Accelerated LV remodeling after myocardial infarction in TIMP-1-deficient mice: effects of exogenous MMP inhibition

2005 ◽  
Vol 288 (1) ◽  
pp. H149-H158 ◽  
Author(s):  
John S. Ikonomidis ◽  
Jennifer W. Hendrick ◽  
Andrea M. Parkhurst ◽  
Amanda R. Herron ◽  
Patricia G. Escobar ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Ejection Fraction ◽  
Left Ventricular ◽  
Wild Type ◽  
End Diastolic Volume ◽  
Coronary Ligation ◽  
Lv Remodeling ◽  
And Function ◽  
Deficient Mice

Alterations in matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) have been implicated in adverse left ventricular (LV) remodeling after myocardial infarction (MI). However, the direct mechanistic role of TIMPs in the post-MI remodeling process has not been completely established. The goal of this project was to define the effects of altering endogenous MMP inhibitory control through combined genetic and pharmacological approaches on post-MI remodeling in mice. This study examined the effects of MMP inhibition (MMPi) with PD-166793 (30 mg·kg−1·day−1) on LV geometry and function (conductance volumetry) after MI in wild-type (WT) mice and mice deficient in the TIMP-1 gene [TIMP-1 knockout (TIMP1-KO)]. At 3 days after MI (coronary ligation), mice were randomized into four groups: WT-MI/MMPi ( n = 10), TIMP1-KO-MI/MMPi ( n = 10), WT-MI ( n = 22), and TIMP1-KO-MI ( n = 23). LV end-diastolic volume (EDV) and ejection fraction were determined 14 days after MI. Age-matched WT ( n = 20) and TIMP1-KO ( n = 28) mice served as reference controls. LVEDV was similar under control conditions in WT and TIMP1-KO mice (36 ± 2 and 40 ± 2 μl, respectively) but was greater in TIMP1-KO-MI than in WT-MI mice (48 ± 2 vs. 61 ± 5 μl, P < 0.05). LVEDV was reduced from MI-only values in WT-MI/MMPi and TIMP1-KO-MI/MMPi mice (42 ± 2 and 36 ± 2 μl, respectively, P < 0.05) but was reduced to the greatest degree in TIMP1-KO mice ( P < 0.05). LV ejection fraction was reduced in both groups after MI and increased in TIMP1-KO-MI/MMPi, but not in WT-MI/MMPi, mice. These unique results demonstrated that myocardial TIMP-1 plays a regulatory role in post-MI remodeling and that the accelerated myocardial remodeling induced by TIMP-1 gene deletion can be pharmacologically “rescued” by MMP inhibition. These results define the importance of local endogenous control of MMP activity with respect to regulating LV structure and function after MI.

Sepiapterin enhances angiogenesis and functional recovery in mice after myocardial infarction

2011 ◽  
Vol 301 (5) ◽  
pp. H2061-H2072 ◽  
Author(s):  
Takayuki Shimazu ◽  
Hajime Otani ◽  
Kei Yoshioka ◽  
Masanori Fujita ◽  
Toru Okazaki ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Myocardial Infarction ◽  
Functional Recovery ◽  
Capillary Density ◽  
Left Ventricular ◽  
Wild Type ◽  
Beneficial Effects ◽  
End Diastolic Volume ◽  
Lv Remodeling ◽  
And Function

Uncoupling of nitric oxide synthase (NOS) has been implicated in left ventricular (LV) remodeling and dysfunction after myocardial infarction (MI). We hypothesized that inducible NOS (iNOS) plays a crucial role in LV remodeling after MI, depending on its coupling status. MI was created in wild-type, iNOS-knockout (iNOS−/−), endothelial NOS-knockout (eNOS−/−), and neuronal NOS-knockout (nNOS−/−) mice. iNOS and nNOS expressions were increased after MI associated with an increase in nitrotyrosine formation. The area of myocardial fibrosis and LV end-diastolic volume and ejection fraction were more deteriorated in eNOS−/− mice compared with other genotypes of mice 4 wk after MI. The expression of GTP cyclohydrolase was reduced, and tetrahydrobiopterin (BH4) was depleted in the heart after MI. Oral administration of sepiapterin after MI increased dihydrobiopterin (BH2), BH4, and BH4-to-BH2 ratio in the infarcted but not sham-operated heart. The increase in BH4-to-BH2 ratio was associated with inhibition of nitrotyrosine formation and an increase in nitrite plus nitrate. However, this inhibition of NOS uncoupling was blunted in iNOS−/− mice. Sepiapterin increased capillary density and prevented LV remodeling and dysfunction after MI in wild-type, eNOS−/−, and nNOS−/− but not iNOS−/− mice. Nω-nitro-l-arginine methyl ester abrogated sepiapterin-induced increase in nitrite plus nitrate and angiogenesis and blocked the beneficial effects of sepiapterin on LV remodeling and function. These results suggest that sepiapterin enhances angiogenesis and functional recovery after MI by activating the salvage pathway for BH4 synthesis and increasing bioavailable nitric oxide predominantly derived from iNOS.

Abstract 1412: Critical Role Of Extracellular Sod For Protecting The Heart Against Myocardial Hypertrophy And Dysfunction After Myocardial Infarction

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Elza D Deel ◽  
Zhongbing LU ◽  
Xin Xu ◽  
Guangshuo Zhu ◽  
Xinli Hu ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Ejection Fraction ◽  
Superoxide Anion ◽  
Left Ventricular ◽  
Wild Type ◽  
Sod Activity ◽  
Superoxide Anion Production ◽  
Lv Remodeling ◽  
Anion Production ◽  
Lv Ejection Fraction

Extracellular SOD ( SOD3 ) contributes only a small fraction to total SOD activity in the normal heart, but is strategically located to scavenge free radicals in the extracellular compartment. SOD3 expression is decreased in the failing heart, but whether SOD3 can abrogate oxidative stress or modify left ventricular (LV) remodeling following myocardial infarction (MI) is unclear. To examine this question, we studied LV remodeling in SOD3 KO mice and wild type mice following MI. Under unstressed conditions, SOD3 KO had no effect on myocardial total SOD activity, SOD1 or SOD2 protein content, or myocardial nitrotyrosine or superoxide anion production, and caused no change in LV ejection fraction. However, 4 weeks or 8 weeks after MI, SOD3 KO mice developed more LV hypertrophy (8 weeks after MI, ventricular mass increased 1.64-fold in KO mice as compared to 1.35-fold in wild type mice, p<0.01) and had a greater reduction of LV ejection fraction (8 weeks after MI, LV ejection fraction was 35±2.4% in wild type mice as compared to 30±2.0% in KO mice, p<0.01). As compared with wild type mice, SOD3 KO mice had significantly greater increases of myocardial nitrotyrosine and superoxide anion production, a significantly greater decrease of ANP in the peri-infarct zone, and a significant more decrease of SERCA2a in both the peri-infarct and remote zones. In addition, MI caused greater activation of mitogen-activated protein kinase (MAPK) signaling pathways in SOD3 KO mice, as demonstrated by significantly greater increases of p-p38 Thr180/ Tyr182 , p-Erk Thr202/Tyr204 and p-JNK Thr183/Tyr185 in SOD3 KO mice 8 weeks after MI. The finding that SOD3 KO had no effect on myocardial total SOD activity, but significantly exacerbated MI induced LV remodeling implies that the specific extracellular location of SOD3 is more important than its contribution to overall SOD activity in protecting the heart against contractile dysfunction following myocardial infarct.

scholarly journals Cyclosporin A in left ventricular remodeling after myocardial infarction

2014 ◽  
Vol 306 (1) ◽  
pp. H53-H59 ◽  
Author(s):  
Andaleb Kholmukhamedov ◽  
Christina Logdon ◽  
Jiangting Hu ◽  
Richard A. McKinney ◽  
Francis G. Spinale ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Ejection Fraction ◽  
Cyclosporin A ◽  
Ventricular Remodeling ◽  
Mitochondrial Permeability Transition ◽  
Left Ventricular ◽  
Terminal Deoxynucleotidyl Transferase ◽  
End Diastolic Volume ◽  
Lv Remodeling ◽  
Lv Ejection Fraction

Recent studies suggest that an increase in apoptosis within the myocardium may be a contributing factor for the progression of late adverse left ventricular (LV) remodeling following myocardial infarction (MI). Given that apoptosis is often triggered by induction of the mitochondrial permeability transition (MPT) pore, the goal of this study was to evaluate the therapeutic efficacy of cyclosporin A (CsA), an MPT blocker, to prevent cells from undergoing apoptosis and consequently attenuate late LV remodeling post-MI. MI was induced in C57BL/6 mice and then randomized to either vehicle or CsA groups. Beginning 48 h after surgery after infarction had already occurred, mice were gavaged with CsA (2 mg/kg) or vehicle once daily. LV end-diastolic volume and LV ejection fraction were assessed by echocardiography before MI induction and terminally at either 7 days ( n = 7) or 28 days ( n = 8) post-MI. LV end-diastolic volume increased and LV ejection fraction decreased in all MI groups with no difference between the CsA-treated and untreated groups. After vehicle and CsA, areas of necrosis were present at 7 and 28 days post-MI with no difference between treatment groups. Caspase-3 activity and terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling in distal nonnecrotic LV both increased after MI but were lower in CsA-treated mice compared with vehicle ( P < 0.05). In conclusion, CsA decreased apoptosis occurring late after MI, confirming involvement of a CsA-sensitive MPT in the cell death. However, CsA-mediated reduction in apoptosis in non-MI myocardium was not beneficial against late pump dysfunction occurring during post-MI remodeling.

Cardiac magnetic resonance T1 mapping allows for predicting adverse left ventricular remodeling post-reperfused st-elevation myocardial infarction

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
L Zhang ◽  
Y.K Guo ◽  
Z.G Yang ◽  
M.X Yang ◽  
K.Y Diao ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
T1 Mapping ◽  
Ventricular Remodeling ◽  
Tissue Injury ◽  
Left Ventricular ◽  
Funding Source ◽  
Native T1 ◽  
End Diastolic Volume ◽  
Significant Difference ◽  
Lv Remodeling

Abstract Background Cardiac magnet resonance (CMR) T1 mapping allows the quantitative characterization of the severity of tissue injury and predict functional recovery in acute myocardial infarction (AMI). Purpose The study aimed to investigate whether native T1 and ECV of infarct myocardium are influenced by microvascular obstruction (MVO) and have predictive value for adverse left ventricular (LV) remodeling post-infarction. Method A cohort of 54 patients with successfully reperfused STEMI underwent CMR imaging at a 3T scanner in AMI and 3 months post-infarction. Native T1 data was acquired using a modified Look-Locker inversion recovery (MOLLI) sequence, and ECV maps were calculated using blood sampled hematocrit. Manual regions-of-interest were drawn within the infarct myocardium to measure native T1 and ECV (native T1infarct and ECVinfarct, respectively). MVO identified as a low-intensity area within the infarct zone on LGE was eliminated. Results MVO was present in 36 patients (66.67%) in AMI. ECVinfarct in patients with MVO was different from those without (58.66±8.71% vs. 49.64±8.82%, P=0.001), while no significant difference in T1infarct was observed between patients with and without MVO (1474.7±63.5ms vs. 1495.4±98.0ms, P=0.352). ECV correlated well with the change in end-diastolic volume (all patients: r=0.564, P&lt;0.001) and predicted LV remodeling in patients with and without MVO (rMVO absent = 0.626, P=0.005; rMVO present = 0.686, P&lt;0.001; all patients: r=0.622, P&lt;0.001); Native T1 was only associated with a 3-month change in LV end-diastolic volume (rMVO absent= 0.483, P=0.042) and predicted LV remodeling in patients without MVO (rMVO absent = 0.659, P=0.003). Furthermore, ECV had an association with LV remodeling (β=0.312, P=0.007) in multivariable logistic analysis. Conclusion Absolute native T1 in infarct myocardium might be affected by MVO but ECV isn't. ECV could predict LV remodeling in MI patients with and without MVO, while native T1 predict it in MI with MVO absent. Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): 1·3·5 project for disciplines of excellence, West China Hospital, Sichuan University

scholarly journals Leukocyte-type 12-lipoxygenase-deficient mice show impaired ischemic preconditioning-induced cardioprotection

2001 ◽  
Vol 280 (5) ◽  
pp. H1963-H1969 ◽  
Author(s):  
Scott A. Gabel ◽  
Robert E. London ◽  
Colin D. Funk ◽  
Charles Steenbergen ◽  
Elizabeth Murphy
Keyword(s):  
Left Ventricular ◽  
Rate Pressure Product ◽  
Wild Type ◽  
Initial Value ◽  
Triphenyltetrazolium Chloride ◽  
Developed Pressure ◽  
12 Lipoxygenase ◽  
Postischemic Recovery ◽  
Deficient Mice

To investigate the role of 12-lipoxygenase in preconditioning, we examined whether hearts lacking the “leukocyte-type” 12-lipoxygenase (12-LOKO) would be protected by preconditioning. In hearts from wild-type (WT) and 12-LOKO mice, left ventricular developed pressure (LVDP) and 31P NMR were monitored during treatment (±preconditioning) and during global ischemia and reperfusion. Postischemic function (rate-pressure product, percentage of initial value) measured after 20 min of ischemia and 40 min of reperfusion was significantly improved by preconditioning in WT hearts (78 ± 12% in preconditioned vs. 44 ± 7% in nonpreconditioned hearts) but not in 12-LOKO hearts (47 ± 7% in preconditioned vs. 33 ± 10% in nonpreconditioned hearts). Postischemic recovery of phosphocreatine was significantly better in WT preconditioned hearts than in 12-LOKO preconditioned hearts. Preconditioning significantly reduced the fall in intracellular pH during sustained ischemia in both WT and 12-LOKO hearts, suggesting that attenuation of the fall in pH during ischemia can be dissociated from preconditioning-induced protection. Necrosis was assessed after 25 min of ischemia and 2 h of reperfusion using 2,3,5-triphenyltetrazolium chloride. In WT hearts, preconditioning significantly reduced the area of necrosis (26 ± 4%) compared with nonpreconditioned hearts (62 ± 10%) but not in 12-LOKO hearts (85 ± 3% in preconditioned vs. 63 ± 11% in nonpreconditioned hearts). Preconditioning resulted in a significant increase in 12( S)-hydroxyeicosatetraenoic acid in WT but not in 12-LOKO hearts. These data demonstrate that 12-lipoxygenase is important in preconditioning.

Role of gp91phox-containing NADPH oxidase in left ventricular remodeling induced by intermittent hypoxic stress

2008 ◽  
Vol 294 (5) ◽  
pp. H2197-H2203 ◽  
Author(s):  
Tetsuya Hayashi ◽  
Chika Yamashita ◽  
Chika Matsumoto ◽  
Chol-Jun Kwak ◽  
Kiwako Fujii ◽  
...  
Keyword(s):  
Cardiovascular Diseases ◽  
Nadph Oxidase ◽  
Intermittent Hypoxia ◽  
Sleep Apnea Syndrome ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Hypoxic Stress ◽  
Wild Type ◽  
Lv Remodeling

Intermittent hypoxia due to sleep apnea syndrome is associated with cardiovascular diseases. However, the precise mechanisms by which intermittent hypoxic stress accelerates cardiovascular diseases are largely unclear. The aim of this study was to investigate the role of gp91 phox-containing NADPH oxidase in the development of left ventricular (LV) remodeling induced by intermittent hypoxic stress in mice. Male gp91 phox-deficient (gp91−/−) mice ( n = 26) and wild-type ( n = 39) mice at 7–12 wk of age were exposed to intermittent hypoxia (30 s of 4.5–5.5% O2 followed by 30 s of 21% O2 for 8 h/day during daytime) or normoxia for 10 days. Mean blood pressure and LV systolic and diastolic function were not changed by intermittent hypoxia in wild-type or gp91−/− mice, although right ventricular systolic pressure tended to be increased. In wild-type mice, intermittent hypoxic stress significantly increased the diameter of cardiomyocytes and interstitial fibrosis in LV myocardium. Furthermore, intermittent hypoxic stress increased superoxide production, 4-hydroxy-2-nonenal protein, TNF-α and transforming growth factor-β mRNA, and NF-κB binding activity in wild-type, but not gp91−/−, mice. These results suggest that gp91 phox-containing NADPH oxidase plays a crucial role in the pathophysiology of intermittent hypoxia-induced LV remodeling through an increase of oxidative stress.

Disproportionate secondary mitral regurgitation: myths, misconceptions and clinical implications

Heart ◽  
2020 ◽  
pp. heartjnl-2020-316992
Author(s):  
Paul A Grayburn ◽  
Milton Packer ◽  
Anna Sannino ◽  
Gregg W Stone
Keyword(s):  
Mitral Regurgitation ◽  
Ejection Fraction ◽  
Medical Therapy ◽  
Mean Value ◽  
Left Ventricular ◽  
Functional Mitral Regurgitation ◽  
Lv Function ◽  
End Diastolic Volume ◽  
Regurgitant Orifice Area ◽  
And Function

Secondary (functional) mitral regurgitation (SMR) most commonly arises secondary to left ventricular (LV) dilation/dysfunction. The concept of disproportionately severe SMR was proposed to help explain the different results of two randomised trials of transcatheter edge-to-edge mitral valve repair (TEER) versus medical therapy. This concept is based on the fact that effective regurgitant orifice area (EROA) depends on LV end-diastolic volume (LVEDV), ejection fraction, regurgitant fraction and the velocity-time integral of SMR. This review focuses on the haemodynamic framework underlying the concept and the myths and misconceptions arising from it. Each component of EROA/LVEDV is prone to measurement error which can result in misclassification of individual patients. Moreover, EROA is typically measured at peak systole rather than its mean value over the duration of MR. This can result in physiologically impossible values of EROA or regurgitant volume. Although the EROA/LVEDV ratio (1) emphasises that grading MR severity needs to consider LV size and function and (2) helps explain the different outcomes between COAPT and MITRAFR, there are important factors that are not included. Among these are left atrial compliance, LV pressure and ejection fraction, pulmonary hypertension, right ventricular function and tricuspid regurgitation. Because medical therapy can reduce LV volumes and improve both LV function and SMR severity, the key to patient selection is forced titration of neurohormonal antagonists to the target doses that have been proven in clinical trials (along with cardiac resynchronisation when appropriate). Patients who continue to have symptomatic severe SMR after doing so should be considered for TEER.

scholarly journals Changes in Cardiac Morphology and Function in Individuals With Diabetes Mellitus

2019 ◽  
Vol 12 (9) ◽  
Author(s):  
Magnus T. Jensen ◽  
Kenneth Fung ◽  
Nay Aung ◽  
Mihir M. Sanghvi ◽  
Sucharitha Chadalavada ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Ejection Fraction ◽  
Right Ventricular ◽  
Left Ventricular ◽  
Right Atrial ◽  
Ventricular Ejection Fraction ◽  
End Diastolic Volume ◽  
Lv Mass ◽  
Lv Ejection Fraction ◽  
And Function

Background: Diabetes mellitus (DM) is associated with increased risk of cardiovascular disease. Detection of early cardiac changes before manifest disease develops is important. We investigated early alterations in cardiac structure and function associated with DM using cardiovascular magnetic resonance imaging. Methods: Participants from the UK Biobank Cardiovascular Magnetic Resonance Substudy, a community cohort study, without known cardiovascular disease and left ventricular ejection fraction ≥50% were included. Multivariable linear regression models were performed. The investigators were blinded to DM status. Results: A total of 3984 individuals, 45% men, (mean [SD]) age 61.3 (7.5) years, hereof 143 individuals (3.6%) with DM. There was no difference in left ventricular (LV) ejection fraction (DM versus no DM; coefficient [95% CI]: −0.86% [−1.8 to 0.5]; P =0.065), LV mass (−0.13 g/m 2 [−1.6 to 1.3], P =0.86), or right ventricular ejection fraction (−0.23% [−1.2 to 0.8], P =0.65). However, both LV and right ventricular volumes were significantly smaller in DM, (LV end-diastolic volume/m 2 : −3.46 mL/m 2 [−5.8 to −1.2], P =0.003, right ventricular end-diastolic volume/m 2 : −4.2 mL/m 2 [−6.8 to −1.7], P =0.001, LV stroke volume/m 2 : −3.0 mL/m 2 [−4.5 to −1.5], P <0.001; right ventricular stroke volume/m 2 : −3.8 mL/m 2 [−6.5 to −1.1], P =0.005), LV mass/volume: 0.026 (0.01 to 0.04) g/mL, P =0.006. Both left atrial and right atrial emptying fraction were lower in DM (right atrial emptying fraction: −6.2% [−10.2 to −2.1], P =0.003; left atrial emptying fraction:−3.5% [−6.9 to −0.1], P =0.043). LV global circumferential strain was impaired in DM (coefficient [95% CI]: 0.38% [0.01 to 0.7], P =0.045). Conclusions: In a low-risk general population without known cardiovascular disease and with preserved LV ejection fraction, DM is associated with early changes in all 4 cardiac chambers. These findings suggest that diabetic cardiomyopathy is not a regional condition of the LV but affects the heart globally.

MiR-223 is dispensable for platelet production and function in mice

2013 ◽  
Vol 110 (12) ◽  
pp. 1207-1214 ◽  
Author(s):  
Xavier Loyer ◽  
Simon Leierseder ◽  
Tobias Petzold ◽  
Lin Zhang ◽  
Steffen Massberg ◽  
...  
Keyword(s):  
Platelet Adhesion ◽  
Cell Types ◽  
Surface Expression ◽  
Wild Type ◽  
Platelet Production ◽  
Multiple Cell ◽  
And Function ◽  
Deficient Mice ◽  
Platelet Depletion

SummaryMicroRNAs (miRNAs) are key physiological regulators in multiple cell types. Here, we assessed platelet production and function in mice deficient in miR-223, one of the most abundantly expressed miRNAs in platelets and megakaryocytes. We found platelet number, size, lifespan as well as surface expression of platelet adhesion receptors to be unchanged in miR-223-deficient mice. Likewise, loss of miR-223 did not affect platelet activation, adhesion and aggregation and also had no effect on bleeding times. Moreover, miR-223 null megakaryocytes developed normally and were capable to form pro-platelets. However, we detected a transient delay in the recovery of platelet numbers following antibody-induced platelet depletion in miR-223-deficient animals. This delay was not observed after transplantation of bone marrow from miR-223-deficient animals into wild-type recipients, indicating a non-cell-autonomous role of miR-223 for thrombopoiesis. Overall, our data indicate a surprisingly modest role of miR-223 in platelet production, while the function of platelets does not seem to depend on miR-223.

Sign in / Sign up

Export Citation Format

Share Document