Effects of AT1 receptor blockade after myocardial infarct on myocardial fibrosis, stiffness, and contractility

1999 ◽  
Vol 276 (3) ◽  
pp. H873-H880 ◽  
Author(s):  
Hoang M. Thai ◽  
Hohai T. Van ◽  
Mohamed A. Gaballa ◽  
Steven Goldman ◽  
Thomas E. Raya
Keyword(s):  
Myocardial Fibrosis ◽  
Diastolic Pressure ◽  
Interstitial Fibrosis ◽  
Myocardial Infarct ◽  
Left Ventricular ◽  
Receptor Blockade ◽  
Myocardial Stiffness ◽  
Abnormal Increase ◽  
Myocardial Collagen

Angiotensin II type 1 (AT1) receptor blockade attenuates myocardial fibrosis after myocardial infarction (MI). However, whether inhibition of fibrosis by AT1 receptor blockade influences myocardial stiffness and contractility is unknown. We measured left ventricular (LV) hemodynamics, papillary muscle function, and myocardial stiffness and fibrosis in rats randomized to losartan or placebo 1 day after MI and treated subsequently for 8 wk. Losartan decreased LV and right ventricular weights as well as mean aortic and LV systolic pressures in sham and MI rats. LV end-diastolic pressure increased after MI and was decreased with losartan. Maximal developed tension and peak rate of tension rise and decline were decreased in MI vs. sham rats. Interstitial fibrosis developed after MI and was prevented in losartan-treated MI rats. The development of abnormal myocardial stiffness after MI was prevented by losartan. After MI, AT1 receptor blockade prevents an abnormal increase in myocardial collagen content. This effect was associated with a normalization of passive myocardial stiffness.

Tenascin-C may aggravate left ventricular remodeling and function after myocardial infarction in mice

2010 ◽  
Vol 298 (3) ◽  
pp. H1072-H1078 ◽  
Author(s):  
Tomohiro Nishioka ◽  
Katsuya Onishi ◽  
Naoshi Shimojo ◽  
Yuka Nagano ◽  
Hidenori Matsusaka ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Ventricular Remodeling ◽  
Diastolic Pressure ◽  
Interstitial Fibrosis ◽  
Left Ventricular Remodeling ◽  
Left Ventricular ◽  
High Serum ◽  
Border Zone ◽  
Myocardial Stiffness ◽  
Tenascin C

Tenascin-C (TN-C) is an extracellular matrix glycoprotein with high bioactivity. It is expressed at low levels in normal adult heart, but upregulated under pathological conditions, such as myocardial infarction (MI). Recently, we (Ref. 34 ) reported that MI patients with high serum levels of TN-C have a greater incidence of maladaptive cardiac remodeling and a worse prognosis. We hypothesized that TN-C may aggravate left ventricular remodeling. To examine the effects of TN-C, MI was induced by ligating coronary arteries of TN-C knockout (KO) mice under anesthesia and comparing them with sibling wild-type (WT) mice. In WT+MI mice, TN-C expression was upregulated at day 1, peaked at day 5, downregulated and disappeared by day 28, and the molecule was localized in the border zone between intact myocardium and infarct lesions. The morphometrically determined infarct size and survival rate on day 28 were comparable between the WT+MI and KO+MI groups. Echocardiography and hemodynamic analyses demonstrated left ventricular end-diastolic diameter, myocardial stiffness, and left ventricular end-diastolic pressure to be significantly increased in both WT+MI and KO+MI mice compared with sham-operated mice. However, end-diastolic pressure and dimension and myocardial stiffness of KO+MI were lower than those of the WT+MI mice. Histological examination revealed normal tissue healing, but interstitial fibrosis in the residual myocardium in peri-infarcted areas was significantly less pronounced in KO+MI mice than in WT+MI mice. TN-C may thus accelerate adverse ventricular remodeling, cardiac failure, and fibrosis in the residual myocardium after MI.

Abstract 370: Type 2 Diabetes Is Associated with the Exacerbation of Heart Failure via Increasing Myocardial NAD(P)H Oxidase-Derived Superoxide Production

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Shintaro Kinugawa ◽  
Shouji Matsushima ◽  
Takashi Yokota ◽  
Yukihiro Ohta ◽  
Naoki Inoue ◽  
...  
Keyword(s):  
Heart Failure ◽  
Type 2 Diabetes ◽  
Diastolic Pressure ◽  
Interstitial Fibrosis ◽  
Left Ventricular ◽  
Lung Weight ◽  
Tissue Mass ◽  
Tibial Length ◽  
Lv Remodeling

Type 2 diabetes mellitus (DM) adversely affects the outcomes in patients with myocardial infarction (MI), which is associated with the development of left ventricular (LV) remodeling and failure. NAD(P)H oxidase-derived superoxide (O 2 − ) production is increased in DM. However, its pathophysiological significance in advanced post-MI LV failure associated with DM remains unestablished. We thus determined whether an inhibitor of NAD(P)H oxidase activation, apocynin, could attenuate the exacerbated LV remodeling and heart failure after MI in high-fat diet (HFD)-induced obese mice with DM. Male C57BL/6J mice were fed on either HFD or normal diet (ND) for 8 weeks. At 4 weeks of feeding, MI was created in all mice by ligating left coronary artery. MI mice were treated with either apocynin (10 mmol/l in drinking water; n = 10 for ND and n = 11 for HFD) or vehicle (n = 15 for ND and n = 13 for HFD). HFD significantly increased body weight (BW), adipose tissue mass, fasting plasma glucose and insulin levels compared to ND after 4 and 8 weeks. HFD + MI had significantly greater LV end-diastolic diameter (LVEDD; 5.7 ± 0.1 vs. 5.3 ± 0.2 mm) by echocardiography, end-diastolic pressure (EDP; 12 ± 2 vs. 8 ± 1 mmHg) and lung weight/tibial length (10.1 ± 0.3 vs. 8.7 ± 0.7 mg/mm) than ND + MI, which was accompanied by an increased interstitial fibrosis of non-infarcted LV. Treatment of HFD + MI with apocynin significantly decreased LVEDD (5.4 ± 0.1 mm), LVEDP (9.7 ± 0.8 mmHg), lung weight/tibial length (9.0 ± 0.3 mg/mm), and concomitantly interstitial fibrosis of non-infarcted LV to ND + MI level without affecting BW, glucose metabolism, infarct size and aortic pressure. On the other hand, treatment of ND + MI with apocynin did not affect LV remodeling and failure. NAD(P)H oxidase activity, O 2 − production measured by lucigenin chemiluminescence, and thiobarbituric acid-reactive substances were increased in non-infarcted LV tissues from HFD + MI, all of which were also attenuated by apocynin to ND + MI level. Type 2 DM was associated with the exacerbation of LV remodeling and failure after MI via increasing NAD(P)H oxidase derived O 2 − production, which may be a novel important therapeutic target in advanced heart failure with DM.

Abstract 4370: Intramyocardial Administration of Erythropoietin Promotes Cell Proliferation, Induces Early Angiogenesis and Attenuates Cardiac Remodeling

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Ralf Gäbel ◽  
Christian Klopsch ◽  
Dario Furlani ◽  
Wenzhong Li ◽  
Can Yerebakan ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Peripheral Blood ◽  
Diastolic Pressure ◽  
Troponin T ◽  
Interstitial Fibrosis ◽  
Capillary Density ◽  
Left Ventricular ◽  
Border Zone ◽  
Ki 67 ◽  
Ventricular Performance

Erythropoietin (EPO) protects the ischemic myocardium from heart failure development after myocardial infarction (MI). However, little is known about its intracardiac cell proliferation and early angiogenesis. We hypothesize that EPO may contribute to cell proliferation, angiogenesis and eventually induce a beneficial remodeling process. Following permanent LAD ligation in rats, EPO (3000 U/kg; n=99) or saline (n=95) was delivered along the infarction border. In control animals without MI (n=55) saline was injected intramyocardially. After 6 weeks follow-up, left ventricle was catheterized and analyzed for cardiac performance. The level of eNOS mRNA was dramatically increased 9.3 fold in non-infarcted area of EPO treated rats at 24 h detected by real time PCR and confirmed by immunohistology. We found a 45 % enhancement in Ki-67+ cell numbers near the infarction at 48 h after EPO treatment (n=6, P<0.001). Hematopoietic cell lineages including c-Kit+ and CD34+ cells were augmented in the peripheral blood after 48h. Capillary density was enhanced by 17% as early as 1 week (n=6, P<0.001). Myocyte apoptosis was reduced by 41% and 37% at border zone after 1 and 6 weeks (n=6, P<0.05). Cardiac troponin T level, a highly sensitive and specific indicator of myocardial cell death, was significantly reduced in peripheral blood 2 weeks after EPO injection (n=5, P<0.05). Cardiomyocyte size and interstitial fibrosis at 6 weeks were decrease by 13% and 23% (n=6, P=0.015, P<0.001). Intramyocardial EPO delivery enhanced left ventricular performance at baseline and Dobutamine stress conditions compared with MI rats (cardiac output: 65% and 71% increase at baseline and stress; end-diastolic pressure: 51% and 53% reduction respectively, n=11–14, P<0.05). To conclude, intramyocardial EPO delivery induces early cell poliferation, angiogenesis and attenuates post MI remodeling.

Abstract 15921: Correlation Between Repolarization Changes in Signal Averaged Electrocardiography and Myocardial Fibrosis in Adults With Hypertrophic Cardiomyopathy

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Ramses Ramirez Damera ◽  
Hernan L Vera-Sarmiento ◽  
David Hurtado-de-Mendoza ◽  
Ketty Dolores-Cerna ◽  
Muhammad I Khan ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Myocardial Fibrosis ◽  
Ventricular Arrhythmias ◽  
Interstitial Fibrosis ◽  
Objective Assessment ◽  
Left Ventricular ◽  
Noninvasive Technique ◽  
Arrhythmogenic Substrate ◽  
Study Results ◽  
Replacement Fibrosis

Introduction: Hypertrophic Cardiomyopathy (HCM) is known as one of the most common causes of sudden cardiac death. Its propensity to lethal arrhythmias is a result of myocardial remodeling leading to aberrant conduction and increased reentrant electrical activity. Previous studies suggest an association between the amount of myocardial fibrosis found on Cardiac Magnetic Resonance (CMR) and the risk of these ventricular arrhythmias. Signal Average Electrocardiography ( SAECG) is a noninvasive technique used to detect subtle conduction abnormalities that can be missed on standard Electrocardiography ( ECG ). Hypothesis: Non-uniform conduction through fibrotic tissue seen in CMR leads to unsynchronized myocardial depolarization which correlates with further repolarization abnormalities that can be detected by SAECG. Method: In this retrospective study, results of SAECG were used to classify 73 HCM patients into Normal or Abnormal groups based on the presence of two or more of three predetermined criteria (fQRS, RMS40, LAS40). Replacement fibrosis was assessed by measuring late gadolinium enhancement (LGE) . Interstitial fibrosis was assessed by measuring T1 relaxation times, using the Look-Locker sequence. Results: A statistically significant association between the presence of myocardial fibrosis on CMR and abnormal SAECG was found with a difference of proportions of 41.3% between the subgroups. Left ventricular mass index was found to be significantly higher in the abnormal subgroup (Normal: 61.2 ± 19.6; Abnormal: 82.4 ± 37.1; p = <0.003, CI 95% [2.93; 39.47]). The presence of T wave inversions on standard ECG was only seen in those who had an abnormal SAECG exam. Conclusion: Abnormal SAECG in patients with HCM is associated with the presence of LGE on CMR. This study showed a subset of patients with absence of LGE despite having abnormal SAECG, which implies that there are other complex mechanisms besides replacement fibrosis, that predisposes this population to ventricular arrhythmias. This can also be highlighted by the fact that there was no difference between the two groups in the T1 mapping time. We believe that SAECG could be an objective assessment of the arrhythmogenic substrate present in patients with HCM.

scholarly journals Ginsenoside Re Improves Isoproterenol-Induced Myocardial Fibrosis and Heart Failure in Rats

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Quan-wei Wang ◽  
Xiao-feng Yu ◽  
Hua-li Xu ◽  
Xue-zhong Zhao ◽  
Da-yuan Sui
Keyword(s):  
Heart Failure ◽  
Myocardial Fibrosis ◽  
Group Treatment ◽  
Transforming Growth Factor ◽  
Diastolic Pressure ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Heart Weight ◽  
Hydroxyproline Content ◽  
Ginsenoside Re

Objective. Panax ginseng is used widely for treatment of cardiovascular disorders in China. Ginsenoside Re is the main chemical component of P. ginseng. We aimed to investigate the protective effect of ginsenoside Re on isoproterenol-induced myocardial fibrosis and heart failure in rats. Methods. A model of myocardial fibrosis and heart failure was established by once-daily subcutaneous injection of isoproterenol (5 mg/kg/day) to rats for 7 days. Simultaneously, rats were orally administrated ginsenoside Re (5 or 20 mg/kg) or vehicle daily for 4 weeks. Results. Isoproterenol enhanced the heart weight, myocardial fibrosis, and hydroxyproline content in rat hearts. Ginsenoside Re inhibited (at least in part) the isoproterenol-induced increase in heart weight, myocardial fibrosis, and hydroxyproline content. Compared with the isoproterenol group, treatment with ginsenoside Re ameliorated changes in left ventricular systolic pressure, left ventricular end diastolic pressure, and the positive and negative maximal values of the first derivative of left ventricular pressure. Ginsenoside Re administration also resulted in decreased expression of transforming growth factor (TGF)-β1 in serum and decreased expression of Smad3 and collagen I in heart tissue. Conclusion. Ginsenoside Re can improve isoproterenol-induced myocardial fibrosis and heart failure by regulation of the TGF-β1/Smad3 pathway.

A neutralizing leptin receptor antibody mitigates hypertrophy and hemodynamic dysfunction in the postinfarcted rat heart

2008 ◽  
Vol 295 (1) ◽  
pp. H441-H446 ◽  
Author(s):  
Daniel M. Purdham ◽  
Venkatesh Rajapurohitam ◽  
Asad Zeidan ◽  
Cathy Huang ◽  
Garrett J. Gross ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Leptin Receptor ◽  
Diastolic Pressure ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Receptor Blockade ◽  
Receptor Antibody ◽  
Postinfarction Remodeling

The 16 kDa adipokine leptin has been shown to exert direct hypertrophic effects on cultured cardiomyocytes although its role as an endogenous contributor to postinfarction remodeling and heart failure has not been determined. We therefore investigated the effect of leptin receptor blockade in vivo on hemodynamic function and cardiac hypertrophy following coronary artery ligation (CAL). Cardiac function and biochemical parameters were measured in rats subjected to 7 or 28 days of left main CAL in the presence and absence of a leptin receptor antibody. Animals subjected to an identical treatment in which the artery was not tied served as sham-operated controls. CAL produced myocardial hypertrophy, which was most pronounced 28 days postinfarction as demonstrated by increases in both left ventricular weight-to-body weight ratio and atrial natriuretic peptide gene expression, both of which were abrogated by leptin receptor antagonism. Leptin receptor blockade also significantly improved left ventricular systolic function, attenuated the increased left ventricular end-diastolic pressure, and reduced the expression of genes associated with extracellular matrix remodeling 28 days following CAL. In conclusion, the ability of a leptin receptor-neutralizing antibody to improve cardiac function offers evidence that endogenous leptin contributes to cardiac hypertrophy following CAL. The possibility exists that targeting the myocardial leptin receptor represents a viable and novel approach toward attenuating postinfarction remodeling.

P4351Validation by cardiac catheterization of noninvasive evaluation of left ventricular chamber and myocardial stiffness as a diastolic function using speckle tracking echocardiography

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
T Yoshizane ◽  
R Tanaka ◽  
M Kawasaki ◽  
M Otsuka ◽  
T Shoji ◽  
...  
Keyword(s):  
Diastolic Function ◽  
Cardiac Catheterization ◽  
Left Atrial ◽  
Speckle Tracking ◽  
Speckle Tracking Echocardiography ◽  
Diastolic Pressure ◽  
Hypertensive Heart Disease ◽  
Left Ventricular ◽  
Minimum Volume ◽  
Myocardial Stiffness

Abstract Background Left ventricular (LV) diastolic function is mainly composed of LV relaxation and LV stiffness. We reported that pulmonary capillary wedge pressure (ePCWP) and LV relaxation assessed by Tau (eTau) are noninvasively evaluated by speckle tracking echocardiography (STE). The minimum LV diastolic pressure (mLVP) was reported to have a strong correlation with Tau. Therefore, LV chamber stiffness (c-stiffness) may be assessed with the use of two LV diastolic pressure-volume coordinates: the mLVP and volume and the end-diastolic pressure (EDP) and volume. Purpose We sought to noninvasively assess LV stiffness using STE and validate the value by cardiac catheterization. Methods Echocardiography and catheterization were performed in 124 patients (age 72±8) (70 angina pectoris, 20 prior myocardial infarction, 19 hypertensive heart disease, 11 congestive heart failure and 4 paroxysmal atrial fibrillation). The ePCWP (mmHg) is noninvasively obtained as 10.8 − 12.4 × Log (left atrial active emptying function/minimum volume) and the eTau (ms) is obtained as isovolumic relaxation time/(ln 0.9 × systolic blood pressure − ln ePCWP) as previously reported. The mLVP (e-mLVP) was estimate using Tau. The estimated EDP (e-EDP) was calculated as 12.3 − 10.1 × Log (left atrial active emptying function / minimum volume). LV c-stiffness (mmHg/ml) was calculated as LV pressure change (from mLVP to EDP) obtained by catheterization divided by LV volume change during diastole which equals to stroke volume by echocardiography. Estimated c-stiffness (e-c-stiffness) was noninvasively obtained using e-mLVP and e-EDP. Furthermore, LV myocardial stiffness (m-stiffness) was calculated by LVED stress / LV longitudinal strain by STE, where LV stress (kdynes/cm2) was calculated as 0.334 × pressure × dimension / [thickness (1 + thickness/dimension)]. The estimated m-stiffness (e-m-stiffness) was calculated using e-EDP. Results The eTau and e-EDP estimated by STE had a good correlation with Tau and EDP invasively obtained by catheterization (r=0.75 and 0.63, respectively, both p<0.001). There was a good correlation between Tau and mLVP (Tau = 2.06 mLVP + 33.7, r=0.70). The estimated LVED stress had good correlation with ED stress obtained by catheterization (r=0.77, p<0.001). The e-c-stiffness and e-m-stiffness had a good correlation with those obtained by catheterization (e-c-stiffness; 0.116±0.07 and c-stiffness; 0.115±0.06, r=0.603, e-m-stiffness; 0.81±0.41 and m-stiffness; 0.85±0.45, r=0.89, respectively). Bland-Altman analysis revealed a good agreement between e-c-stiffness and c-stiffness, and between e-m-stiffness and m-stiffness without fixed and proportional bias. Conclusion This study demonstrated that LV stiffness may be noninvasively assessed by STE with reasonable accuracy and may have utility and value in the routine clinical practice for the diagnosis and treatment in patients with diastolic dysfunction.

Coronary artery narrowing in rats: mechanical alterations of left and right myocardium

1991 ◽  
Vol 261 (6) ◽  
pp. H1802-H1810
Author(s):  
J. M. Capasso ◽  
P. Li ◽  
X. Zhang ◽  
P. Anversa
Keyword(s):  
Coronary Artery ◽  
Diastolic Pressure ◽  
Interstitial Fibrosis ◽  
Left Ventricular ◽  
Left Ventricular Wall ◽  
Ventricular Pressure ◽  
Ventricular Wall ◽  
Time To Peak ◽  
Muscle Shortening ◽  
Left And Right

To determine the effects of chronic coronary artery narrowing on myocardial contractile performance, nonocclusive constriction of the left coronary artery near its origin was surgically induced in rats and global cardiac hemodynamics, left and right myocardial mechanics, and the magnitude and distribution of tissue damage and interstitial fibrosis in the left ventricular wall were analyzed 1 mo later. Reductions in coronary artery luminal diameter of 55% resulted in left ventricular failure as characterized by decreases in systemic arterial pressures, systolic ventricular pressure, rise and decay in first derivative of left ventricular pressure (+/- dP/dt), and an increase in left ventricular end-diastolic pressure. Right side dysfunction was also present as documented by an elevation in right ventricular end-diastolic pressure and a reduction in -dP/dt. In vitro measurements of papillary muscle mechanics revealed a biventricular reduction in isometric developed tension and peak rates of tension rise and decay. Moreover, the kinetic parameters of isometric contraction duration, time to peak tension and time to one-half relaxation, were significantly shorter in left muscles from coronary artery-narrowed animals. Isotonically, peak muscle shortening was reduced in the left muscle, whereas time to peak shortening was prolonged in the right myocardium. In addition, the velocities of muscle shortening and relengthening were decreased in both ventricles. Foci of replacement fibrosis and diffuse interstitial fibrosis were found in the epimyocardium, midmyocardium, and endomyocardium, demonstrating that a significant amount of myocyte loss occurred throughout the left ventricular wall.(ABSTRACT TRUNCATED AT 250 WORDS)

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