in comparison with the control group. Patients with arterial hypertension have a restructuring of the intercellular matrix components and imbalance in the MMP-1/TIMMP-1 system characterized by a shift of the collagen balance towards fibrosis (increase of THF-β1, TIMMP-1 level, decrease of MMP-1/TIMMP-1 52 ВЕСТНИК СОВРЕМЕННОЙ КЛИНИЧЕСКОЙ МЕДИЦИНЫ 2021 Том 14, вып. 6ОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯ ratio and increase of interstitial collagen volume fraction). Significant increase of interstitial collagen volume fraction index in the group of patients with arterial hypertension comparing to the control group also indirectly indicates high intensity of interstitial collagen genesis in myocardium of these patients. Conclusion. In arterial hypertension, serum levels of THF-β1, MMP-1, and TIMMP-1 increase, which indirectly indicates an increase in myocardial collagen content.

P931Assosiation of the levels of galectin-3 and MMP-1 with the type of myocardial dyssynchrony in patients with heart failure and concomitant type 2 diabetes mellitus

Abstract Background Myocardial dyssynchrony leads to heart remodeling and the progression of heart failure (HF) in patients with type 2 diabetes mellitus. Studying the mechanisms of the development of myocardial dyssynchrony can help in timely diagnosis and treatment. Aims To study the association of the level of galectin-3 and matrix metalloproteinase 1 (MMP-1) and the type of myocardial dyssynchrony in patients with heart failure and concomitant type 2 diabetes mellitus. Methods 98 patients with heart failure and concomitant type 2 diabetes mellitus were examined, average age (67.45 + 10.32) years. Patients were divided into two groups due to the presence or absence of myocardial dyssynchrony: the first group: with myocardial dyssynchrony (n = 56), the second group: patients without myocardial dyssynchrony ( n = 42). All patients were examined for electrical (enhanced QRS ≥ 120 ms) and mechanical myocardial dyssynchrony using echocardiographic and electrocardiographic methods for assessing intraventricular, interventricular, atrioventricular and combined myocardial dyssynchrony, as well as serum concentration of fibrosis markers - galectin-3 and MMP-1. The determination of percentage of interstitial collagen volume fraction (CVF) was performed in both groups. Results To determine the levels of fibrosis markers depending on the presence of diabetes, the results of patients with myocardial dyssynchrony (n = 56) were compared with the results of the control group without myocardial dyssynchrony (n = 42). In patients with myocardial dyssynchrony, there was an increase in the levels of galectin-3 (7.49 + 0.6 ng / ml) and CVF (7.6 ± 4.03%), a decrease in MMP-1 (0.46 + 0.2 ng / ml ) compared with the group without myocardial dyssynchrony (p <0.05). An increase in galectin-3 levels was observed in the presence of combined forms of myocardial dyssynchrony. In patients with a combination of intraventricular, interventricular, or atrioventricular myocardial dyssynchrony (n = 28), the levels of galectin-3 (9.03 + 0.3 ng / ml) and CVF (8.04 + 1.6%) were the highest; in patients with isolated forms of myocardial dyssynchrony, the levels of galectin-3 (6.67 + 0.2 ng / ml) and CVF (6,93 + 1,4%) were significantly lower. MMP-1 was greater in patients with isolated forms of myocardial dyssynchrony (0.78 + 0.2 ng / ml), compared with patients with combined forms of myocardial dyssynchrony (0.2 + 0.01 ng / ml) (p <0.05 ). Conclusions An association is observed between myocardial dyssynchrony and the levels of galectin-3 and MMP-1 in the blood. These findings are important for prognostic implications and require further research.

Erythropoietin reduces collagen deposition after myocardial infarction but does not improve cardiac function

Myocardial remodeling includes inappropriate collagen deposition in the interstitium. Erythropoietin (EPO) may have cardioprotective effects. We aimed to assess the role of EPO on myocardial remodeling during the chronic phase. We studied 60 Wistar rats divided into the following groups: control (CT), control + EPO (CT + EPO), myocardial infarction + EPO (MI + EPO), and myocardial infarction (MI). The interstitial collagen volume fraction (ICVF) was quantified and echocardiography was performed. We quantified asymmetric dimethylarginine and glutathione by ELISA, and used real-time PCR to assess apoptosis and inflammation. Western blotting was used to evaluate inflammatory proteins and tissue inhibitors of metalloproteinases (TIMPs), and TUNEL staining was used to detect apoptosis. For matrix metalloproteinases (MMPs), we performed zymography. Parametric and nonparametric analyses were performed according to normality testing. ICVF was greater in MI groups (p < 0.001) and was attenuated by EPO (p = 0.05). The MMP-2 did not show any difference between groups. The TIMP-1 and TIMP-2 did not have difference between groups. The MI groups had worse fraction shortening (p < 0.001), without EPO protection (p = 0.666). The MI groups had increased left ventricle diastolic dimension (p < 0.001) without EPO attenuation (p = 0.79). EPO did not act on oxidative stress. Apoptosis and inflammation were not modulated by EPO. We concluded that EPO attenuated interstitial collagen accumulation, but did not protect from heart dilation or dysfunction.

Short-term and long-term models of doxorubicin-induced cardiomyopathy in rats: A comparison of functional and histopathological changes

ObjectivesDoxorubicin (DXR), an anthracyclic antineoplastic agent, is one of the most commonly drug utilized to induce dilated cardiomyopathy (DCM) and heart failure (HF), but the well optimized protocol for cardiomyopathy induction leading to development of cardiac systolic dysfunction is unclear. This study aims to critically compare short-term and long-term DXR injection protocols for the induction of DCM in rats. MethodsAnimals were allocated into 3 experimental groups: a ST (short-term DXR injection) group, in which animals received 6 intraperitoneal (i.p.) injections of DXR (2.5mg/kg per dose) over a period of 2 weeks (cumulative dose of 15mg/kg); a LT (long-term DXR injection) group in which animals received weekly i.p. injections of DXR (2mg/kg per dose) over a period of 9 weeks (cumulative dose of 18mg/kg); and a control group in which animals received an appropriate volume of 0.9% saline i.p. All animals were submitted to echocardiography analysis at baseline and after completion treatment. Afterwards, the hearts were collected for conventional light microscopy and collagen quantification. ResultsMorphological myocardial analysis of both DXR-treated groups showed an identical pattern of swollen and vacuolated cardiomyocytes and disorganization of myofibrils. There was pronounced interstitial fibrosis in both groups of DXR-treated hearts as compared to controls, as assessed by the interstitial collagen volume fraction. There was no difference in interstitial fibrosis between the ST and LT groups. The echocardiography analysis of the LT group showed structural and functional findings compatible with DCM, including increased left ventricular systolic (5.02±0.96mm) and diastolic (7.68±0.96mm) dimensions and reduction of ejection fraction (69.40±8.51%) as compared to the ST group (4.10±0.89mm, 7.32±0.84, and 79.68±7.23%, respectively) and control group (4.07±0.72mm, 7.17±0.68mm and 80.08±4.71%, respectively), ANOVA p<0.01. ConclusionsThese results indicate that LT injection of DXR is more effective than ST injection in inducing left ventricular dysfunction and structural cardiac changes resembling those found in dilated cardiomyopathy.

Resistance training attenuates salt overload-induced cardiac remodeling and diastolic dysfunction in normotensive rats.

Elevated salt intake induces changes in the extracellular matrix collagen, leading to myocardial stiffness and impaired relaxation. Resistance training (RT) has been used as a remarkably successful strategy in the treatment of heart disease. Therefore, the aim of this study was to investigate the effects of RT on preventing pathological adaptation of the left ventricle (LV) induced by salt overload. Male Wistar rats (10 weeks old) were distributed into four groups (n=8/group): control (CO), control+1% salt (CO+SALT), RT and RT+1% salt (RT+SALT). The RT protocol consisted of 4×12 bouts of squat training, 5/week for 8 weeks, with 80% of one repetition maximum (1RM). Echocardiographs were analyzed and interstitial collagen volume fraction (CVF) was determined in the LV. The 1RM tests in the RT and RT+SALT groups increased 145 and 137%, respectively, compared with the test performed before the training program. LV weight-to-body weight ratio and LV weight-to-tibia length ratio were greater in the RT and RT+SALT groups, respectively, compared with the CO group. Although there was no difference in the systolic function between groups, diastolic function decreased 25% in the CO+SALT group compared with the CO group measured by E/A wave ratio. RT partially prevented this decrease in diastolic function compared with the CO+SALT group. A 1% salt overload increased CVF more than 2.4-fold in the CO+SALT group compared with the CO group and RT prevented this increase. In conclusion, RT prevented interstitial collagen deposition in LV rats subjected to 1% NaCl and attenuated diastolic dysfunction induced by salt overload independent of alterations in blood pressure.

Intervention effect of Qingxin-II Recipe on myocardial cell apoptosis and fibrosis in viral myocarditis mice

Objective To investigate the intervention effect of Qingxin-Ⅱ Recipe on myocardial cell apoptosis and its fibrosis in viral myocarditis mice and its mechanism. Methods A total of 120 Balb/c mice were randomly divided into the model group (n=50), the treatment group (n=50) and the control group (n=20). Mice in the model and treatment groups were given intraperitoneal injection of CVB3 to establish the experimental model of viral myocarditis. The control and model groups were treated with normal saline and water by intragastric administration respectively and the treatment group was given Qingxin-Ⅱ Recipe. The expression level of nuclear factor-κB (NF-κB), tumor necrosis factor (TNF-α), interleukin-1β(IL-1β), collagen type I-A1 (COL1-A1), collagen type Ⅲ-A1 (COL3-A1), matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metallproteinase-1 (TIMP-1), myocardial interstitial collagen volume fraction (CVF) and apoptosis rate (Rapo) were assessed after treatment. Results The levels of NF-κB, TNF-α, IL-1 in cardiomyocytes, serum levels of COL1-A1, MMP-9, TIMP-1, the mRNA expression levels of COL1-A1, COL3-A1, MMP-9, TIMP-1 in cardiomyocytes, CVF and Rapo were lower in the treatment and control groups than in the model group (F=21.541, 12.146, 32.583, 4.212, 6.863, 4.868, 9.089, 8.662, 7.307, 6.646, 4.324, 41.237, respectively, all P 0.05) were found, but serum MMP-9 level was higher in the treatment group than in the control group (P=0.033). Conclusions Qingxin-Ⅱ Recipe can effectively reduce inflammatory cytokines levels, protect myocardial cells from inflammatory damages and inhibit myocardial fibrosis in viral myocarditis. Key words: Myocarditis; Apoptosis; Fibrosis

Effects of Tongxinluo on myocardial fibrosis in diabetic rats

BackgroundThe aim of this study was to explore the effect of Tongxinluo on myocardial fibrosis in diabetic rats and its possible mechanism of action. MethodsDiabetic rat models were established and then divided into three groups: control, diabetes, and Tongxinluo groups. Heart function and myocardial interstitial collagen volume fraction were investigated, and the protein and mRNA expression levels of transforming growth factor beta 1 (TGF-β1), Smad3, and Smad7 were measured. ResultsHeart function was clearly abnormal in the diabetes group compared with that in the control group, and the collagen volume fraction and mRNA expression levels of TGF-β1 and Smad3 were higher. However, the protein and mRNA expression levels of Smad7 were lower. In the Tongxinluo group, it was observed that these indicators were improved. ConclusionTongxinluo was effective for the prevention and treatment of myocardial fibrosis in diabetic rats. It probably mediates the expressions of TGF-β1, Smad3, and Smad7 in rat cardiomyocytes to reduce the occurrence of myocardial fibrosis in diabetic rats.

Abstract 14309: A Novel Fibroblast Activation Inhibitor, NM922, Attenuates Maladaptive Fibrotic Remodeling to Preserve Cardiac Function Following the Onset of Heart Failure

Background: Cardiac fibroblasts are critical mediators of fibrotic remodeling in the failing heart. These maladaptive structural changes can worsen cardiac function accelerating the progression to decompensated heart failure (HF). We investigated the effects of a novel inhibitor of the conversion of normal fibroblast to the myofibroblast phenotype in the setting of pressure overload induced HF. Methods: Male C57BL/6J mice (10 wks) were subjected to transverse aortic constriction (TAC; 27 g needle) and NM922 (NovoMedix, LLC50 mg/kg/d i.p.) or VEH (DMSO + HS-15) was administered daily starting at 6 wks post TAC. Echocardiography was assessed at baseline and for 16 wks post TAC. At the 16 wk endpoint, mice were sacrificed and hearts were collected for biochemical and molecular assessment. Results: NM922 significantly attenuated TAC-induced left ventricular (LV) dilation at 16 wks post TAC (LVEDD: 3.5 ± 0.1 vs. 4.5 ± 0.2 mm, p &lt; 0.01; LVESD: 2.5 ± 0.2 vs. 3.8 ± 0.3 mm, p &lt; 0.01) compared to VEH. NM922 treated mice displayed reduced wall thickening (LVPWd: 1.0 ± 0.03 vs. 1.2 ± 0.05 mm; p &lt; 0.05) at 10 wks post TAC compared to VEH. LV ejection fraction (LVEF) was preserved in NM922 treated mice at 8-16 wks post TAC compared to VEH (*p &lt; 0.05; **p &lt; 0.001) compared to VEH. Treatment with NM922 resulted in reductions in heart (8.5 ± 0.5 vs. 12.0 ± 0.9 mg/mm; p &lt; 0.01) and lung (8.2 ± 0.3 vs. 11.5 ± 0.6 mg/mm; p &lt; 0.0001) weights compared to VEH. Picrosirius Red staining revealed that NM922 reduced cardiac interstitial collagen volume fraction by 50% (p &lt; 0.05 vs. VEH). Circulating BNP levels trended toward lower (p = 0.08) in the NM922 mice when compared to VEH. Conclusion: Chronic treatment with NM922 following the onset of cardiac hypertrophy and HF resulted in attenuated myocardial collagen formation and adverse remodeling with preservation of LVEF. Future studies are aimed at further elucidation of the molecular and cellular mechanisms by which this novel agent protects the failing heart.

Abstract 15511: A Novel Mitochondrial Targeted DNA Repair Enzyme Attenuates Maladaptive Myocardial Remodeling and Preserves Cardiac Function in Heart Failure

Background: Sustained increases in mitochondrial oxidative stress results in mitochondrial DNA (mtDNA) damage further worsening oxidative damage and cellular injury. These cellular events are pivotal in development and progression of myocardial damage and heart failure. We investigated the effects of a novel mitochondrial targeted fusion protein that traffics endonuclease III (Exscien1-III) and repairs mtDNA in the setting of pressure overload heart failure. Methods: Male C57/BL6J mice (n=10) were subjected to transverse aortic constriction (TAC; 27 g needle) and Exscien1-III (4 mg/kg/d, i.p.) or VEH were administered daily starting at 3 wks post TAC. Left ventricular (LV) function (Vevo 2100) was assessed at baseline and biweekly for 12 weeks post TAC. At the 12 wk endpoint, mice were sacrificed and hearts were collected for biochemical and molecular assessment of cellular injury. Results: Exscien1-III significantly attenuated TAC-induced LV dilation at 12 wks post TAC (LVEDD: 3.9 ± 0.1 vs. 4.6 ± 0.1 mm, p &lt; 0.05; LVESD: 3.1 ± 0.2 vs. 3.9 ± 0.1 mm, p &lt; 0.05) compared to VEH. Exscien1-III displayed a reduced LV wall thickness (LVPWd: 1.1 ± 0.1 vs. 1.4 ± 0.1 mm, p &lt; 0.05) at 8 wks post TAC compared to VEH. In comparison to VEH, LV ejection fraction (LVEF) was preserved in the Exscien1-III treated mice at 8-12 weeks post TAC compared to VEH (*p &lt; 0.05; **p &lt; 0.01). Treatment with Exscien1-III resulted in a reduction in heart weights (9.7 ± 0.4 vs. 12.15 ± 1.2 mg/mm, p &lt; 0.05) compared to VEH. Picrosirius Red staining of LV collagen revealed that Exscien1-III significantly decreased myocardial interstitial collagen volume fraction by 55% (p &lt; 0.05 vs. VEH). Conclusion: Delayed treatment with Exscien1-III attenuated interstitial myocardial collagen deposition and preserved LVEF following the onset of TAC-induced cardiac hypertrophy and heart failure. Current studies are underway to further investigate the mechanisms by which this novel mtDNA repair enzyme protects the failing heart.

TVP1022

The current cornerstone treatment of myocardial infarction (MI) is restoration of coronary blood flow by means of thrombolytic therapy or primary percutaneous coronary intervention. However, reperfusion of ischemic myocardium can actually provoke tissue damage, defined as "ischemia-reperfusion (I/R) injury." TVP1022 [the S-isomer of rasagiline (Azilect), FDA-approved anti-Parkinson's drug] was found to exert cardioprotective activities against various cardiac insults, such as chronic heart failure and I/R, in rat models. Therefore, we tested the hypothesis that TVP1022 will provide cardioprotection against I/R injury and post-MI remodeling in a pig model. For inducing MI, we used an I/R model of midleft anterior descending artery occlusion for 90 minutes followed by follow-up for 8 weeks in 18 farm pigs (9 pigs in each group, MI + TVP1022 or MI + Vehicle). Echocardiographic measurements were performed and cardiac scar size was calculated using histopathological methods. For fibrosis evaluation, we measured the interstitial collagen volume fraction in the remote noninfarcted tissue. TVP1022 administration significantly decreased cardiac scar size, attenuated left ventricular dilation, and improved cardiac function assessed by segmental circumferential strain analysis. Furthermore, TVP1022 significantly reduced myocardial fibrosis 8 weeks post-MI. Collectively, these findings indicate that TVP1022 provides prominent cardioprotection against I/R injury and post-MI remodeling in this I/R pig model.

Sang-qi Granula Reduces Blood Pressure and Myocardial Fibrosis by Suppressing Inflammatory Responses Associated with the Peroxisome Proliferator-Activated Receptors and Nuclear FactorκB Protein in Spontaneously Hypertensive Rats

Aim. Sang-qi Granula (SQ) is a compound prepared from Chinese herbs and is currently used for treatment of hypertension in China. Given its protective effects on cardial function in decreasing blood pressure, we investigated the mechanism of protective effects of SQ on myocardium. Methods. 16 male normal Wistar-Kyoto rats and 16 spontaneous hypertension rats (SHR) were employed without medical treatment. 16 SHR were employed with SQ treatment. Rats in each group were sacrificed at two time points (8-week treatment and 16-week treatment). Blood pressure (BP), and heart weight/body weight (HW/BW) were measured. The expression of myeloperoxidase (MCP-1), ICAM-1, TNF-α, and CD68-positive cells was assessed. The interstitial collagen volume fraction (CVF), perivascular collagen volume area (PVCA), and the expression of TGF-β, Smad-3, PPARα, γ, and NF-κB (P65 and P50) were observed. Results. SQ significantly inhibited the elevation of the blood pressure and HW/BW of SHR. Next, SQ prevented myocardial fibrosis. Finally, a proinflammatory mediator associated with NF-κB (TNF-α, ICAM-1, MCP-1, CD68), TGF-β, and Smad-3 related to collagen deposition, which is upregulated in SHR group, was significantly suppressed by SQ. Expression of NF-κB was decreased in SHQ+SQ group compared to PPARα, and γ expression was increased by SQ. Conclusion. Treatment with SQ ameliorates cardial fibrosis induced by hypertension by attenuating the upregulation of ICAM-1, TNF-α, MCP-1, TGF-β, Smad-3, P65, and P50 expression and improving PPARα and PPARγ expression level. The results suggest that SQ may be an option for preventing cardial fibrosis through PPAR signalling pathway.

The Role of Erythropoietin Upon Myocardial Fibrosis

IntroductionRegarding the process of myocardial remodeling occurs myocyte hypertrophy and inappropriate collagen deposition in the interstitium developing an overall process of structural and geometric remodeling of the heart. Erythropoietin (EPO) has been studied because exerts cardioprotective effects including inflammatory and oxidative stress modulation.HypothesisThe aim of this study was to assess the role of EPO upon structural, geometric and functional remodeling.Materials and Methods75 Wistar rats were divided into 5 groups: Control, Control+EPO, Sham, Infarcted, Infarcted+EPO. Interstitial collagen volume fraction in the left (LV-ICVF) and right ventricle (RV-ICVF) was quantified by videomorphometry using a Quantimet 520 Image Analyses System (LEICA Microsystems). The analyzed echocardiographic parameters were the left ventricle ejection fraction (LVEF) and diastolic diameter (LVDD, cm).ResultsLV-ICVF (%) was greater in the infarcted groups compared to controls (p<0.001), and attenuated by EPO (p<0.001, MI vs MI+EPO) (CT= 0.76±0.21; CT+EPO= 0.63±0.15; MI+EPO= 1.43±0.92; MI= 3.47±2.5 and Sham= 0.37±0.04). The RV-ICVF (%) was also greater in the infarcted groups compared to controls (CT=0.60±0.2; CT+EPO= 0.83±0.3; MI+EPO= 1.01±0.55; IAM= 1.60±1.15 and Sham= 0.53±0.11) (p<0.001) but without statistical difference between MI vs MI+EPO. The infarcted groups had a worsening ejection fraction compared to controls (CT= 81%±6.5; CT+EPO=77%±5; MI+EPO= 40%±12 and MI= 38%±11.5) (p<0,001) but without EPO protection. The infarcted groups also showed increased LV dilation (p<0.001) (CT= 0.73±0.06; CT+EPO= 0.74±0.05; MI+EPO= 0.81±0.09; MI= 0.87±0.11) without EPO attenuation.ConclusionsEPO significantly attenuated the accumulation of interstitial collagen, but it did not reflected in the protection of the heart dilation or dysfunction in this model.Grant Fapesp: 2010/06834-2 IntroductionRegarding the process of myocardial remodeling occurs myocyte hypertrophy and inappropriate collagen deposition in the interstitium developing an overall process of structural and geometric remodeling of the heart. Erythropoietin (EPO) has been studied because exerts cardioprotective effects including inflammatory and oxidative stress modulation. Regarding the process of myocardial remodeling occurs myocyte hypertrophy and inappropriate collagen deposition in the interstitium developing an overall process of structural and geometric remodeling of the heart. Erythropoietin (EPO) has been studied because exerts cardioprotective effects including inflammatory and oxidative stress modulation. HypothesisThe aim of this study was to assess the role of EPO upon structural, geometric and functional remodeling. The aim of this study was to assess the role of EPO upon structural, geometric and functional remodeling. Materials and Methods75 Wistar rats were divided into 5 groups: Control, Control+EPO, Sham, Infarcted, Infarcted+EPO. Interstitial collagen volume fraction in the left (LV-ICVF) and right ventricle (RV-ICVF) was quantified by videomorphometry using a Quantimet 520 Image Analyses System (LEICA Microsystems). The analyzed echocardiographic parameters were the left ventricle ejection fraction (LVEF) and diastolic diameter (LVDD, cm). 75 Wistar rats were divided into 5 groups: Control, Control+EPO, Sham, Infarcted, Infarcted+EPO. Interstitial collagen volume fraction in the left (LV-ICVF) and right ventricle (RV-ICVF) was quantified by videomorphometry using a Quantimet 520 Image Analyses System (LEICA Microsystems). The analyzed echocardiographic parameters were the left ventricle ejection fraction (LVEF) and diastolic diameter (LVDD, cm). ResultsLV-ICVF (%) was greater in the infarcted groups compared to controls (p<0.001), and attenuated by EPO (p<0.001, MI vs MI+EPO) (CT= 0.76±0.21; CT+EPO= 0.63±0.15; MI+EPO= 1.43±0.92; MI= 3.47±2.5 and Sham= 0.37±0.04). The RV-ICVF (%) was also greater in the infarcted groups compared to controls (CT=0.60±0.2; CT+EPO= 0.83±0.3; MI+EPO= 1.01±0.55; IAM= 1.60±1.15 and Sham= 0.53±0.11) (p<0.001) but without statistical difference between MI vs MI+EPO. The infarcted groups had a worsening ejection fraction compared to controls (CT= 81%±6.5; CT+EPO=77%±5; MI+EPO= 40%±12 and MI= 38%±11.5) (p<0,001) but without EPO protection. The infarcted groups also showed increased LV dilation (p<0.001) (CT= 0.73±0.06; CT+EPO= 0.74±0.05; MI+EPO= 0.81±0.09; MI= 0.87±0.11) without EPO attenuation. LV-ICVF (%) was greater in the infarcted groups compared to controls (p<0.001), and attenuated by EPO (p<0.001, MI vs MI+EPO) (CT= 0.76±0.21; CT+EPO= 0.63±0.15; MI+EPO= 1.43±0.92; MI= 3.47±2.5 and Sham= 0.37±0.04). The RV-ICVF (%) was also greater in the infarcted groups compared to controls (CT=0.60±0.2; CT+EPO= 0.83±0.3; MI+EPO= 1.01±0.55; IAM= 1.60±1.15 and Sham= 0.53±0.11) (p<0.001) but without statistical difference between MI vs MI+EPO. The infarcted groups had a worsening ejection fraction compared to controls (CT= 81%±6.5; CT+EPO=77%±5; MI+EPO= 40%±12 and MI= 38%±11.5) (p<0,001) but without EPO protection. The infarcted groups also showed increased LV dilation (p<0.001) (CT= 0.73±0.06; CT+EPO= 0.74±0.05; MI+EPO= 0.81±0.09; MI= 0.87±0.11) without EPO attenuation. ConclusionsEPO significantly attenuated the accumulation of interstitial collagen, but it did not reflected in the protection of the heart dilation or dysfunction in this model.Grant Fapesp: 2010/06834-2 EPO significantly attenuated the accumulation of interstitial collagen, but it did not reflected in the protection of the heart dilation or dysfunction in this model.

Effect of Colchicine on Myocardial Injury Induced by Trypanosoma cruzi in Experimental Chagas Disease

BackgroundThe hallmark of Chagas disease (CD) is multifocal myocarditis and extensive fibrosis. We investigated the potential effect of colchicine on myocardial remodeling in experimental CD. Methods and ResultsOne hundred Syrian hamsters were randomly divided into noninfected untreated control (CG), noninfected control treated with colchicine (COLG 0.4 mg kg−1 d−1 by gavage), infected (IG), and infected treated with colchicine (ICOLG, 0.4 mg kg−1 d−1) groups. The interstitial collagen volume fraction (ICVF) was evaluated by videomorphometry with picrosirius red staining. The gelatinolytic activities of matrix metalloproteinase (MMP) 2 were examined with the use of zymography. Myocarditis was described according to the Dallas criteria. Statistical comparisons were performed with parametric analysis of variance and Tukey test. ICVF (%) accumulation was attenuated in infected colchicine-treated animals in the left (CG 0.81 ± 0.13, COLG 0.85 ± 0.13, IG: 1.35 ± 0.31,* ICOLG 1.06 ± 0.19; *P < .05 compared with ICOLG) and right ventricles (CG 1.4 ± 0.36, COLG 1.26 ± 0.14, IG 1.97 ± 0.058,* ICOLG: 1.52 ± 0.23; *P < .05 compared with ICOLG). A significant increase in MMP-2 enzymatic activity (UA) was observed in ICOLG (17,432.8*) compared with GC (3731.6), COLG (2,792.6), and IG (4,286.3; *P < .001). In IG, 66% of animals had myocarditis compared with only 49% in ICOLG. ConclusionsColchicine had a protective effect on myocardium, indicated by decreased interstitial myocardial fibrosis, increased intensity of MMP-2, and attenuated myocardial inflammation.

P029 * Brain natriuretic peptide as a predictor of volume overload in childrenwith congenital cardiac shunt lesion

P029 * Brain natriuretic peptide as a predictor of volume overload in childrenwith congenital cardiac shunt lesion

Early but not late insulin treatment improves left ventricular remodelling and cardiac function induced by myocardial infarction in rats

ObjectivesInsulin exerts significant cardioprotective effects in acute myocardial ischaemia/reperfusion (MI/R) through the PI3K-Akt signalling. The present study was aimed at investigating the effect of insulin treatment on the prolonged postischemic...

The impact of right ventricular myocardial remodeling on ventricular function in patients with tetralogy of Fallot

ObjectiveThe purpose of this study was to assess the impact of right ventricular (RV) myocardial histopathologic changes on ventricular function in patients with Tetralogy of Fallot (TOF).MethodsOperatively resected crista supraventricularis...

Tobacco Smoke Induces Ventricular Remodeling Associated with an Increase in NADPH Oxidase Activity

Background: Recent studies have assessed the direct effects of smoking on cardiac remodeling and function. However, the mechanisms of these alterations remain unknown. The aim of this study was to investigate de role of cardiac NADPH oxidase and antioxidant enzyme system on ventricular remodeling induced by tobacco smoke. Methods: Male Wistar rats that weighed 200-230 g were divided into a control group (C) and an experimental group that was exposed to tobacco smoke for a period of two months (ETS). After the two-month exposure period, morphological, biochemical and functional analyses were performed. Results: The myocyte cross-sectional area and left ventricle end-diastolic dimension was increased 16.2% and 33.7%, respectively, in the ETS group. The interstitial collagen volume fraction was also higher in ETS group compared to the controls. In addition to these morphological changes, the ejection fraction and fractional shortening were decreased in the ETS group. Importantly, these alterations were related to augmented heart oxidative stress, which was characterized by an increase in NADPH oxidase activity, increased levels of lipid hydroperoxide and depletion of antioxidant enzymes (e.g., catalase, superoxide dismutase and glutathione peroxidase). In addition, cardiac levels of IFN-γ, TNF-α and IL-10 were not different between the groups. Conclusion: Cardiac alterations that are induced by smoking are associated with increased NADPH oxidase activity, suggesting that this pathway plays a role in the ventricular remodeling induced by exposure to tobacco smoke.

Influence of different doses of retinoic acid on cardiac remodeling

Objective The role of retinoic acid in promoting postnatal heart alterations is still unclear. The aim of this study was to evaluate whether the cardiac alterations caused by all-trans- retinoic acid (ATRA) in normal adult rat hearts are physiologic or pathologic and if these alterations are dose-dependent. Methods Rats were allocated into a control group that received a diet without ATRA ( n = 16), a group that received 0.3 mg of ATRA/kg of diet ( n = 17), a group that received a diet containing 10 mg of ATRA/kg ( n = 18), or a group that received 50 mg of ATRA/kg in the diet ( n = 18). After 4 wk, the animals were evaluated echocardiographically, morphologically, and biochemically. Results The 50-mg ATRA group presented cardiac hypertrophy with maintenance of cardiac geometry and increased systolic function, whereas diastolic function was similar to that of the control group. In addition, progressive increases in the ATRA dose resulted in gradual augmentations of left atrial diameter, left ventricular diastolic and systolic diameters, left ventricular mass index, cardiac output, cardiac index, and aortic velocity. The ATRA did not produce alterations in interferon-γ and tumor necrosis factor-α cardiac levels, interstitial collagen volume fraction, or the intensity and localization of connexin-43. In addition, no alteration was observed in β-hydroxyacyl coenzyme A dehydrogenase, lactate dehydrogenase, or citrate synthase, suggesting that cardiac energetic metabolism was preserved with ATRA. Conclusion These results suggest that ATRA produced dose-dependent effects and cardiac remodeling that is more compatible with a physiologic response.

Interleukin 6 Mediates Myocardial Fibrosis, Concentric Hypertrophy, and Diastolic Dysfunction in Rats

Although there is a correlation between hypertension and levels of interleukin (IL) 6, the exact role this cytokine plays in myocardial remodeling is unknown. This is complicated by the variable tissue and circulating levels of IL-6 reported in numerous experimental models of hypertension. Accordingly, we explored the hypothesis that elevated levels of IL-6 mediate adverse myocardial remodeling. To this end, adult male Sprague-Dawley rats were infused with IL-6 (2.5 microg . kg(-1) . h(-1), IP) for 7 days via osmotic minipump and compared with vehicle-infused, aged-matched controls. Left ventricular function was evaluated using a blood-perfused isolated heart preparation. Myocardial interstitial collagen volume fraction and isolated cardiomyocyte size were also assessed. Isolated adult cardiac fibroblast experiments were performed to determine the importance of the soluble IL-6 receptor in mediating cardiac fibrosis. IL-6 infusions in vivo resulted in concentric left ventricular hypertrophy, increased ventricular stiffness, a marked increase in collagen volume fraction (6.2% versus 1.7%; P<0.001), and proportional increases in cardiomyocyte width and length, all independent of blood pressure. The soluble IL-6 receptor in combination with IL-6 was found to be essential to producing increased collagen concentration by isolated cardiac fibroblasts and also played a role in mediating a phenotypic conversion to myofibroblasts. These novel observations demonstrate that IL-6 induces a myocardial phenotype almost identical to that of the hypertensive heart, identifying IL-6 as potentially important in this remodeling process.

Inhibition of matrix metalloproteinase activity prevents increases in myocardial tumor necrosis factor-α

TNF-α is known to cause adverse myocardial remodeling. While we have previously shown a role for cardiac mast cells in mediating increases in myocardial TNF-α, however, matrix metalloproteinase (MMP) activation of TNF-α may also be contributory. We sought to determine the relative roles of MMPs and cardiac mast cells in the activation of TNF-α in the hearts of rats subjected to chronic volume overload. Interventions with the broad spectrum MMP inhibitor, GM6001, or the mast cell stabilizer, nedocromil, were performed in the rat aortocaval fistula (ACF) model of volume overload. Myocardial TNF-α levels were significantly increased in the ACF. This increase was prevented by MMP inhibition with GM6001 (p≤0.001 vs. ACF). Conversely, myocardial TNF-α levels were increased in the ACF+nedocromil treated fistula groups (p≤0.001 vs. sham). The degradation of interstitial collagen volume fraction seen in the untreated ACF group was prevented in both the GM6001 and nedocromil treated hearts. Significant increases in LV myocardial ET-1 levels also occurred in the ACF group at 3days post-fistula. Whereas administration of GM6001 significantly attenuated this increase, mast cell stabilization with nedocromil markedly exacerbated the increase, producing ET-1 levels 6.5 fold and 2 fold greater than that in the sham-operated control and ACF group, respectively. The efficacy of the MMP inhibitor, GM6001, to prevent increased levels of myocardial TNF-α is indicative of MMP-mediated cleavage of latent extracellular membrane-bound TNF-α protein as the primary source of bioactive TNF-α in the myocardium of the volume overload heart.