Abstract 1342: The NF-kappaB P50 Subunit Protects Against Remodeling and Cardiac Dysfunction Following Myocardial Infarction

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Leo Timmers ◽  
J Karlijn van Keulen ◽  
Imo I Hoefer ◽  
Joost P Sluijter ◽  
Marie Jose Goumans ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Molecular Mechanisms ◽  
Interstitial Fibrosis ◽  
Systolic Dysfunction ◽  
Protective Role ◽  
Left Ventricular ◽  
Lv Remodeling ◽  
Nf Kappab

Introduction Left ventricular (LV) remodeling leads to congestive heart failure and is a main determinant of morbidity and mortality following myocardial infarction (MI). To further improve the treatment of post infarct LV remodeling, a better understanding of the molecular mechanisms involved in this complicated process is required. The nuclear factor (NF)- κB family (p50, p52, p65) usually forms dimers that regulate DNA transcription in response to a variety of stimuli including pro-inflammatory cytokines, oxidative stress and also ischemia. Inhibition of NF- κB has been shown to reduce heart failure following MI in rats. The specific role of the different NF- κB subunits during LV remodeling, however, has not been clarified thus far. In this study, we elucidate the role of the NF- κB p50 subunit in post infarct LV remodeling. Methods and Results MI was induced in wild type C57Bl6 mice and NF- κB p50 KO mice. Without affecting infarct size (45.4 ± 4.3 vs. 42.5 ± 4.6%; p=0.461), the absence of NF- κB p50 increased the extent of LV remodeling (EDV: 175 ± 13 vs. 107 ± 11 μl; p=0.005) and aggravated systolic dysfunction (LVEF: 16.1 ± 1.5 % vs. 24.7 ± 3.7%; p=0.045) 28 days following MI as assessed by magnetic resonance imaging (9.4 T). In the non-infarcted myocardium, interstitial fibrosis (1.53 ± 0.28 vs. 1.05 ± 0.15 grayvalue/μm 2 ; p=0.042) and hypertrophy (426 ± 51 vs. 251 ± 12 μm 2 /cardiomyocyte; p=0.018) were increased in NF-κB p50 KO mice. In the infarct area, however, collagen density was decreased (15.11 ± 1.16 vs. 27.28 ± 4.93 grayvalue/μm 2 ; p=0.028), which was accompanied by increased TNF-alpha mRNA expression (0.086 ± 0.04 vs. 0.026 ± 0.015; p=0.046) and increased MMP9 activity (0.31 ± 0.03 vs. 0.19 ± 0.03; p=0.049) Conclusion These data provide evidence for a protective role of NF- κB p50 in post infarct maladaptive LV remodeling, most likely by reducing inflammatory cytokine production and matrix degradation.

Abstract 15863: Macrophage Foxp1 is a Regulator of Pathologic Cardiac Hypertrophy

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Shuichi Yoneda ◽  
Saptarsi M Haldar ◽  
Jessica Jenkins ◽  
Yunmei Wang ◽  
Teruo Inoue ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Molecular Mechanisms ◽  
Interstitial Fibrosis ◽  
Systolic Dysfunction ◽  
Disease Process ◽  
Left Ventricular ◽  
Negative Regulator ◽  
Control Male ◽  
Pathologic Cardiac Hypertrophy

Introduction: Pathologic cardiac hypertrophy is a maladaptive response to neurohormonal and hemodynamic stress that is a hallmark of human heart failure. While inflammation has been implicated in pathologic hypertrophy, the molecular mechanisms underlying innate immune dysregulation in this disease process are incompletely defined. We have previously demonstrated that the forkhead transcription factor Foxp1 controls monocyte differentiation and suppresses inflammatory activation of macrophages. In this study, we hypothesized that monocyte/macrophage Foxp1 regulates pathologic cardiac hypertrophy. Methods: Macrophage-specific Foxp1 over-expressing (macFoxp1tg=anti-inflammatory) vs. non-tg controls, as well as macrophage-specific Foxp1 knockdown (macFoxp1ko=pro-inflammatory) vs. Cre-control male mice were subject to chronic angiotensin II (AII) infusion (1.8 mcg/kg/min via subcutaneous osmotic mini-pump) for 4 weeks. Results: AII-mediated cardiac hypertrophy (heart mass and cardiomyocyte cross-sectional area), left ventricular (LV) systolic dysfunction, LV dilation, interstitial fibrosis and macrophage (Mac-3+ cells) accumulation were significantly attenuated in macFoxp1tg mice compared to non-tg controls. In contrast, AII-mediated cardiac hypertrophy, LV systolic dysfunction and cavity dilation were significantly exacerbated in macFoxp1ko mice compared to Cre controls. There were no differences in systemic blood pressure between these groups, corroborating a load-independent role for macrophage Foxp1 in cardiac hypertrophy. Conclusion: These studies identify macrophage Foxp1 as a novel negative regulator of pathologic cardiac hypertrophy in vivo. Modulation of Foxp1 signaling may provide a novel strategy for prevention and treatment of heart failure.

Abstract 486: Increased Afterload In Sub-acute Phase Of Myocardial Infarction Exacerbates Heart Failure

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Kiyotake Ishikawa ◽  
Jaume Aguero ◽  
Kenneth Fish ◽  
Lauren Leonardson ◽  
Roger J Hajjar
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Acute Phase ◽  
Diastolic Pressure ◽  
Interstitial Fibrosis ◽  
Myocardial Dysfunction ◽  
Resistance Index ◽  
Left Ventricular ◽  
Systolic Volume ◽  
Lv Remodeling

Background: Hypertension (HT) increases cardiac afterload and is one of the risk factors of poor prognosis after myocardial infarction (MI). However, there is little information on how HT impacts the healing processes during sub-acute phase MI. We investigated the role of an increased afterload on left ventricular (LV) performance and remodeling shortly after MI. Methods: Anterior MIs were created in 15 Yorkshire pigs via percutaneous access. To mimic HT condition, 7 pigs (Banding, n=7) underwent surgical banding of the ascending aorta 10 days after the MI, and were compared to the remaining pigs (Control, n=8). LV remodeling and function were assessed one month after MI using 3-D echocardiography and invasive hemodynamic measurements. Results: Echocardiographic assessment at day 10 revealed no significant differences in LV ejection fraction (EF) or LV volumes. One month after MI, aortic banding increased the systemic vascular resistance index, but was not statistically significant (1658±282 dyn/s/cm5/m 2 vs 1153±658 dyn/s/cm5/m 2 , P=0.08). Banding group presented with significantly impaired LVEF (Figure, P=0.002), larger end systolic volume (Figure, P=0.045), lower cardiac index (3.1±0.9 L/min/m 2 vs 4.4±0.6 L/min/m 2 , P=0.01), and elevated LV end diastolic pressure (22.4±5.0 mmHg vs 14.4±7.5 mmHg: P=0.04, Banding vs Control, respectively). Reduced EF was associated with remote myocardial dysfunction and histological analysis revealed increased interstitial fibrosis in this area. Conclusion: Increased afterload in sub-acute phase of MI induces more severely impaired cardiac function and LV remodeling, and was associated with worse heart failure status.

Role of oxidative stress in left ventricular remodeling and heart failure after myocardial infarction

1999 ◽  
Vol 5 (3) ◽  
pp. 79
Author(s):  
Shintaro Kinugawa ◽  
Hiroyuki Tsutsui ◽  
Tomomi Ide ◽  
Hideo Ustumi ◽  
Nobuhiro Suematsu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Infarction ◽  
Heart Failure ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Left Ventricular

scholarly journals Diagnosis and Treatment of Asymptomatic Left Ventricular Systolic Dysfunction after Myocardial Infarction

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Laura Ajello ◽  
Giuseppe Coppola ◽  
Egle Corrado ◽  
Eluisa La Franca ◽  
Antonino Rotolo ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Acute Myocardial Infarction ◽  
Early Detection ◽  
Left Ventricular Systolic Dysfunction ◽  
Systolic Dysfunction ◽  
Left Ventricular ◽  
Diagnosis And Treatment ◽  
Ventricular Systolic Dysfunction

The increased survival after acute myocardial infarction induced an increase in heart failure with left ventricular systolic dysfunction. Early detection and treatment of asymptomatic left ventricular systolic dysfunction give the chance to improve outcomes and to reduce costs due to the management of patients with overt heart failure.

scholarly journals The relevance of prescribing triple neurohormonal blockade in real clinical practice: the role of mineralocorticoid receptor antagonists

2021 ◽  
Vol 23 (6) ◽  
pp. 491-497
Author(s):  
Igor V. Zhirov ◽  
◽  
Igor V. Zhirov ◽  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Mineralocorticoid Receptor ◽  
Systolic Dysfunction ◽  
Term Treatment ◽  
Mineralocorticoid Receptor Antagonists ◽  
Long Term Treatment ◽  
Real Clinical Practice

In the article is outlined the main concepts use of the mineralocorticoids receptors antagonists in the treatment of congestive heart failure and systolic dysfunction after acute myocardial infarction. Claimed the pivotal role of eplerenone in the long-term treatment strategy due to decrease of mortality and improving the clinical outcomes.

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 744: Arrhythmogenesis in Heart Failure: Role of Interstitial Fibrosis

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Jorge E Massare ◽  
R. Haris Naseem ◽  
Jeff M Berry ◽  
Farhana Rob ◽  
Joseph A Hill
Keyword(s):  
Heart Failure ◽  
Interstitial Fibrosis ◽  
Systolic Dysfunction ◽  
Ventricular Tachyarrhythmia ◽  
Severe Heart Failure ◽  
Pressure Overload ◽  
Cellular Events ◽  
Action Potential Prolongation

Background: Sudden cardiac death due to ventricular tachyarrhythmia (VT) accounts for a large number of deaths in patients with heart failure. Several cellular events which occur during pathological remodeling of the failing ventricle are implicated in the genesis of VT, including action potential prolongation, dysregulation of intercellular coupling, and fibrosis. Interestingly, transgenic mice over-expressing constitutively active PKD (caPKD) develop severe heart failure without interstitial fibrosis, an otherwise prominent feature of the disease. The goal here was to define the role of interstitial fibrosis in the proarrhythmic phenotype of failing myocardium. Methods and Results: We performed echocardiographic, electrocardiographic, and in vivo electrophysiologic studies in 8 –10 week old caPKD mice (n=12). Similar studies were performed in mice with load-induced heart failure induced by surgical pressure overload (sTAB, n=10), a model of heart failure with prominent interstitial fibrosis. caPKD and sTAB mice showed similar degrees of ventricular dilation (LV systolic dimension caPKD 2.4±0.8 mm vs 3.0±0.9 sTAB, p=0.18) and severe systolic dysfunction (% fractional shortening caPKD 25±11 vs 28±11 sTAB, p=0.62). Yet, caPKD mice showed minimal interstitial fibrosis, comparable to unoperated controls. With the exception of ventricular refractory period, which was higher in caPKD (48±11 msec vs 36±7 TAB and 40±8 WT, p<0.05), other electrocardiographic and electrophysiologic variables were similar among the 3 groups (p=NS), including heart rate, QT duration, and mean VT threshold. As expected, VT (≥3beats) was readily inducible by programmed stimulation in sTAB mice (7/10). By contrast, VT was less inducible in caPKD mice (4/12; p=0.1 vs TAB and <0.05 vs WT), and uninducible in unoperated controls (0/12). VT was polymorphic in both models, but episodes of VT were both slower (VT cycle length caPKD 58±4.0 msec vs 48±1 sTAB, p=0.016) and longer in caPKD mice (caPKD 1.8±0.7 sec vs 0.47±0.3 sTAB, p=0.038). Conclusion: Interstitial fibrosis contributes to the inducibility, maintenance, and rate of VT in heart failure. These findings highlight the importance of anti-remodeling therapies known to target fibrosis in heart disease.

scholarly journals Macrophage Activities in Myocardial Infarction and Heart Failure

2020 ◽  
Vol 2020 ◽  
pp. 1-16 ◽  
Author(s):  
Sophia Esi Duncan ◽  
Shan Gao ◽  
Michael Sarhene ◽  
Joel Wake Coffie ◽  
Deng Linhua ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Ventricular Remodeling ◽  
Left Ventricular Systolic Dysfunction ◽  
Heart Diseases ◽  
Systolic Dysfunction ◽  
Left Ventricular ◽  
Hibernating Myocardium ◽  
Clear Understanding ◽  
Myocardial Repair

Heart diseases remain the major cause of death worldwide. Advances in pharmacological and biomedical management have resulted in an increasing proportion of patients surviving acute heart failure (HF). However, many survivors of HF in the early stages end up increasing the disease to chronic HF (CHF). HF is an established frequent complication of myocardial infarction (MI), and numerous influences including persistent myocardial ischemia, shocked myocardium, ventricular remodeling, infarct size, and mechanical impairments, as well as hibernating myocardium trigger the development of left ventricular systolic dysfunction following MI. Macrophage population is active in inflammatory process, yet the clear understanding of the causative roles for these macrophage cells in HF development and progression is actually incomplete. Long ago, it was thought that macrophages are of importance in the heart after MI. Also, though inflammation is as a result of adverse HF in patients, but despite the fact that broad immunosuppression therapeutic target has been used in various clinical trials, no positive results have showed up, but rather, the focus on proinflammatory cytokines has proved more benefits in patients with HF. Therefore, in this review, we discuss the recent findings and new development about macrophage activations in HF, its role in the healthy heart, and some therapeutic targets for myocardial repair. We have a strong believe that there is a need to give maximum attention to cardiac resident macrophages due to the fact that they perform various tasks in wound healing, self-renewal of the heart, and tissue remodeling. Currently, it has been discovered that the study of macrophages goes far beyond its phagocytotic roles. If researchers in future confirm that macrophages play a vital role in the heart, they can be therapeutically targeted for cardiac healing.

Plasma cardiotrophin-1 following acute myocardial infarction: relationship with left ventricular systolic dysfunction

2001 ◽  
Vol 102 (1) ◽  
pp. 9-14 ◽  
Author(s):  
Suneel TALWAR ◽  
Iain B. SQUIRE ◽  
Russell J. O'BRIEN ◽  
Paul F. DOWNIE ◽  
Joan E. DAVIES ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Acute Myocardial Infarction ◽  
Left Ventricular Systolic Dysfunction ◽  
Systolic Function ◽  
Systolic Dysfunction ◽  
Clinic Visit ◽  
Left Ventricular ◽  
Lv Function ◽  
Ventricular Remodelling

The glycoprotein 130 (gp130) signalling pathway is important in the development of heart failure. Cardiotrophin-1 (CT-1), a cytokine acting via the gp130 pathway, is involved in the process of ventricular remodelling following acute myocardial infarction (AMI) in animals. The aims of the present study were to examine the profile of plasma CT-1 following AMI in humans, and its relationship with echocardiographic parameters of left ventricular (LV) systolic function. Serial measurements of plasma CT-1 levels were made in 60 patients at 14-48h, 49-72h, 73-120h and 121-192h following AMI and at a later clinic visit. LV function was assessed using a LV wall motion index (WMI) score on admission (WMI-1) and at the clinic visit (WMI-2). Compared with values in control subjects (29.5±3.6fmol/ml), the plasma CT-1 concentration was elevated in AMI patients at 14-48h (108.1±15.1fmol/ml), 49-72h (105.2±19.7fmol/ml), 73-120h (91.2±14.9fmol/ml) and 121-192h (118.8±22.6fmol/ml), and at the clinic visit (174.9±30.9 fmol/ml) (P < 0.0001). Levels were higher following anterior compared with inferior AMI. For patients with anterior AMI, CT-1 levels were higher at the clinic visit than at earlier times. WMI-1 correlated with CT-1 at all times prior to hospital discharge (P < 0.05). On best subsets analysis, the strongest correlate with WMI-1 was CT-1 level at 49-72h (R2 = 20%, P < 0.05). In conclusion, plasma levels of CT-1 are elevated soon after AMI in humans and rise further in the subsequent weeks in patients after anterior infarction. CT-1 measured soon after AMI is indicative of LV dysfunction, and this cytokine may have a role in the development of ventricular remodelling and heart failure after AMI.

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