Preserved heart function after left ventricular pressure overload in adult mice subjected to neonatal cardiac hypoplasia

2017 ◽  
Vol 9 (1) ◽  
pp. 112-124
Author(s):  
K. Heinecke ◽  
A. Heuser ◽  
F. Blaschke ◽  
C. Jux ◽  
L. Thierfelder ◽  
...  
Keyword(s):  
Mouse Model ◽  
Heart Function ◽  
Pressure Overload ◽  
Left Ventricular Pressure ◽  
Cellular Level ◽  
Left Ventricular ◽  
P38 Map Kinase ◽  
Cross Sectional ◽  
Hypertrophic Response ◽  
Cardiomyocyte Number

Intrauterine growth restriction in animal models reduces heart size and cardiomyocyte number at birth. Such incomplete cardiomyocyte endowment is believed to increase susceptibility toward cardiovascular disease in adulthood, a phenomenon referred to as developmental programming. We have previously described a mouse model of impaired myocardial development leading to a 25% reduction of cardiomyocyte number in neonates. This study investigated the response of these hypoplastic hearts to pressure overload in adulthood, applied by abdominal aortic constriction (AAC). Echocardiography revealed a similar hypertrophic response in hypoplastic hearts compared with controls over the first 2 weeks. Subsequently, control mice develop mild left ventricular (LV) dilation, wall thinning and contractile dysfunction 4 weeks after AAC, whereas hypoplastic hearts fully maintain LV dimensions, wall thickness and contractility. At the cellular level, controls exhibit increased cardiomyocyte cross-sectional area after 4 weeks pressure overload compared with sham operated animals, but this hypertrophic response is markedly attenuated in hypoplastic hearts. AAC mediated induction of fibrosis, apoptosis or cell cycle activity was not different between groups. Expression of fetal genes, indicative of pathological conditions, was similar in hypoplastic and control hearts after AAC. Among various signaling pathways involved in cardiac hypertrophy, pressure overload induces p38 MAP-kinase activity in hypoplastic hearts but not controls compared with the respective sham operated animals. In summary, based on the mouse model used in this study, our data indicates that adult hearts after neonatal cardiac hypoplasia show an altered growth response to pressure overload, eventually resulting in better functional outcome compared with controls.

Abstract P471: Mechanisms Controlling Regression Of Cardiac Fibrosis By Removal Of Pressure Overload

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Lily Neff ◽  
An Van Laer ◽  
Catalin F Baicu ◽  
Michael R Zile ◽  
Amy Bradshaw
Keyword(s):  
Cardiac Fibrosis ◽  
Volume Fraction ◽  
Lysyl Oxidase ◽  
Cardiac Fibroblasts ◽  
Pressure Overload ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Cellular Mechanisms ◽  
Cross Sectional ◽  
Fibroblast Activation

Background: Antecedent conditions, like aortic stenosis, can induce left ventricular pressure overload (LVPO), that can lead to Heart Failure with Preserved Ejection Fraction (HFpEF). Myocardial fibrosis and stiffness are key characteristics of HFpEF. Cardiac fibroblasts are the primary cell type regulating ECM production and deposition. In previous studies, biopsies isolated at the time of SAVR surgery, to correct stenosis, and then at 1-year and 5-years post-SAVR showed reductions in hypertrophy and fibrosis demonstrating these processes can regress. However, cellular mechanisms, including fibroblast activity, are poorly defined. Objective: Define mechanisms that contribute to remodeling of ECM before and after LVPO. Methods: LVPO was induced using transverse aortic constriction (TAC). LVPO was relieved by removal of the band (unTAC) at 4 wks. Cardiomyocyte cross-sectional area (CSA), collagen volume fraction (CVF), and protein production was measured by histology and immunoblot for five time points: nonTAC, 2wk TAC, 4wk TAC, 4wk TAC+2wk unTAC, and 4wk TAC+4wk unTAC. Results: In response to LVPO, myocyte CSA increased by 23% at 2wk TAC and by 47% at 4wk. CVF increased by 64% and 204% at 2wk and 4wk TAC, respectively, versus nonTAC. In 2wk TAC hearts, SMA, a marker of fibroblast activation was increased as was production of two collagen cross-linking enzymes, lysyl oxidase (LOX) and LOXL2, in the absence of significant increases in markers of ECM degradation. After unloading, myocyte CSA decreased by 20% in 2wk unTAC versus 4wk TAC and CVF decreased by 38% in 4wk unTAC versus 4wk TAC. Coincident with decreases in CVF, levels of pro-MMP2 increased at 2wk unTAC as did levels of degraded collagen measured by collagen hybridizing peptide reactivity. Whereas markers of ECM deposition, LOX and LOXL2, were not increased in unTAC myocardium, a resurgence of SMA production occurred in 2wk unTAC. Conclusions: In LVPO hearts, hypertrophy was characterized by increases in myocyte CSA, greater CVF, and fibroblast activation with increased production of pro-fibrotic ECM. After unloading, hypertrophy and fibrosis significantly decreased accompanied by increases in ECM degrading activity and reductions in proteins that contribute to collagen assembly.

scholarly journals Atrial Remodeling Is Directly Related to End-Diastolic Left Ventricular Pressure in a Mouse Model of Ventricular Pressure Overload

PLoS ONE ◽  
2013 ◽  
Vol 8 (9) ◽  
pp. e72651 ◽  
Author(s):  
Anne Margreet De Jong ◽  
Isabelle C. Van Gelder ◽  
Inge Vreeswijk-Baudoin ◽  
Megan V. Cannon ◽  
Wiek H. Van Gilst ◽  
...  
Keyword(s):  
Mouse Model ◽  
Pressure Overload ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Ventricular Pressure ◽  
Atrial Remodeling

Abstract 540: Effects Of Altered Levels Of Adenylyl Cyclase Type 5 In Cardiac Myocytes From Chimeric Mice

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Che-Lin Hu ◽  
Shumin Gao ◽  
Chull Hong ◽  
Jing Liu ◽  
Heather Reinhardt ◽  
...  
Keyword(s):  
Ejection Fraction ◽  
Adenylyl Cyclase ◽  
Heart Function ◽  
Pressure Overload ◽  
Chimeric Mice ◽  
Aortic Banding ◽  
Cross Sectional ◽  
Hypertrophic Response ◽  
Cardiac Decompensation ◽  
Lv Ejection Fraction

The role of adenylyl cyclase (AC) isoforms in the heart has remained controversial in regards to their ability to enhance or impair cardiac function. We examined the effects of chronic pressure overload (aortic banding) in transgenic (TG) mice with cardiac overexpressed AC isoform type 5 (AC5TG), a major cardiac AC isoform. In AC5TG, the hypertrophic response, as assessed by LV/tibia length (TL), was greater, p<0.05, in AC5TG (6.6±0.2) than wildtype (WT) (5.1±0.2). In addition, cardiac decompensation occurred, as reflected by decreased LV ejection fraction and increased lung/body weight, which could exert systemic effects through reflexes and hormones. We sought to examine whether the effects of overexpressed AC5 on the response to pressure overload is due to the affects on the myocyte or its environment. Chimeric mice from fusion between embryos from the transgenic overexpressed AC5 parents and the Rosa26 parents, which ubiquitously express beta-galactosidase in all tissues and can be identified histologically with X-gal staining, were developed. The proportion of the AC5TG (FVB background) cells in the myocardium ranged from 2% to 75% (n=9). We subjected these animals to 2 wk aortic banding at 4 – 6 months of age and examined the physiological and histological changes in the heart. There was a direct correlation (r= 0.91) between the percentage of AC5OE cells and LV hypertrophy index (LV weight/BW) including LV end diastolic and systolic wall thickness (r=0.98 and 0.92, respectively). We then determined the myocyte cross-sectional cell size from different cell origin micrographically. After 2wk banding, myocytes originating from the Rosa26 (C57/BL6) and FVB background were similar in size, but myocytes overexpressing AC5 were significantly larger (33%, p<0.05). Conversely, there was a negative correlation between the amount of AC5OE cells and heart function: LV ejection fraction and contractility decreased in mice with a higher percentage of AC5OE myocytes (r = −0.89 and r = −0.81, respectively). Thus, overexpression of AC5 even in only a small fraction of total myocytes in the heart induced myocyte hypertrophy independent of any systemic influences.

Abstract 278: Domain-specific Roles for GRK2 in Cardiac Hypertrophy and Heart Failure

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Sarah M Schumacher ◽  
Erhe Gao ◽  
J. Kurt Chuprun ◽  
Walter J. Koch
Keyword(s):  
Heart Failure ◽  
Interstitial Fibrosis ◽  
Heart Function ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Cross Sectional ◽  
Amino Terminal ◽  
Domain Specific ◽  
Rgs Domain

During heart failure (HF), cardiac levels and activity of the G protein-coupled receptor (GPCR) kinase (GRK) GRK2 are elevated and contribute to adverse remodeling and contractile dysfunction, while inhibition via a carboxyl-terminal peptide, βARKct, enhances heart function and can prevent HF. Mounting evidence supports the idea of a dynamic “interactome” in which GRK2 can uncouple GPCRs via novel protein-protein interactions. Several GRK2 interacting partners are important for adaptive and maladaptive myocyte growth; therefore, an understanding of domain-specific interactions with signaling and regulatory molecules could lead to novel targets for HF therapy. For instance, GRK2 contains a putative amino-terminal R egulator of G protein S ignaling (RGS) domain (βARKrgs) that directly interacts with Gαq and inhibits signaling. Previously, our lab investigated cardiac-specific transgenic expression of a fragment of this RGS domain (βARKnt), that did not reduce acute hypertrophy after pressure overload or demonstrate RGS activity in vivo against Gαq-mediated signaling. In contrast, βARKnt induced hypertrophy and elevated β-adrenergic receptor (βAR) density without altering agonist-induced contractility or adenylyl cyclase activity, due to a compensatory increase in GRK2 activity. Importantly, βAR downregulation in response to chronic agonist administration was attenuated by βARKnt expression, indicating a novel regulation of βAR receptor density. Herein, we investigated the effect of βARKnt expression during chronic pressure overload post trans-aortic constriction (TAC). Echocardiographic analysis revealed increased posterior wall thickness and left-ventricular mass 4 weeks post-TAC compared to non-transgenic littermate controls. Importantly, despite enhanced hypertrophy, the progression to HF was inhibited in βARKnt mice 14 weeks post-TAC. Histological analysis of interstitial fibrosis and cross-sectional area is underway to determine alterations in maladaptive remodeling. Further, cardiomyocyte signaling and βARKnt protein-binding partners are a focus, since our data indicate that βARKnt-mediated regulation of βAR density may provide a novel means of cardioprotection during pressure-overload induced HF.

scholarly journals Protective Effects of Thyroid Hormone Deprivation on Progression of Maladaptive Cardiac Hypertrophy and Heart Failure

2021 ◽  
Vol 8 ◽  
Author(s):  
Helena Kerp ◽  
Georg Sebastian Hönes ◽  
Elen Tolstik ◽  
Judith Hönes-Wendland ◽  
Janina Gassen ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Heart Function ◽  
Pressure Overload ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Ventricular Pressure ◽  
Cardiovascular Morbidity And Mortality ◽  
The Impact

Purpose: Thyroid hormones (TH) play a central role for cardiac function. TH influence heart rate and cardiac contractility, and altered thyroid function is associated with increased cardiovascular morbidity and mortality. The precise role of TH in onset and progression of heart failure still requires clarification.Methods: Chronic left ventricular pressure overload was induced in mouse hearts by transverse aortic constriction (TAC). One week after TAC, alteration of TH status was induced and the impact on cardiac disease progression was studied longitudinally over 4 weeks in mice with hypo- or hyperthyroidism and was compared to euthyroid TAC controls. Serial assessment was performed for heart function (2D M-mode echocardiography), heart morphology (weight, fibrosis, and cardiomyocyte cross-sectional area), and molecular changes in heart tissues (TH target gene expression, apoptosis, and mTOR activation) at 2 and 4 weeks.Results: In diseased heart, subsequent TH restriction stopped progression of maladaptive cardiac hypertrophy and improved cardiac function. In contrast and compared to euthyroid TAC controls, increased TH availability after TAC propelled maladaptive cardiac growth and development of heart failure. This was accompanied by a rise in cardiomyocyte apoptosis and mTOR pathway activation.Conclusion: This study shows, for the first time, a protective effect of TH deprivation against progression of pathological cardiac hypertrophy and development of congestive heart failure in mice with left ventricular pressure overload. Whether this also applies to the human situation needs to be determined in clinical studies and would infer a critical re-thinking of management of TH status in patients with hypertensive heart disease.

Abstract 260: Time Course Observation of Left Ventricular Hypertrophy and Regression Induced by an Improved Technique

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Xiu Zhang ◽  
Ling Li ◽  
Amanda Szucsik ◽  
Hadi Javan ◽  
Yubin Deng ◽  
...  
Keyword(s):  
Left Ventricular Hypertrophy ◽  
Mouse Model ◽  
Ventricular Hypertrophy ◽  
Time Course ◽  
Heart Function ◽  
Systolic Pressure ◽  
Weight Ratio ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Cardiac Wall

In order to study the left ventricular hypertrophy (LVH) and its regression, we improved the surgical technique for producing LV pressure overload and its reversing mouse model using the titanium clip placement for transverse aortic banding (AB) and removal for debanding (DB). A time course study on heart function and histology proved the importance of the regression time. Materials and methods: The technique was applying titanium clip for AB and removing for DB with minimal invasion. A total of 95 male C57BL6 mice weighing 20-30 g were used in this study. Experimental groups included: control (n=11), AB 3 (11), 4 (12), and 6 (12) wks, DB at 3 (12), 4 (11), and 6 (12) wks of AB for 1 wk. Carotid arteries velocity were measured to evaluate the constrictive level. Heart/body weight ratio, cardiac wall thickness from echocardiography, LV pressure from catheterization and heart histology studies were used to evaluate the pressure overload and hypertrophy. Results: The echocardiographic and histology results indicated that AB induce significent LVH which was a concentric hypertrophy at AB 3 wks and then progressively become a dilated hypertrophy at AB 6 wks. The cardiac function also indicated a stable ejection fraction before 3 wks of AB and then gradually declined at AB 6 wks. After 6 wks AB, the enlargement in LV dimensions becomes significant. When deband at 3 and 4 wks for one week, there were significant regression of hypertrophy but the regression is limited after AB 6 wks and the evidences of lung congestion were apparent. In catheterizaiton, the LV systolic pressure were markedly elevated in AB mice but these pressure elevations became less at AB 6 wks and the LV end-diastolic pressure (LVEDP) at AB 6 wks was elevated significantly. After DB at AB 3 and 4 wks, the pressure parameters retriced close to normal but LVEPD elevation retreat is limited in the DB 6 wks group. Conclusion: With applying and removing titanium clip to induce pressure overload and reversing can provide a relatively simple, effecive, consistent and minimal invasive methods to establish the mouse model for studying LVH and its regression. Our data indicate that AB induced mouse LVH could be retriced close to normal when remove the constriction at the concentric LVH phase but the regression is limited in dilated LVH.

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