scholarly journals Macrophage depletion impairs adequate cardiac repair in mouse models of myocardial infarction with variable transmurality - insights from multimodality molecular imaging

2021 ◽  
Vol 22 (Supplement_3) ◽  
Author(s):  
A Hess ◽  
LBN Langer ◽  
TL Ross ◽  
FM Bengel ◽  
JT Thackeray
Keyword(s):  
Myocardial Infarction ◽  
Ex Vivo ◽  
Left Ventricular ◽  
Cardiac Repair ◽  
Lv Function ◽  
Cardiac Inflammation ◽  
Macrophage Depletion ◽  
Pet Ct ◽  
Ex Vivo Autoradiography ◽  
The Impact

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Deutsche Forschungsgemeinschaft (DFG) Introduction Balanced myocardial tissue inflammation following acute myocardial infarction (MI) is needed for optimal cardiac repair. Macrophages contribute to wound healing, but may also be deleterious. Purpose We investigated the impact of macrophage depletion on early cardiac inflammation and later functional outcome in two models of MI with variable transmurality. Methods C57BL/6N mice received clodronate-liposomes for macrophage depletion (n = 49) or control PBS-liposomes (n = 23). After 24h, mice underwent permanent occlusion (PO) or transient ischemia-reperfusion (I/R, 60min) of the left coronary artery or sham surgery. Cardiac inflammation was assessed on MI + 1d, 3d, and 7d by CXCR4-targeted PET/CT using 68Ga-pentixafor. 99mTc-sestamibi SPECT/CT and cardiac magnetic resonance (CMR) calculated infarct sizes and left ventricular (LV) function at 1wk and 6wks. 18F-NaF PET/CT measured tissue microcalcification at 4wks. Imaging signals were validated by ex vivo autoradiography and immunohistochemistry. Results Clodronate macrophage depletion did not affect infarct size compared to PBS, but perfusion defects at 6wks were significantly larger after PO compared to I/R (%LV, 32 ± 11 vs 14 ± 10, p = 0.01). In both models, infarct CXCR4 expression was higher after macrophage depletion vs PBS at all timepoints (%injected dose (ID)/g; d3: PO: 1.4 ± 0.2 vs 0.9 ± 0.1; I/R: 1.4 ± 0.2 vs 1.0 ± 0.02; p < 0.05), and confirmed by ex vivo autoradiography. Immunostaining demonstrated fewer macrophages and higher neutrophil content within the myocardium after macrophage depletion vs PBS at 1d, 3d, and 7d post-MI. Acute LV rupture after PO was more frequent in macrophage-depleted than PBS mice (37% vs 17%). Conversely, surviving PO mice showed a similarly impaired ejection fraction (EF) after macrophage depletion vs PBS at 6wks (%, 32 ± 9 vs 32 ± 11, p = 0.84). No acute LV rupture was observed after I/R, but macrophage depletion led to worse EF (%, 42 ± 11 vs 54 ± 3, p = 0.1). Macrophage-depleted mice exhibited a dense intracavity thrombus adherent to the infarct wall after either injury, as visualized on CMR at 1wk. 18F-NaF PET identified active calcification localized to the thrombus region 4wks after MI, which was colocalized to CT opaque regions at 6wks. Conclusion Macrophage depletion impairs cardiac repair via several mechanisms including neutrophil-dominated inflammation, LV thrombus formation and tissue calcification. This observation underscores the requirement of macrophages for effective healing and may explain adverse response to broad anti-inflammatory therapy in myocardial ischemia.

A Model of Blood Component–Heart Interaction in Cardiac Ischemia–Reperfusion Injury using a Langendorff-Based Ex Vivo Assay

2019 ◽  
Vol 25 (2) ◽  
pp. 164-173 ◽  
Author(s):  
Johanna M. Muessig ◽  
Sema Kaya ◽  
Luise Moellhoff ◽  
Johanna Noelle ◽  
Leonie Hidalgo Pareja ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Left Ventricular Function ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Cardiac Ischemia ◽  
Transfer Model ◽  
Blood Components ◽  
The Impact ◽  
Human Rbcs

Introduction: Myocardial infarction is one of the leading causes of morbidity and mortality worldwide. Cellular interactions of red blood cells (RBCs) and platelets with endothelial cells and cardiomyocytes play a crucial role in cardiac ischemia/reperfusion (I/R) injury. However, addressing the specific impact of such cell-to-cell interactions in commonly employed in vivo models of cardiac I/R injury is challenging due to overlap of neuronal, hormonal, and immunological pathways. This study aimed to refine a Langendorff-based ex vivo transfer model to evaluate the impact of specific blood components on cardiac I/R injury. Material and methods: Murine whole blood, defined murine blood components (RBCs, platelet-rich plasma [PRP], and platelet-poor plasma [PPP], respectively) as well as human RBCs were loaded to the coronary system of isolated murine hearts in a Langendorff system before initiating global ischemia for 40 minutes. Following 60 minutes of reperfusion with Krebs Henseleit Buffer, left ventricular function and coronary flow were assessed. Infarct size was determined by specific histological staining following 120 minutes of reperfusion. Results: Loading of murine whole blood to the coronary system of isolated murine hearts at the beginning of 40 minutes of global ischemia improved left ventricular function after 60 minutes of reperfusion and reduced the infarct size in comparison to buffer-treated controls. Similarly, isolated murine RBCs, PRP, and PPP mediated a protective effect in the cardiac I/R model. Furthermore, human RBCs showed a comparable protective capacity as murine RBCs. Conclusion: This Langendorff-based transfer model of cardiac I/R injury is a feasible, time-, and cost-effective model to evaluate the impact of blood components on myocardial infarction. The presented method facilitates loading of blood components of genetically modified mice to murine hearts of a different mouse strain, thus complementing time- and cost-intensive chimeric models and contributing to the development of novel targeted therapies.

P5011Impact of guideline-recommended medical therapy at discharge on long-term mortality in patients with or without left ventricular dysfunction after primary PCI for STEMI

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M Radomirovic ◽  
D Milasinovic ◽  
Z Mehmedbegovic ◽  
D Jelic ◽  
V Zobenica ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Beta Blocker ◽  
Beta Blockers ◽  
Left Ventricular ◽  
Lv Function ◽  
Primary Pci ◽  
Lv Dysfunction ◽  
Concurrent Use ◽  
Tertiary Center ◽  
The Impact

Abstract Background Clinical practice guidelines provide class I recommendation for the use of angiotensin-converting enzyme inhibitors (ACE-I) and beta-blockers in patients with prior myocardial infarction and left ventricular (LV) dysfunction, whereas their use in patients without LV dysfunction is considered to be a class IIa recommendation. Purpose Our aim was to comparatively assess the impact of ACE-I and/or beta-blockers on 3-year mortality in patients with or without impaired left ventricular (LV) function undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI). Methods The analysis included 4425 patients admitted for primary PCI during 2009–2015 from a prospective, electronic registry of a high-volume tertiary center, who survived initial hospitalization, and for whom information on LV function and discharge medication were available. Patients were stratified according to LV systolic dysfunction, defined as LVEF <40%. Unadjusted and adjusted Cox regression models were created to investigate the impact of beta-blocker and/or ACE-I therapy on 3-year mortality. Results 22.9% (n=1013) had LV dysfunction, 23.0% (n=1017) received either an ACE-I or a beta-blocker and 72.2% received both medications at discharge (n=3197). The concurrent use of both ACE-I and beta-blockers was not different in LVEF≥40% vs. LVEF<40% (72.4% vs. 71.7%, p=0.43). The use of at least one of the guideline-recommended medications was associated with a significantly lower 3-year mortality in both patients with LVEF≥40% (18.7% if neither was used, 11.2% if either a beta-blocker or an ACE-I were used and 9.4% if both were used, p=0.001), and LVEF<40% (55.4% if neither was used, 32.5% if either a beta-blocker or an ACE-I were used and 22.9% if both were used, p<0.001) (Figure). After adjusting for significant mortality predictors including older age, diabetes, hypertension, renal failure, previous stroke, Killip class ≥2 and non-culprit chronic total occlusion (CTO), the concurrent use of both a beta-blocker and an ACE-I remained independently associated with lower 3-year mortality in both patients with LVEF<40% (HR 0.30, p<0.001) and LVEF≥40% (HR=0.41, p=0.001). The use of a single agent was independently associated with lower mortality in patients with LVEF<40% (HR 0.45, p=0.002), but not in patients with LVEF≥40% (HR 0.61, p=0.07). Conclusions Guideline-recommended use of both a beta-blocker and an ACE-I in post-MI patients was associated with a lower 3-year mortality regardless of the LV function, whereas using only one of the two agents was associated with improved prognosis only in patients with LV dysfunction, but not in patients without LV impairment.

scholarly journals Expandable human cardiovascular progenitors from stem cells for regenerating mouse heart after myocardial infarction

2019 ◽  
Vol 116 (3) ◽  
pp. 545-553 ◽  
Author(s):  
Verena Schwach ◽  
Maria Gomes Fernandes ◽  
Saskia Maas ◽  
Sophie Gerhardt ◽  
Roula Tsonaka ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Growth Factor ◽  
Mouse Model ◽  
High Efficiency ◽  
Left Ventricular ◽  
Cardiac Repair ◽  
Mouse Heart ◽  
Cell Renewal ◽  
The Impact

Abstract Aims Cardiovascular diseases caused by loss of functional cardiomyocytes (CMs) are a major cause of mortality and morbidity worldwide due in part to the low regenerative capacity of the adult human heart. Human pluripotent stem cell (hPSC)-derived cardiovascular progenitor cells (CPCs) are a potential cell source for cardiac repair. The aim of this study was to examine the impact of extensive remuscularization and coincident revascularization on cardiac remodelling and function in a mouse model of myocardial infarction (MI) by transplanting doxycycline (DOX)-inducible (Tet-On-MYC) hPSC-derived CPCs in vivo and inducing proliferation and cardiovascular differentiation in a drug-regulated manner. Methods and results CPCs were injected firstly at a non-cardiac site in Matrigel suspension under the skin of immunocompromised mice to assess their commitment to the cardiovascular lineage and ability to self-renew or differentiate in vivo when instructed by systemically delivered factors including DOX and basic fibroblast growth factor (bFGF). CPCs in Matrigel were then injected intra-myocardially in mice subjected to MI to assess whether expandable CPCs could mediate cardiac repair. Transplanted CPCs expanded robustly both subcutis and in the myocardium using the same DOX/growth factor inducing regime. Upon withdrawal of these cell-renewal factors, CPCs differentiated with high efficiency at both sites into the major cardiac lineages including CMs, endothelial cells, and smooth muscle cells. After MI, engraftment of CPCs in the heart significantly reduced fibrosis in the infarcted area and prevented left ventricular remodelling, although cardiac function determined by magnetic resonance imaging was unaltered. Conclusion Replacement of large areas of muscle may be required to regenerate the heart of patients following MI. Our human/mouse model demonstrated that proliferating hPSC-CPCs could reduce infarct size and fibrosis resulting in formation of large grafts. Importantly, the results suggested that expanding transplanted cells in situ at the progenitor stage maybe be an effective alternative causing less tissue damage than injection of very large numbers of CMs.

scholarly journals Variability in coronary artery anatomy affects consistency of cardiac damage after myocardial infarction in mice

2017 ◽  
Vol 313 (2) ◽  
pp. H275-H282 ◽  
Author(s):  
Jiqiu Chen ◽  
Delaine K. Ceholski ◽  
Lifan Liang ◽  
Kenneth Fish ◽  
Roger J. Hajjar
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Coronary Artery ◽  
Left Coronary Artery ◽  
Ex Vivo ◽  
Left Ventricular ◽  
Fluorescent Imaging ◽  
Lv Function ◽  
Coronary Artery Ligation ◽  
Functional Parameters

Low reliability and reproducibility in heart failure models are well established. The purpose of the present study is to explore factors that affect model consistency of myocardial infarction (MI) in mice. MI was induced by left coronary artery (LCA) ligation. The coronary artery was casted with resin and visualized with fluorescent imaging ex vivo. LCA characteristics and MI size were analyzed individually in each animal, and MI size was correlated with left ventricular (LV) function by echocardiography. Coronary anatomy varies widely in mice, posing challenges for surgical ligation and resulting in inconsistent MI size postligation. The length of coronary arterial trunk, level of bifurcation, number of branches, and territory supplied by these branches are unique in each animal. When the main LCA trunk is ligated, this results in a large MI, but when a single branch is ligated, MI size is variable due to differing levels of LCA ligation and area supplied by the branches. During the ligation procedure, nearly 40% of LCAs are not grossly visible to the surgeon. In these situations, the surgeon blindly sutures a wider and deeper area of tissue in an attempt to catch the LCA. Paradoxically, these situations have greater odds of resulting in smaller MIs. In conclusion, variation in MI size and LV function after LCA ligation in mice is difficult to avoid. Anatomic diversity of the LCA in mice leads to inconsistency in MI size and functional parameters, and this is independent of potential technical modifications made by the operator. NEW & NOTEWORTHY In the present study, we demonstrate that left coronary artery diversity in mice is one of the primary causes of variable myocardial infarction size and cardiac functional parameters in the left coronary artery ligation model. Recognition of anatomic diversity is essential to improve reliability and reproducibility in heart failure research.

Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists in Cardiac Disorders

2016 ◽  
Vol 50 (12) ◽  
pp. 1041-1050 ◽  
Author(s):  
Jamie Wroge ◽  
Nancy Toedter Williams
Keyword(s):  
Diabetes Mellitus ◽  
Myocardial Infarction ◽  
Heart Failure ◽  
Left Ventricular ◽  
Lv Function ◽  
Receptor Agonists ◽  
Cardiac Disorders ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
The Impact

Objective: To evaluate the literature about the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in the treatment of cardiac disorders, specifically myocardial infarction (MI) and heart failure (HF). Data Sources: Searches were conducted in MEDLINE (1946-May 2016) and Excerpta Medica (1980-May 2016) using EMBASE with the search terms glucagon-like peptide 1, exenatide, albiglutide, liraglutide, dulaglutide, myocardial infarction, heart failure, and cardiovascular. The references of relevant articles were reviewed to identify additional citations. Study Selection and Data Extraction: Clinical trials were limited to the English language and human trials. In all, 18 trials explored the use of GLP-1 RAs in the treatment of cardiac disorders in patients with and without diabetes mellitus. Data Synthesis: Of the 18 trials reviewed, 11 trials studied the impact of GLP-1 RAs in MI. All showed a significant beneficial effect on various cardiac parameters. Favorable outcome improvements included myocardial blood flow, left ventricular (LV) function, and MI size. Seven trials reviewed the use of GLP-1 RAs in the treatment of HF. Three trials showed significant improvements in LV ejection fraction, cardiac index, and peak oxygen consumption. Conclusions: Limited data suggest that GLP-1 RAs may be effective for the treatment of cardiac disorders in patients with and without diabetes mellitus. These studies suggest that GLP-1 RAs may have potential pleiotropic beneficial effects in patients with cardiovascular disease beyond their role in managing diabetes. These medications may be cardioprotective after a MI but are less promising in HF.

scholarly journals Effect of cardiosphere-derived cells on segmental myocardial function after myocardial infarction: ALLSTAR randomised clinical trial

Open Heart ◽  
2021 ◽  
Vol 8 (2) ◽  
pp. e001614
Author(s):  
Mohammad R Ostovaneh ◽  
Raj R Makkar ◽  
Bharath Ambale-Venkatesh ◽  
Deborah Ascheim ◽  
Tarun Chakravarty ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Clinical Trial ◽  
Myocardial Function ◽  
Randomised Clinical Trial ◽  
Scar Tissue ◽  
Left Ventricular ◽  
Lv Function ◽  
Cardiac Events ◽  
Lv Dysfunction ◽  
Registration Number

BackgroundMost cell therapy trials failed to show an improvement in global left ventricular (LV) function measures after myocardial infarction (MI). Myocardial segments are heterogeneously impacted by MI. Global LV function indices are not able to detect the small treatment effects on segmental myocardial function which may have prognostic implications for cardiac events. We aimed to test the efficacy of allogeneic cardiosphere-derived cells (CDCs) for improving regional myocardial function and contractility.MethodsIn this exploratory analysis of a randomised clinical trial, 142 patients with post-MI with LVEF <45% and 15% or greater LV scar size were randomised in 2:1 ratio to receive intracoronary infusion of allogenic CDCs or placebo, respectively. Change in segmental myocardial circumferential strain (Ecc) by MRI from baseline to 6 months was compared between CDCs and placebo groups.ResultsIn total, 124 patients completed the 6-month follow-up (mean (SD) age 54.3 (10.8) and 108 (87.1%) men). Segmental Ecc improvement was significantly greater in patients receiving CDC (−0.5% (4.0)) compared with placebo (0.2% (3.7), p=0.05). The greatest benefit for improvement in segmental Ecc was observed in segments containing scar tissue (change in segmental Ecc of −0.7% (3.5) in patients receiving CDC vs 0.04% (3.7) in the placebo group, p=0.04).ConclusionsIn patients with post-MI LV dysfunction, CDC administration resulted in improved segmental myocardial function. Our findings highlight the importance of segmental myocardial function indices as an endpoint in future clinical trials of patients with post-MI.Trial registration numberNCT01458405.

scholarly journals Cardiac magnetic resonance derived global longitudinal strain outperfoms established functional parameters in prognostication after ST-elevation myocardial infarction

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Holzknecht ◽  
M Reindl ◽  
C Tiller ◽  
I Lechner ◽  
T Hornung ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Magnetic Resonance ◽  
Magnetic Resonance ◽  
Prognostic Value ◽  
Longitudinal Strain ◽  
Independent Predictor ◽  
Global Longitudinal Strain ◽  
Left Ventricular ◽  
Lv Function ◽  
St Elevation

Abstract Background Left ventricular ejection fraction (LVEF) is the parameter of choice for left ventricular (LV) function assessment and risk stratification of patients with ST-elevation myocardial infarction (STEMI); however, its prognostic value is limited. Other measures of LV function such as global longitudinal strain (GLS) and mitral annular plane systolic excursion (MAPSE) might provide additional prognostic information post-STEMI. However, comprehensive investigations comparing these parameters in terms of prediction of hard clinical events following STEMI are lacking so far. Purpose We aimed to investigate the comparative prognostic value of LVEF, MAPSE and GLS by cardiac magnetic resonance (CMR) imaging in the acute stage post-STEMI for the occurrence of major adverse cardiac events (MACE). Methods This observational study included 407 consecutive acute STEMI patients treated with primary percutaneous coronary intervention (PCI). Comprehensive CMR investigations were performed 3 [interquartile range (IQR): 2–4] days after PCI to determine LVEF, GLS and MAPSE as well as myocardial infarct characteristics. Primary endpoint was the occurrence of MACE defined as composite of death, re-infarction and congestive heart failure. Results During a follow-up of 21 [IQR: 12–50] months, 40 (10%) patients experienced MACE. LVEF (p=0.005), MAPSE (p=0.001) and GLS (p&lt;0.001) were significantly related to MACE. GLS showed the highest prognostic value with an area under the curve (AUC) of 0.71 (95% CI 0.63–0.79; p&lt;0.001) compared to MAPSE (AUC: 0.67, 95% CI 0.58–0.75; p=0.001) and LVEF (AUC: 0.64, 95% CI 0.54–0.73; p=0.005). After multivariable analysis, GLS emerged as sole independent predictor of MACE (HR: 1.22, 95% CI 1.11–1.35; p&lt;0.001). Of note, GLS remained associated with MACE (p&lt;0.001) even after adjustment for infarct size and microvascular obstruction. Conclusion CMR-derived GLS emerged as strong and independent predictor of MACE after acute STEMI with additive prognostic validity to LVEF and parameters of myocardial damage. Funding Acknowledgement Type of funding source: None

scholarly journals Computational Investigation of Transmural Differences in Left Ventricular Contractility

2016 ◽  
Vol 138 (11) ◽  
Author(s):  
Hua Wang ◽  
Xiaoyan Zhang ◽  
Shauna M. Dorsey ◽  
Jeremy R. McGarvey ◽  
Kenneth S. Campbell ◽  
...  
Keyword(s):  
Myocardial Contractility ◽  
Ex Vivo ◽  
Experimental Studies ◽  
Contractile Force ◽  
Left Ventricular ◽  
Lv Function ◽  
Fe Model ◽  
Myocardial Layers ◽  
Best Fit

Myocardial contractility of the left ventricle (LV) plays an essential role in maintaining normal pump function. A recent ex vivo experimental study showed that cardiomyocyte force generation varies across the three myocardial layers of the LV wall. However, the in vivo distribution of myocardial contractile force is still unclear. The current study was designed to investigate the in vivo transmural distribution of myocardial contractility using a noninvasive computational approach. For this purpose, four cases with different transmural distributions of maximum isometric tension (Tmax) and/or reference sarcomere length (lR) were tested with animal-specific finite element (FE) models, in combination with magnetic resonance imaging (MRI), pressure catheterization, and numerical optimization. Results of the current study showed that the best fit with in vivo MRI-derived deformation was obtained when Tmax assumed different values in the subendocardium, midmyocardium, and subepicardium with transmurally varying lR. These results are consistent with recent ex vivo experimental studies, which showed that the midmyocardium produces more contractile force than the other transmural layers. The systolic strain calculated from the best-fit FE model was in good agreement with MRI data. Therefore, the proposed noninvasive approach has the capability to predict the transmural distribution of myocardial contractility. Moreover, FE models with a nonuniform distribution of myocardial contractility could provide a better representation of LV function and be used to investigate the effects of transmural changes due to heart disease.

Regulation of components of the brain and cardiac renin-angiotensin systems by 17β-estradiol after myocardial infarction in female rats

2006 ◽  
Vol 291 (1) ◽  
pp. R155-R162 ◽  
Author(s):  
Stephanie A. Dean ◽  
Junhui Tan ◽  
Roselyn White ◽  
Edward R. O’Brien ◽  
Frans H. H. Leenen
Keyword(s):  
Myocardial Infarction ◽  
Left Ventricular ◽  
Female Rats ◽  
Lv Function ◽  
Coronary Artery Ligation ◽  
Brain Nuclei ◽  
Renin Angiotensin ◽  
Lv Dysfunction ◽  
17Β Estradiol ◽  
The Brain

The present study tested the hypothesis that 17β-estradiol (E2) inhibits increases in angiotensin-converting enzyme (ACE) and ANG II type 1 receptor (AT1R) in the brain and heart after myocardial infarction (MI) and, thereby, inhibits development of left ventricular (LV) dysfunction after MI. Age-matched female Wistar rats were treated as follows: 1) no surgery (ovary intact), 2) ovariectomy + subcutaneous vehicle treatment (OVX + Veh), or 3) OVX + subcutaneous administration of a high dose of E2 (OVX + high-E2). After 2 wk, rats were randomly assigned to coronary artery ligation (MI) and sham operation groups and studied after 3 wk. E2 status did not affect LV function in sham rats. At 2–3 wk after MI, impairment of LV function was similar across MI groups, as measured by echocardiography and direct LV catheterization. LV ACE mRNA abundance and activity were increased severalfold in all MI groups compared with respective sham animals and to similar levels across MI groups. In most brain nuclei, ACE and AT1R densities increased after MI. Unexpectedly, compared with the respective sham groups the relative increase was clearest (20–40%) in OVX + high-E2 MI rats, somewhat less (10–15%) in ovary-intact MI rats, and least (<10–15%) in OVX + Veh MI rats. However, because in the sham group brain ACE and AT1R densities increased in the OVX + Veh rats and decreased in the OVX + high-E2 rats compared with the ovary-intact rats, actual ACE and AT1R densities in most brain nuclei were modestly higher (<20%) in OVX + Veh MI rats than in the other two MI groups. Thus E2 does not inhibit upregulation of ACE in the LV after MI and amplifies the percent increases in ACE and AT1R densities in brain nuclei after MI, despite E2-induced downregulation in sham rats. Consistent with these minor variations in the tissue renin-angiotensin system, during the initial post-MI phase, E2 appears not to enhance or hinder the development of LV dysfunction.

scholarly journals Impaired left ventricular mechanical and energetic function in mice after cardiomyocyte-specific excision of Serca2

2014 ◽  
Vol 306 (7) ◽  
pp. H1018-H1024 ◽  
Author(s):  
N. T. Boardman ◽  
J. M. Aronsen ◽  
W. E. Louch ◽  
I. Sjaastad ◽  
F. Willoch ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Left Ventricular ◽  
Lv Function ◽  
Mechanical Function ◽  
Transport Mechanisms ◽  
Working Capacity ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Plasmic Reticulum ◽  
The Relationship

Sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2 transports Ca2+ from the cytosol into the sarcoplasmic reticulum of cardiomyocytes and is essential for maintaining myocardial Ca2+ handling and thus the mechanical function of the heart. SERCA2 is a major ATP consumer in excitation-contraction coupling but is regarded to contribute to energetically efficient Ca2+ handling in the cardiomyocyte. Previous studies using cardiomyocyte-specific SERCA2 knockout (KO) mice have demonstrated that decreased SERCA2 activity reduces the Ca2+ transient amplitude and induces compensatory Ca2+ transport mechanisms that may lead to more inefficient Ca2+ transport. In this study, we examined the relationship between left ventricular (LV) function and myocardial O2 consumption (MV̇o2) in ex vivo hearts from SERCA2 KO mice to directly measure how SERCA2 elimination influences mechanical and energetic features of the heart. Ex vivo hearts from SERCA2 KO hearts developed mechanical dysfunction at 4 wk and demonstrated virtually no working capacity at 7 wk. In accordance with the reported reduction in Ca2+ transient amplitude in cardiomyocytes from SERCA2 KO mice, work-independent MV̇o2 was decreased due to a reduced energy cost of excitation-contraction coupling. As these hearts also showed a marked impairment in the efficiency of chemomechanical energy transduction (contractile efficiency, i.e, work-dependent MV̇o2), hearts from SERCA2 KO mice were found to be mechanically inefficient. This ex vivo evaluation of mechanical and energetic function in hearts from SERCA2 KO mice brings together findings from previous experimental and mathematical modeling-based studies and demonstrates that reduced SERCA2 activity not only leads to mechanical dysfunction but also to energetic dysfunction.

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