Detrimental effect of combined exercise training and eNOS overexpression on cardiac function after myocardial infarction

2009 ◽  
Vol 296 (5) ◽  
pp. H1513-H1523 ◽  
Author(s):  
Monique C. de Waard ◽  
Jolanda van der Velden ◽  
Nicky M. Boontje ◽  
Dick H. W. Dekkers ◽  
Rien van Haperen ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Exercise Training ◽  
Left Ventricular ◽  
Lv Function ◽  
Enos Expression ◽  
Beneficial Effects ◽  
Protein Levels ◽  
Enos Uncoupling ◽  
Lv Remodeling ◽  
Exercise Induced

It has been reported that exercise after myocardial infarction (MI) attenuates left ventricular (LV) pump dysfunction by normalization of myofilament function. This benefit could be due to an exercise-induced upregulation of endothelial nitric oxide synthase (eNOS) expression and activity. Consequently, we first tested the hypothesis that the effects of exercise after MI can be mimicked by elevated eNOS expression using transgenic mice with overexpression of human eNOS (eNOSTg). Both exercise and eNOSTg attenuated LV remodeling and dysfunction after MI in mice and improved cardiomyocyte maximal force development (Fmax). However, only exercise training restored myofilament Ca2+-sensitivity and sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2a protein levels and improved the first derivative of LV pressure at 30 mmHg. Conversely, only eNOSTg improved survival. In view of these partly complementary actions, we subsequently tested the hypothesis that combining exercise and eNOSTg would provide additional protection against LV remodeling and dysfunction after MI. Unexpectedly, the combination of exercise and eNOSTg abolished the beneficial effects on LV remodeling and dysfunction of either treatment alone. The latter was likely due to perturbations in Ca2+ homeostasis, as myofilament Fmax actually increased despite marked reductions in the phosphorylation status of several myofilament proteins, whereas the exercise-induced increases in SERCA2a protein levels were lost in eNOSTg mice. Antioxidant treatment with N-acetylcysteine or supplementation of tetrahydrobiopterin and l-arginine prevented these detrimental effects on LV function while partly restoring the phosphorylation status of myofilament proteins and further enhancing myofilament Fmax. In conclusion, the combination of exercise and elevated eNOS expression abolished the cardioprotective effects of either treatment alone after MI, which appeared to be, at least in part, the result of increased oxidative stress secondary to eNOS “uncoupling.”

Abstract 14119: Contrasting Effects of Exercise Training After Acute Myocardial Infarction versus Aortic Stenosis Depend Critically on the Regulation of Endothelial Nitric Oxide Synthase

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Yanti Octavia ◽  
Elza D van Deel ◽  
Monique de Waard ◽  
Martine de Boer ◽  
Dirk J Duncker
Keyword(s):  
Nitric Oxide ◽  
Myocardial Infarction ◽  
Exercise Training ◽  
Wheel Running ◽  
Left Ventricular ◽  
Lv Function ◽  
Enhanced Chemiluminescence ◽  
Lv Dysfunction ◽  
Enos Uncoupling ◽  
Endothelial Nitric Oxide

Introduction: The cardiovascular benefits of exercise training (EX) are widely appreciated. Previously we found that the cardiac effects of EX critically depend on the underlying cause of heart disease. Hypothesis: The underlying etiology determines how EX affects the endothelial nitric oxide (NO) synthase (eNOS)-mediated balance between NO and superoxide (O2-). Methods: Mice were subjected to sham surgery, myocardial infarction (MI) or transverse aortic constriction (TAC), and subsequently exposed to 8 weeks of voluntary wheel running or sedentary housing. Left ventricular (LV) function was assessed by echocardiography and hemodynamic measurements; fibrosis by Picro-sirius Red staining; peroxynitrite (ONOO-) and O2- production by luminol- and lucigenin-enhanced chemiluminescence respectively, with or without the NOS inhibitor L-NAME; eNOS uncoupling and eNOS S-glutathionylation by western blot and coimmunoprecipitation, respectively; cardiac NO by the Griess reaction. Results: EX ameliorated LV dysfunction and fibrosis in MI but not TAC (Table 1). Strikingly, O2- generation was blunted by EX in MI, but exacerbated by EX in TAC, which was largely NOS-dependent. Accordingly, eNOS uncoupling and eNOS S-glutathionylation were corrected by EX in MI but aggravated in TAC mice. In parallel, ONOO- levels was attenuated by EX in MI but aggravated by EX in TAC. Cardiac NO levels were reduced in MI and TAC and normalized by EX in MI. Conclusions: The contrasting effects of EX in MI vs TAC can be explained by the highly divergent effects of EX on eNOS regulation, resulting in blunted vs aggravated oxidative stress by EX in MI vs TAC.

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 1509: Exercise Training Started Before Myocardial Infarction Improves Survival but Aggravates Left Ventricular Dysfunction

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Monique C de Waard ◽  
Dirk J Duncker
Keyword(s):  
Myocardial Infarction ◽  
Exercise Training ◽  
Wheel Running ◽  
Left Ventricular ◽  
Lv Function ◽  
Cardiac Events ◽  
Cross Sectional ◽  
Voluntary Wheel Running ◽  
Lv Dysfunction ◽  
Voluntary Wheel

Introduction: Regular physical activity in patients with established coronary heart disease not only reduces the incidence of cardiac events, but also reduces the risk of all-cause mortality. Recently, we showed in mice that exercise training (EX) started immediately after myocardial infarction (MI) ameliorates left ventricular (LV) dysfunction. Here we tested the hypothesis that additional exercise training prior to an acute MI, i.e. a higher level of physical fitness at the time of MI, is associated with improved survival and attenuated LV dysfunction after MI. Methods and Results: MI was induced by permanent coronary ligation in 128 C57Bl/6 mice and subsequently followed by 8 weeks of voluntary wheel running (MI-EX) or sedentary housing (MI). In a third group, voluntary wheel running was started two weeks before induction of MI (EX-MI-EX). Sham operated mice served as controls. EX after MI had no effect on survival, infarct size, LV hypertrophy or dilation (Table ). However, EX improved LV function, reflected in enhanced LV fractional shortening (FS), rate of rise in LV pressure at 30 mmHg (LVdP/dt P30 ), and decreased pulmonary congestion and right ventricular weight (RVW). When EX was started prior to MI, post-MI survival nearly doubled and mice ran an average post-MI distance of ~7km/d compared to ~5km/d in MI-EX mice. Infarct cross-sectional area was larger, which was principally due to an increased infarct thickness (0.15±0.02mm EX-MI-EX vs 0.11±0.01mm MI; P =0.06). Surprisingly, however, LV hypertrophy and dysfunction were aggravated in the EX-MI-EX group compared to MI-EX. Conclusion: In line with our hypothesis, EX started prior to MI improved survival. However, contrary to our hypothesis, the improved survival was associated with a deterioration of LV dysfunction. The latter may have been the result of survival and hence inclusion of mice with the most severe LV dysfunction.

Beneficial effects of exercise training after myocardial infarction require full eNOS expression

2010 ◽  
Vol 48 (6) ◽  
pp. 1041-1049 ◽  
Author(s):  
Monique C. de Waard ◽  
Rien van Haperen ◽  
Thomas Soullié ◽  
Dennie Tempel ◽  
Rini de Crom ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Exercise Training ◽  
Enos Expression ◽  
Beneficial Effects

P2582Signature of plasma extracellular vesicles associated proteins in acute myocardial infarction patients

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
J W Wang ◽  
S M J M Yatim ◽  
X C Lim ◽  
S Y Chong ◽  
X Wang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Healthy Subjects ◽  
Structural Equation ◽  
Longitudinal Data Analysis ◽  
Equation Model ◽  
Left Ventricular ◽  
Protein Levels ◽  
Lv Remodeling ◽  
Associated Proteins ◽  
Multi Level

Abstract Background Prediction of left ventricular (LV) remodeling post-acute myocardial infarction (AMI) remains challenging. Several circulating biomarkers have been associated with post-AMI LV remodeling, however, there is no biomarker available to distinguish adverse versus reverse LV remodeling. Purpose In this study, we aimed to assess the association of extracellular vesicles (EVs) associated proteins with LV remodeling post-AMI. Methods Plasma EVs were isolated via precipitation with dextran sulphate as we previously reported. The protein levels of EV associated von Willebrand factor (VWF), SerpinC1 (antithrombin-III), plasminogen and SerpinF2 (alpha 2-antiplasmin) were determined in the citrate-anticoagulated plasma from 57 healthy subjects and 200 patients recruited in the Post-AMI Left Ventricular Remodeling Biomarker Analysis (PAMILA) study. Patients were categorized into two groups: adverse LV remodeling (n=100) characterized by an increase or reverse LV remodeling (n=100) characterized by a decrease, in LV end systolic volume by ≥15% over 6 months. Patients' plasma was collected at baseline (within 3 days after percutaneous coronary intervention), 1 month and 6 months post-AMI. Log transformation of EV protein levels was performed for assessment in a multiple multi-level longitudinal data analysis with structural equation model (with level of significance fixed at 0.05). Results Compared to healthy subjects, baseline protein levels of EV associated VWF and SerpinF2 were significantly higher in post-AMI patients, whereas no difference was observed in SerpinC1 and plasminogen. Among the patients, those on statins (196 out of 200 patients) showed lower protein levels of EV associated VWF (p<0.001) and plasminogen (p=0.003), whereas patients treated with P2Y12 platelet inhibitors (195 out of 200 patients) showed higher protein levels of EV associated VWF (p=0.003) and plasminogen (p=0.035). Multiple multi-level longitudinal data analysis with structural equation model showed that protein levels of EV associated VWF (p<0.001) and SerpinC1 (p=0.021) were lower in patients with adverse LV remodeling than that in patients with reverse LV remodeling during the 6-month follow-up post-AMI. In contrast, protein levels of EV associated plasminogen (p=0.002) and SerpinF2 (p=0.002) were higher in patients with adverse LV remodeling. The differences in the four EV associated proteins between patients with adverse versus reverse LV remodeling remain significant after adjusting for age, gender, ethnicity, medications, lipid profile and risk factors (diabetes, hypertension, dyslipidemia and smoking). Conclusions Lower levels of EV associated coagulation proteins (VWF and SerpinC1) and higher levels of EV associated fibrinolytic proteins (plasminogen and SerpinF2) were presented in patients with adverse LV remodeling compared to those with reverse LV remodeling post-AMI. Acknowledgement/Funding National University Health System Singapore (NUHS O-CRG 2016 Oct-23) to JW Wang

Abstract 13469: Novel Role of Extracellular SOD-derived H 2 O 2 Signaling in Exercise-induced Vascular Adaptation in Type 2 Diabetes

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Sudhahar Varadarajan ◽  
Kareem Abdelsaid ◽  
Malgorzata McMenamin ◽  
Xuexiu Fang ◽  
Yali Hou ◽  
...  
Keyword(s):  
Exercise Training ◽  
Endothelial Function ◽  
Skeletal Muscles ◽  
Dependent Manner ◽  
Vascular Adaptation ◽  
Beneficial Effects ◽  
Initial Event ◽  
Enos Uncoupling ◽  
Exercise Induced

Background: Exercise training promotes vascular adaptation (restoration of endothelial function and angiogenesis) in type2 diabetes (T2D). Since eNOS uncoupling/O 2 - are increased in T2D, exercise may promote vascular adaptation via mechanism other than eNOS-NO axis. Extracellular superoxide dismutase (ecSOD) is a secreted copper (Cu) containing SOD that catalyzes the dismutation of O 2 - to H 2 O 2 and its full activity requires Cu transporter ATP7A. We reported that ATP7A-ecSOD pathway is reduced in T2D and that ecSOD-derived H 2 O 2 promotes VEGFR2 signaling and angiogenesis in endothelial cells. However, role of ATP7A-ecSOD axis and H 2 O 2 signaling in vascular adaptation to exercise in T2D have not been reported. Oxidation of Cysteine residues of targets proteins to generate cysteine sulfenic acid (Cys-OH) is a key initial event in H 2 O 2 -mediated signaling. Results: Here we show that ATP7A protein (49%), ecSOD activity (51%) and extracellular H 2 O 2 levels in blood vessels and skeletal muscles were significantly decreased in high fat diet-induced T2D mice compared to control C57Bl6 mice, which were rescued by volunteer wheel exercise (2 weeks) or in T2D/ATP7A overexpressing mice. In parallel, exercise training restored impaired endothelium-dependent relaxation (EDR) of resistant arteries and angiogenesis (CD31+ capillary, 2.4-fold) in skeletal muscle of T2D mice, which were inhibited by exogenous catalase or in T2D/ecSOD KO mice, but not by L-NAME, suggesting that ecSOD-derived H 2 O 2 , but not eNOS/NO, mediates exercise-induced beneficial effects. Mechanistically, exercise significantly increased Cys-OH formation of PKG1α (2.3-fold), which was shown to induce EDR in H 2 O 2 -, but not NO/cGMP-, dependent manner, in T2D vascular tissues as well as Cys-OH formation of AMPK (3.6-fold) and AMPK downstream angiogenic PGC1α and VEGF protein expression in T2D skeletal muscles. Of note, these exercise-induced Cys oxidation of PKG1α and AMPK were not observed in control or T2D/ecSOD KO mice. Conclusion: Exercise-induced ATP7A-ecSOD axis-mediated out-side in H 2 O 2 signaling plays an important role in promoting vascular adaptation in T2D via Cys oxidation of redox-sensitive kinases required for endothelial function and angiogenesis in skeletal muscles.

Changes in left ventricular function and remodeling after myocardial infarction in hypothyroid rats

2010 ◽  
Vol 298 (1) ◽  
pp. H259-H262 ◽  
Author(s):  
Yue-Feng Chen ◽  
Rebecca A. Redetzke ◽  
Suleman Said ◽  
April J. Beyer ◽  
A. Martin Gerdes
Keyword(s):  
Myocardial Infarction ◽  
Left Ventricular ◽  
Experimental Myocardial Infarction ◽  
Lv Function ◽  
Sprague Dawley ◽  
Lv Dysfunction ◽  
Long Term Effect ◽  
Sprague Dawley Rats ◽  
Lv Remodeling

It has been shown that hypothyroidism may lead to delayed wound healing after experimental myocardial infarction (MI) in rats and increased infarct size in dogs. However, the long-term effect of hypothyroidism on left ventricular (LV) remodeling after MI has not been determined. Adult female Sprague-Dawley rats with and without surgical thyroidectomy (TX) were used in the study. Four weeks after TX, MI or sham MI was performed on TX and non-TX rats. Rats from all groups were examined 4 wk later. Four weeks after TX, hypothyroid-induced LV dysfunction was confirmed by echocardiography. In terminal experiments 4 wk after MI, TX sham-MI rats showed smaller hearts and impaired LV function compared with non-TX sham-MI controls. TX + MI rats showed smaller hearts with bigger infarct areas, higher LV end-diastolic pressures, and greater impairment of relaxation (−dP/d t) compared with non-TX MI rats. Relative changes after MI between TX and non-TX rats for most other hemodynamic and echocardiographic indexes were similar. These results suggest that preexisting hypothyroidism exaggerates post-MI remodeling and worsens LV function, particularly diastolic function.

scholarly journals Added Value of Modified Anderson–Wilkins Acuteness Score in Prognostication of Patients with Acute Myocardial Infarction

2020 ◽  
Vol 8 (B) ◽  
pp. 1171-1179
Author(s):  
Aleksandar Serafimov ◽  
Hajber Taravari ◽  
Enes Shehu ◽  
Darko Kitanoski ◽  
Visar Miftari ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Left Ventricular ◽  
Added Value ◽  
Lv Function ◽  
Stress Hyperglycemia ◽  
St Segment Elevation ◽  
St Segment ◽  
Lv Remodeling ◽  
Ecg Score ◽  
The University

BACKGROUND: Electrocardiogram (ECG) signs on admission can serve as a prognostic marker in patients treated for myocardial infarction (MI). AIM: The aim of the study was to determine the predictive role of modified Anderson–Wilkins (MAW) ECG score of acuteness on the extent of myocardial injury, left ventricular (LV) remodeling, and clinical outcome in patients with acute MI. METHODS: Prospective, observational cohort study on patients treated for MI at the University Clinic for Cardiology. Subjects were analyzed for their demographic, clinical, ECG, LV functional, angiographic variables, course of treatment, and in-hospital outcome. MAW score was calculated for each patient. Patients were comparatively analyzed divided in two groups (score <3 and ≥3). RESULTS: One hundred fifty patients (70% males and 30% females), aged 60.9 years were included in the study. Sixty-eight patients had MAW score <3 (mean 1.7), and 82 had score ≥3 (mean 3.5), p>0.001. Patients with ST-segment elevation MI had OR 2.1 (p>0.000), and patients with multiple locations (excluding anterior) had OR 2.1 (p > 0.000) of having MAW score ≥3. They received mechanical reperfusion 1.9 (p = 0.032) times more often. High MAW score was associated with stress hyperglycemia (OR 2.1; p = 0.032); low potassium (OR 2.8; p = 0.032), lower creatinine (p = 0.050), and higher NT-proBNP (OR 2.5; p = 0.050). High MAW score was associated with decreased LV function and increased LV dimensions on the follow-up echocardiography (p = 0.050 and 0.012, respectively). CONCLUSION: ECG is an important prognostic tool in MI patients. ECG-derived MAW score demonstrates a strong correlation with stress hyperglycemia, potassium, creatinine, and natriuretic peptides level and can serve as an early marker of LV remodeling after MI.

scholarly journals The Apolipoprotein A-I Mimetic L-4F Attenuates Monocyte Activation and Adverse Cardiac Remodeling after Myocardial Infarction

2020 ◽  
Vol 21 (10) ◽  
pp. 3519
Author(s):  
Tariq Hamid ◽  
Mohamed Ameen Ismahil ◽  
Shyam S. Bansal ◽  
Bindiya Patel ◽  
Mehak Goel ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Immune Cell ◽  
Left Ventricular ◽  
Beneficial Effects ◽  
Glycolytic Gene ◽  
Inflammatory Monocytes ◽  
Apolipoprotein A ◽  
Lv Remodeling ◽  
Monocytes And Macrophages

Excessive inflammation after myocardial infarction (MI) can promote infarct expansion and adverse left ventricular (LV) remodeling. L-4F, a mimetic peptide of apolipoprotein A-I (apoA-I), exhibits anti-inflammatory and anti-atherogenic properties; however, whether L-4F imparts beneficial effects after myocardial infarction (MI) is unknown. Here we demonstrate that L-4F suppresses the expansion of blood, splenic, and myocardial pro-inflammatory monocytes and macrophages in a mouse model of reperfused MI. Changes in immune cell profiles were accompanied by alleviation of post-MI LV remodeling and dysfunction. In vitro, L-4F also inhibited pro-inflammatory and glycolytic gene expression in macrophages. In summary, L-4F treatment prevents prolonged and excessive inflammation after MI, in part through modulation of pro-inflammatory monocytes and macrophages, and improves post-MI LV remodeling. These data suggest that L-4F could be a used as a therapeutic adjunct in humans with MI to limit inflammation and alleviate the progression to heart failure.

Exercise attenuates inflammation and limits scar thinning after myocardial infarction in mice

2015 ◽  
Vol 309 (2) ◽  
pp. H345-H359 ◽  
Author(s):  
Sarah-Lena Puhl ◽  
Andreas Müller ◽  
Michael Wagner ◽  
Yvan Devaux ◽  
Michael Böhm ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Systolic Function ◽  
Left Ventricular ◽  
Heart Weight ◽  
Lv Function ◽  
Sham Operation ◽  
Beneficial Effects ◽  
End Diastolic Volume ◽  
Underlying Mechanisms ◽  
And Function

Although exercise mediates beneficial effects in patients after myocardial infarction (MI), the underlying mechanisms as well as the question of whether an early start of exercise after MI is safe or even beneficial are incompletely resolved. The present study analyzed the effects of exercise before and reinitiated early after MI on cardiac remodeling and function. Male C57BL/6N mice were housed sedentary or with the opportunity to voluntarily exercise for 6 wk before MI induction (ligation of the left anterior descending coronary artery) or sham operation. After a 5-day exercise-free phase after MI, mice were allowed to reexercise for another 4 wk. Exercise before MI induced adaptive hypertrophy with moderate increases in heart weight, cardiomyocyte diameter, and left ventricular (LV) end-diastolic volume, but without fibrosis. In sedentary mice, MI induced eccentric LV hypertrophy with massive fibrosis but maintained systolic LV function. While in exercised mice gross LV end-diastolic volumes and systolic function did not differ from sedentary mice after MI, LV collagen content and thinning of the infarcted area were reduced. This was associated with ameliorated activation of inflammation, mediated by TNF-α, IL-1β, and IL-6, as well as reduced activation of matrix metalloproteinase 9. In contrast, no differences in the activation patterns of various MAPKs or adenosine receptor expressions were observed 5 wk after MI in sedentary or exercised mice. In conclusion, continuous exercise training before and with an early reonset after MI ameliorates adverse LV remodeling by attenuating inflammation, fibrosis, and scar thinning. Therefore, an early reonset of exercise after MI can be encouraged.

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