Abstract 069: Mitochondrial Mechanisms Of Reverse Remodeling In Heart Failure

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Preeti Ahuja ◽  
William R MacLellan ◽  
Yibin Wang
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Cardiac Myocyte ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Reverse Remodeling ◽  
Ventricular Assist ◽  
Hypertrophic Response ◽  
Mtdna Deletions ◽  
And Function

Enhancement of myocardial mitochondrial (mt) function resulting in efficient energy production by means of Left ventricular assist device (LVAD) has been suggested in heart failure (HF) which could have important clinical implications and may represent a novel therapeutic target. However, the basis for this improvement remains unknown. To characterize mt biogenesis, mt genomic integrity and mitophagy in reversing pathological remodeling, we investigated LV tissue from post-LVAD human hearts and after reversal of transaortic constriction (TAC) in mice. In Post-LVAD human hearts there was increased expression of mt fusion and biogenesis, mtDNA levels were normalized and deletion mutation rates were significantly reduced with reverse remodeling and these changes were associated with enhancement of mt ETC complex I and II activities and improved cardiac-myocyte morphology. To better understand the mechanisms underlying mt repair/remodeling with LVAD support, we developed a model of aortic banding (AB) and debanding (DB) in mice. C57BL/6 mice were subjected to 2 weeks of AB and subsequent DB for period of 1 to 20 days and cardiac function and hypertrophy were evaluated by echocardiography and real-time PCR, respectively. Compared with control animals, mice that had undergone banding had a robust hypertrophic response with decline in cardiac function. These parameters were reversed following removal of pressure overload by DB. Even 1 day of unloading led to significant increase in the expression of mt fusion and biogenesis genes. Hearts from AB (2 weeks) mice showed a 3.7-fold (P<0.05) increase in frequency of mtDNA deletions. However, mtDNA deletions were significantly reduced in frequency with DB when compared with AB hearts alone. Increase in expression of autophagy related genes could also be observed after hemodynamic unloading in mouse failing hearts. Removal of pressure overload by DB led to 2.58-fold (P<0.05) increase in expression of LC3B when compared to sham and AB mice. Thus, our data strongly suggest that protective effect of enhanced mt biogenesis, fusion/mtDNA repair and removal of damaged mitochondria by mitophagy could play an important role in maintaining mt integrity and function in the adult heart with reverse remodeling.

Contribution of ventricular remodeling to pathogenesis of heart failure in rats

2001 ◽  
Vol 280 (2) ◽  
pp. H674-H683 ◽  
Author(s):  
Gregory L. Brower ◽  
Joseph S. Janicki
Keyword(s):  
Heart Failure ◽  
Ventricular Remodeling ◽  
Volume Fraction ◽  
Volume Overload ◽  
Left Ventricular ◽  
Morbidity And Mortality ◽  
Compliance Matrix ◽  
Hypertrophic Response ◽  
Lv Volume ◽  
And Function

We previously reported an approximately 50% incidence of rats with symptoms of congestive heart failure (CHF) at 8 wk postinfrarenal aorto-caval fistula. However, it was not clear whether compensatory ventricular remodeling could continue beyond 8 wk or whether the remaining animals would have developed CHF or died. Therefore, the intent of this study was to complete the characterization of this model of sustained volume overload by determining the morbidity and mortality and the temporal response of left ventricular (LV) remodeling and function beyond 8 wk. The findings demonstrate an upper limit to LV hypertrophy and substantial increases in LV volume and compliance, matrix metalloproteinase activity, and collagen volume fraction associated with the development of CHF. There was an 80% incidence of morbidity and mortality following 21 wk of chronic volume overload. These findings indicate that the development of CHF is triggered by marked ventricular dilatation and increased compliance occurring once the myocardial hypertrophic response is exhausted.

scholarly journals Cytosolic H2O2 mediates hypertrophy, apoptosis, and decreased SERCA activity in mice with chronic hemodynamic overload

2014 ◽  
Vol 306 (10) ◽  
pp. H1453-H1463 ◽  
Author(s):  
Fuzhong Qin ◽  
Deborah A. Siwik ◽  
David R. Pimentel ◽  
Robert J. Morgan ◽  
Andreia Biolo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Cardiac Myocyte ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Transgenic Expression ◽  
Myocardial Oxidative Stress ◽  
Plasmic Reticulum ◽  
Oxidative Modifications ◽  
Hemodynamic Overload

Oxidative stress in the myocardium plays an important role in the pathophysiology of hemodynamic overload. The mechanism by which reactive oxygen species (ROS) in the cardiac myocyte mediate myocardial failure in hemodynamic overload is not known. Accordingly, our goals were to test whether myocyte-specific overexpression of peroxisomal catalase (pCAT) that localizes in the sarcoplasm protects mice from hemodynamic overload-induced failure and prevents oxidation and inhibition of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA), an important sarcoplasmic protein. Chronic hemodynamic overload was caused by ascending aortic constriction (AAC) for 12 wk in mice with myocyte-specific transgenic expression of pCAT. AAC caused left ventricular hypertrophy and failure associated with a generalized increase in myocardial oxidative stress and specific oxidative modifications of SERCA at cysteine 674 and tyrosine 294/5. pCAT overexpression ameliorated myocardial hypertrophy and apoptosis, decreased pathological remodeling, and prevented the progression to heart failure. Likewise, pCAT prevented oxidative modifications of SERCA and increased SERCA activity without changing SERCA expression. Thus cardiac myocyte-restricted expression of pCAT effectively ameliorated the structural and functional consequences of chronic hemodynamic overload and increased SERCA activity via a post-translational mechanism, most likely by decreasing inhibitory oxidative modifications. In pressure overload-induced heart failure cardiac myocyte cytosolic ROS play a pivotal role in mediating key pathophysiologic events including hypertrophy, apoptosis, and decreased SERCA activity.

scholarly journals Cardiac-restricted overexpression or deletion of tissue inhibitor of matrix metalloproteinase-4: differential effects on left ventricular structure and function following pressure overload-induced hypertrophy

2014 ◽  
Vol 307 (5) ◽  
pp. H752-H761 ◽  
Author(s):  
William M. Yarbrough ◽  
Catalin Baicu ◽  
Rupak Mukherjee ◽  
An Van Laer ◽  
William T. Rivers ◽  
...  
Keyword(s):  
Pressure Overload ◽  
Left Ventricular ◽  
Lv Function ◽  
Type I ◽  
Matrix Remodeling ◽  
Protective Effects ◽  
Ecm Remodeling ◽  
Hypertrophic Response ◽  
Lv Mass ◽  
And Function

Historically, the tissue inhibitors of matrix metalloproteinases (TIMPs) were considered monochromatic in function. However, differential TIMP profiles more recently observed with left ventricular (LV) dysfunction and matrix remodeling suggest more diverse biological roles for individual TIMPs. This study tested the hypothesis that cardiac-specific overexpression (TIMP-4OE) or deletion (knockout; TIMP-4KO) would differentially affect LV function and structure following pressure overload (LVPO). LVPO (transverse aortic constriction) was induced in mice (3.5 ± 0.1 mo of age, equal sex distribution) with TIMP-4OE ( n = 38), TIMP-4KO ( n = 24), as well as age/strain-matched wild type (WT, n = 25), whereby indexes of LV remodeling and function such as LV mass and ejection fraction (LVEF) were determined at 28 days following LVPO. Following LVPO, both early (7 days) and late (28 days) survival was ∼25% lower in the TIMP-4KO group ( P < 0.05). While LVPO increased LV mass in all groups, the relative hypertrophic response was attenuated with TIMP-4OE. With LVPO, LVEF was similar between WT and TIMP-4KO (48 ± 2% and 45 ± 3%, respectively) but was higher with TIMP-4OE (57 ± 2%, P < 0.05). With LVPO, LV myocardial collagen expression (type I, III) increased by threefold in all groups ( P < 0.05), but surprisingly this response was most robust in the TIMP-4KO group. These unique findings suggest that increased myocardial TIMP-4 in the context of a LVPO stimulus may actually provide protective effects with respect to survival, LV function, and extracellular matrix (ECM) remodeling. These findings challenge the canonical belief that increased levels of specific myocardial TIMPs, such as TIMP-4 in and of themselves, contribute to adverse ECM accumulation following a pathological stimulus, such as LVPO.

scholarly journals Osteopontin RNA aptamer can prevent and reverse pressure overload-induced heart failure

2017 ◽  
Vol 113 (6) ◽  
pp. 633-643 ◽  
Author(s):  
Jihe Li ◽  
Keyvan Yousefi ◽  
Wen Ding ◽  
Jayanti Singh ◽  
Lina A. Shehadeh
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Cardiac Fibrosis ◽  
Cardiac Myocyte ◽  
Pressure Overload ◽  
Cardiomyocyte Hypertrophy ◽  
Therapeutic Effects ◽  
Rna Aptamer ◽  
Myocyte Hypertrophy

Aims Cardiac myocyte hypertrophy, the main compensatory response to chronic stress in the heart often progresses to a state of decompensation that can lead to heart failure. Osteopontin (OPN) is an effector for extracellular signalling that induces myocyte growth and fibrosis. Although increased OPN activity has been observed in stressed myocytes and fibroblasts, the detailed and long term effects of blocking OPN signalling on the heart remain poorly defined. Targeting cardiac OPN protein by an RNA aptamer may be beneficial for tuning down OPN pathologic signalling. We aimed to demonstrate the therapeutic effects of an OPN RNA aptamer on cardiac dysfunction. Methods and results In vivo, we show that in a mouse model of pressure overload, treating at the time of surgeries with an OPN aptamer prevented cardiomyocyte hypertrophy and cardiac fibrosis, blocked OPN downstream signalling (PI3K and Akt phosphorylation), reduced expression of extracellular matrix (Lum, Col3a1, Fn1) and hypertrophy (Nppa, Nppb) genes, and prevented cardiac dysfunction. Treating at two months post-surgeries with the OPN aptamer reversed cardiac dysfunction and fibrosis and myocyte hypertrophy. While genetic homozygous deletion of OPN reduced myocardial wall thickness, surprisingly cardiac function and myocardial fibrosis, specifically collagen deposition and myofibroblast infiltration, were worse compared with wild type mice at three months of pressure overload. Conclusion Taken together, these data demonstrate that tuning down cardiac OPN signalling by an OPN RNA aptamer is a novel and effective approach for preventing cardiac hypertrophy and fibrosis, improving cardiac function, and reversing pressure overload-induced heart failure.

scholarly journals Myocardial Insulin-Like Growth Factor-I Gene Expression During Recovery From Heart Failure After Combined Left Ventricular Assist Device and Clenbuterol Therapy

Circulation ◽  
2005 ◽  
Vol 112 (9_supplement) ◽  
Author(s):  
Paul J. R. Barton ◽  
Leanne E. Felkin ◽  
Emma J. Birks ◽  
Martin E. Cullen ◽  
Nicholas R. Banner ◽  
...  
Keyword(s):  
Heart Failure ◽  
Stromal Cell ◽  
Left Ventricular ◽  
Reverse Remodeling ◽  
Assist Device ◽  
Ventricular Assist ◽  
Factor I ◽  
Left Ventricular Assist ◽  
Igf I ◽  
Stromal Cell Derived Factor

Background— Patients who undergo mechanical support with a left ventricular assist device (LVAD) exhibit reverse remodeling and in some cases recover from heart failure. We have developed a combination therapy using LVAD support combined with pharmacological therapy to maximize reverse remodeling, followed by the β 2 adrenergic agonist clenbuterol. We recently found that clenbuterol induces insulin-like growth factor I (IGF-I) in cardiac myocytes in vitro. The purpose of this study is to examine IGF-I expression in recovery patients after combination therapy. Methods and Results— Myocardial mRNA levels were determined by real-time quantitative polymerase chain reaction in 12 recovery patients (at LVAD implantation, explantation, and 1 year after explantation). IGF-I mRNA was elevated at the time of LVAD explantation relative to donors, with 2 groups distinguishable: Those with low IGF-I mRNA at implantation who showed significant increase during recovery and those with high IGF-I mRNA at implantation who remained high. Levels returned to normal by 1 year after explantation. Microarray analysis of implantation and explantation samples of recovery patients further revealed elevated IGF-II and IGF binding proteins IGFBP4 and IGFBP6. IGF-I levels correlated with stromal cell-derived factor mRNA measured both in LVAD patients and in a wider cohort of heart failure patients. Conclusions— The data suggest involvement of elevated myocardial IGF-I mRNA in recovery. IGF-I may act to limit atrophy and apoptosis during reverse remodeling and to promote repair and regeneration in concert with stromal cell derived factor.

Abstract 87: Alterations to Cardiac Mechanics Do Not Preserve Normal Cardiac Function in a Novel Ossabaw Swine Model of Heart Failure with Preserved Ejection Fraction

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Jenna C Edwards ◽  
Madeleine Dionne ◽  
T. D Olver ◽  
Jan R Ivey ◽  
Pamela K Thorne ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Cardiac Function ◽  
Strain Rate ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Volume Index ◽  
Lv Function ◽  
Swine Model ◽  
Preserved Ejection Fraction

Introduction: Heart failure with preserved ejection fraction (HFpEF) is clinically characterized by an increased incidence in females and many comorbidities including type 2 diabetes (T2D) and obesity. Animal models accurately representing clinical HFpEF are lacking; thus, the purpose of this study was to examine left ventricular (LV) mechanics in a novel Ossabaw swine model of chronic pressure-overload (aortic-banding; AB) and T2D (Western diet; WD) using two dimensional speckle tracking echocardiography (2D-STE). We hypothesized that global LV strain would be decreased primarily in the longitudinal direction in WD-AB animals. Methods: Female Ossabaws were randomly divided into 2 groups: CON (n=5) and WD-AB (n=5). LV function and strain were measured at 1 year of age after 6 mo. of AB and 9 mo. of WD via pressure-volume relations and 2D-STE. Significance was set at P < 0.05 using t-test vs. CON. Results: In the WD-AB group, ejection fraction (EF%) and end diastolic volume were normal (>50%), and observed in parallel with increased LV weight, lung weight, and LV diastolic wall thickness (i.e. concentric hypertrophy). WD-AB group had increased HOMA-IR and body surface area, two common features in T2D. In WD-AB animals, although global longitudinal systolic strain rate and end systolic displacement were increased, stroke volume index was decreased. Early diastolic rotation rate was decreased, while global longitudinal late diastolic strain rate was increased in the WD-AB group. These changes, considered in parallel with an increased end diastolic pressure-volume relationship in WD-AB animals, are consistent with diastolic dysfunction. In contrast, longitudinal, radial, and circumferential early diastolic strain rates increased in the WD-AB group. Conclusion: Contrary to our hypothesis, LV longitudinal strain was increased during both systole and diastole, and observed in parallel with decreased early diastolic untwisting in WD-AB animals. Our results suggest alterations to LV mechanics do not preserve normal systolic and diastolic cardiac function, despite normal resting EF%, in this novel translational model of pressure-overload HF with potential relevance to human HFpEF including associated clinical comorbidities (sex, obesity, and T2D).

Abstract 203: Protein Synthesis Inhibitors 4E-BPs Regulate Cardiac Function

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Denghong Zhang ◽  
Riccardo Contu ◽  
Michael Latronico ◽  
Kirk Peterson ◽  
Ju Chen ◽  
...  
Keyword(s):  
Heart Failure ◽  
Protein Synthesis ◽  
Cardiac Function ◽  
Pressure Overload ◽  
Mrna Translation ◽  
Protein Synthesis Inhibitors ◽  
Negative Effects ◽  
Hypertrophic Response ◽  
Improvement In Survival

Rationale: mTOR regulates cardiac functionality and hypertrophy. We have shown that cardiac-specific deletion of mTOR induces fatal dilated cardiomyopathy. This model of heart failure is characterized biochemically by accumulation of the mTOR substrate 4E-BP1, which inhibits protein synthesis through the regulation of translation initiation. Deletion of the 4E-BP1 gene, Eif4ebp1, in mTOR-KO mice significantly, albeit partially, improved cardiac function and survival. Objective: To investigate the role of the 4E-BP family in the heart by determining whether absence of its members improves cardiac function in different models of heart failure. Methods and Results: In the absence of Eif4ebp1, cardiac expression of the 4E-BP2 homolog increases strikingly. Deletion of Eif4ebp2 along with Eif4ebp1 (4E-BP1/4E-BP2-dKO mice) abrogated the negative effects of the loss of mTOR on cardiac function, and led to a further significant improvement in survival rate. Moreover, when 4E-BP1/4E-BP2-dKO mice where subjected to pressure-overload stress, cardiac function and survival were significantly improved compared with similarly treated control mice. The hypertrophic response to pressure overload in these mice was not affected by the absence of 4E-BPs. Conclusions: Our data indicate that 4E-BPs are responsible for an important part of mTOR effects on cardiac function, further strengthening the concept that the regulation of mRNA translation profoundly affects cardiac inotropism under stress.

Sign in / Sign up

Export Citation Format

Share Document