Abstract 212: Role of Monocytes and Inflammation in Vascular Endothelial Dysfunction in Mice With Heart Failure After Myocardial Infarction

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Michael Molitor ◽  
Stefanie Finger ◽  
Sabine Kossmann ◽  
Venkata S Garlapati ◽  
Jérémy Lagrange ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Muscle Function ◽  
Diphtheria Toxin ◽  
Vascular Dysfunction ◽  
Aortic Tissue ◽  
Vascular Endothelial ◽  
Smooth Muscle Function ◽  
Myelomonocytic Cells

Background: Heart failure (HF) after myocardial infarction (MI) leads to impaired left ventricular function and reduced blood flow in peripheral arteries. Angiotensin II (ATII) signaling is crucial in MI, and inflammatory myelomonocytic cells are involved in the process of ATII-induced vascular dysfunction. Their role in MI-mediated vascular dysfunction has not been defined yet. Objective: Test the impact of selective depletion of lysozyme M positive (LysM+) myelomonocytic cells on endothelial dysfunction in a model of ischemic heart failure in mice Methods and results: 8 to 12 week old mice (C57B6 background) were subjected to permanent coronary ligation of the left anterior descending artery (LAD) to induced HF post MI. We measured a reduced vascular endothelial and smooth muscle function in isolated aortic segments 7d and 28d post MI in isometric tension studies. Also the production of vascular superoxide (chemiluminescence, oxidative fluorescence microtopography) and vascular mRNA expression of MCP-1, VCAM-1, IL-6 and ATII receptor type 1 were increased (assessed by mRNA reverse transcription polymerase chain reaction) in HF mice compared to sham. FACS analysis of aortic tissue of HF mice shows an increased infiltration of CD45+ immune cells in the aortic wall, including CD11b+Gr-1lowF4/80+ monocytes/macrophages. Using mice with LysM dependent cre-inducible expression of diphtheria toxin receptor (LysMCreIDTR) we selectively ablated LysM+ myelomonocytic cells 28d after MI for 10d via diphtheria toxin. We assessed a significantly improved vascular endothelial and smooth muscle function, less vascular superoxide production and a reduced expression of VCAM-1 and ATII receptor type 1 in aortic tissue. The number of circulating monocytes in blood was reduced, while the cardiac function (EF (%), LV size) in sonography stays constant between depleted and non-depleted HF mice. Conclusion: Our results suggest that vascular dysfunction post MI is at least in part mediated by inflammatory leukocyte infiltrating the vessel wall and that depletion of inflammatory monocytes in HF after MI improves the vascular function. It can potentially be a new target to protect endothelial function in HF and prevent secondary events after a MI.

Nox2+ myeloid cells drive vascular inflammation and endothelial dysfunction in heart failure after myocardial infarction via angiotensin II receptor type 1

2020 ◽  
Author(s):  
Michael Molitor ◽  
Wolf-Stephan Rudi ◽  
Venkata Garlapati ◽  
Stefanie Finger ◽  
Rebecca Schüler ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Bone Marrow ◽  
Angiotensin Ii ◽  
Endothelial Dysfunction ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Angiotensin Ii Receptor ◽  
Myelomonocytic Cells

Abstract Aims Heart failure (HF) ensuing myocardial infarction (MI) is characterized by the initiation of a systemic inflammatory response. We aimed to elucidate the impact of myelomonocytic cells and their activation by angiotensin II on vascular endothelial function in a mouse model of HF after MI. Methods and results HF was induced in male C57BL/6J mice by permanent ligation of the left anterior descending coronary artery. Compared to sham, HF mice had significantly impaired endothelial function accompanied by enhanced mobilization of Sca-1+c-Kit+ haematopoietic stem cells and Sca-1−c-Kit+ common myeloid and granulocyte-macrophage progenitors in the bone marrow as well as increased vascular infiltration of CD11b+Ly6G−Ly6Chigh monocytes and accumulation of CD11b+ F4/80+ macrophages, assessed by flow cytometry. Using mice with Cre-inducible expression of diphtheria toxin receptor in myeloid cells, we selectively depleted lysozyme M+ myelomonocytic cells for 10 days starting 28 days after MI. While the cardiac phenotype remained unaltered until 38 days post-MI, myeloid cell depletion attenuated vascular accumulation of Nox2+CD45+ cells, endothelial dysfunction, oxidative stress, and vascular expression of adhesion molecules and angiotensin II receptor type 1 (AT1R). Pharmacological blockade of this receptor for 4 weeks did not significantly alter cardiac function, but mimicked the effects of myeloid cell depletion: telmisartan (20 mg/kg/day, fed to C57BL/6J mice) diminished bone marrow myelopoesis and myeloid reactive oxygen species production, attenuated endothelial leucocyte rolling and vascular accumulation of CD11b+Ly6G−Ly6Chigh monocytes and macrophages, resulting in improved vascular function with less abundance of Nox2+CD45+ cells. Conclusion Endothelial dysfunction in HF ensuing MI is mediated by inflammatory Nox2+ myeloid cells infiltrating the vessel wall that can be targeted by AT1R blockade.

scholarly journals Vascular Dysfunction Predicts Future Deterioration of Left Ventricular Ejection Fraction in Patients with Heart Failure with Mildly Reduced Ejection Fraction

2021 ◽  
Vol 10 (24) ◽  
pp. 5980
Author(s):  
Shinji Kishimoto ◽  
Tatsuya Maruhashi ◽  
Masato Kajikawa ◽  
Takahiro Harada ◽  
Takayuki Yamaji ◽  
...  
Keyword(s):  
Heart Failure ◽  
Smooth Muscle ◽  
Ejection Fraction ◽  
Vascular Smooth Muscle ◽  
Endothelial Function ◽  
Muscle Function ◽  
Vascular Dysfunction ◽  
Left Ventricular Ejection ◽  
Reduced Ejection Fraction ◽  
Smooth Muscle Function

The purpose of this study was to evaluate whether heart failure with mildly reduced ejection fraction (HFmrEF) is associated with vascular dysfunction and whether vascular function predicts future deterioration of LVEF in patients with HFmrEF. We evaluated endothelial function assessed by flow-mediated vasodilation (FMD) and vascular smooth muscle function assessed by nitroglycerine-induced vasodilation (NID) in 69 patients with HFmrEF and 426 patients without HF and evaluated the future deterioration of LVEF, defined as a decrease in LVEF to <40%, in 39 patients with HFmrEF for up to 3 years. Both FMD and NID were significantly lower in patients with HFmrEF than in patients without HF. We categorized patients into two groups based on low tertiles of NID: a low group (NID of <7.0%) and an intermediate and high group (NID of ≥7.0%). There were significant differences between the Kaplan–Meier curves for the deterioration of LVEF in the two groups (p < 0.01). Multivariate Cox proportional hazard analysis revealed that NID of <7.0% was an independent predictor of future deterioration of LVEF in patients with HFmrEF. Both endothelial function and vascular smooth muscle function are impaired in patients with HFmrEF compared with those in patients without HF. In addition, low NID of <7.0% predicts future deterioration of LVEF.

Nox2+ myeloid cells drive vascular inflammation and endothelial dysfunction in heart failure after myocardial infarction via angiotensin II receptor type 1

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Molitor ◽  
W.S Rudi ◽  
V.S Garlapati ◽  
S Finger ◽  
J Wild ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Bone Marrow ◽  
Angiotensin Ii ◽  
Endothelial Dysfunction ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Angiotensin Ii Receptor ◽  
Myelomonocytic Cells

Abstract Background Ischemic heart failure (HF) ensuing myocardial infarction (MI) leads to impaired left ventricular function, reduced cardiac output and counterregulatory activation of angiotensin II (AngII) levels. Furthermore, it is characterized by the initiation of a systemic inflammatory response. Objective We aimed to elucidate the impact of myelomonocytic cells and their activation by angiotensin II on vascular endothelial function in a mouse model of HF after MI. Results HF was induced in male C57BL/6J mice by permanent ligation of the left anterior descending coronary artery. Compared to sham, HF mice had significantly impaired endothelial function accompanied by enhanced mobilization of Sca-1+c-Kit+ hematopoietic stem cells and Sca-1-c-Kit+ common myeloid and granulocyte-macrophage progenitors in the bone marrow as well as increased vascular infiltration of CD11b+Ly6G-Ly6Chigh monocytes and accumulation of CD11b+ F4/80+ macrophages, assessed by flow cytometry. Using mice with Cre-inducible expression of diphtheria toxin receptor in myeloid cells, we selectively depleted lysozyme M+ myelomonocytic cells for 10 d starting 28d after MI. While the cardiac phenotype remained unaltered until 38d post MI, myeloid cell depletion attenuated vascular accumulation of Nox2+CD45+ cells, endothelial dysfunction, oxidative stress and vascular expression of adhesion molecules and angiotensin II receptor type 1 (AT1R). Pharmacological blockade of this receptor for 4 weeks did not significantly alter cardiac function, but mimicked the effects of myeloid cell depletion: Telmisartan (20 mg/kg/d, fed to C57BL/6J mice) diminished bone marrow myelopoesis and myeloid ROS production, attenuated endothelial leukocyte rolling and vascular accumulation of CD11b+Ly6G-Ly6Chigh monocytes and macrophages, resulting in improved vascular function with less abundance of Nox2+CD45+ cells. Conclusion Endothelial dysfunction in HF ensuing MI is mediated by inflammatory Nox2+ myeloid cells infiltrating the vessel wall that can be targeted by AT1R blockade. Funding Acknowledgement Type of funding source: None

Effect of Flush-Perfusion on Vascular Endothelial and Smooth Muscle Function

1997 ◽  
Vol 64 (4) ◽  
pp. 1075-1081 ◽  
Author(s):  
Richard Ingemansson ◽  
Algimantas Budrikis ◽  
Ramunas Bolys ◽  
Trygve Sjöberg ◽  
Stig Steen
Keyword(s):  
Smooth Muscle ◽  
Muscle Function ◽  
Vascular Endothelial ◽  
Smooth Muscle Function

Abstract 352: Myocardial Neuregulin-1/ErbB Signaling Is Impaired in the Setting of Post--Myocardial Infarction Heart Failure Complicated by Type 1 Diabetes Mellitus

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Oghenerukevwe Odiete ◽  
Kathleen E Dennis ◽  
Douglas B Sawyer ◽  
Michael F Hill
Keyword(s):  
Diabetes Mellitus ◽  
Myocardial Infarction ◽  
Heart Failure ◽  
Type 1 Diabetes ◽  
Protein Expression ◽  
Type 1 Diabetes Mellitus ◽  
Neuregulin 1 ◽  
Erbb Signaling ◽  
Type 1 Dm

Background: Type 1 diabetes mellitus (DM) patients surviving myocardial infarction (MI) are at heightened risk for the subsequent development of heart failure (HF). Despite the worse outcomes, investigations into the pathophysiological mechanisms that contribute to the increased frequency of HF after MI in the type 1 DM heart remain scarce. Neuregulin-1 (NRG-1), along with the ErbB family of receptor tyrosine kinases through which NRG-1 ligands signal, have been shown to be intimately involved in mediating cardiac recovery after MI. However, the impact of type 1 DM on this signaling system post-MI remains to be elucidated. Therefore, in the present study, we examined myocardial NRG-1/ErbB signaling during post-MI HF in the presence of type 1 DM. Methods: Type 1 DM was induced in male Sprague-Dawley rats via a single intraperitoneal injection of streptozotocin (STZ) (65 mg/kg). Two weeks after induction of type 1 DM, MI was produced in DM and non-DM rats by ligation of the left anterior descending (LAD) coronary artery. Residual left ventricular (LV) function was assessed by echocardiography at 4 weeks post-MI. Following echocardiographic assessment, NRG-1, ErbB2, and ErbB4 protein expression was assessed in the remote, surviving LV myocardium of DM and non-DM rats using Western blot techniques. Results: LV Fractional Shortening (FS) and LV Ejection Fraction (EF) were significantly lower in the DM + MI group compared to the MI group ([LVFS: DM + MI, 17.9 ± 0.7 (n=6) vs. MI, 25.2 ± 2.2 (n=6), p <0.05; LVEF: DM + MI, 35.5 ± 1.4 (n=6) vs. MI, 47.5 ± 3.5 (n=6), p <0.05]), indicating an increased functional severity of HF in the diabetic post-MI group. The weight of myocardial scar caused by the infarction was not significantly different between the MI groups ([DM + MI, 0.19 ± 0.02 g (n=4) vs. MI, 0.20 ± 0.03 g (n=4), p =0.70]). ErbB2, ErbB4, and NRG-1 protein expression levels were all significantly lower in the DM + MI group compared to the MI group. Conclusions: These findings demonstrate that type 1 DM impairs myocardial NRG-1/ErbB signaling in response to MI, which may contribute to the accelerated progression of subsequent HF. Augmentation of NRG-1 or its downstream signaling pathways may represent a novel therapeutic strategy for ameliorating post-MI HF in the setting of type 1 DM.

scholarly journals Getting to the heart of intracellular glucocorticoid regeneration: 11β-HSD1 in the myocardium

2017 ◽  
Vol 58 (1) ◽  
pp. R1-R13 ◽  
Author(s):  
Gillian A Gray ◽  
Christopher I White ◽  
Raphael F P Castellan ◽  
Sara J McSweeney ◽  
Karen E Chapman
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Systemic Corticosteroid ◽  
Physiological Function ◽  
Pressure Overload ◽  
Hydroxysteroid Dehydrogenase ◽  
And Function ◽  
Glucocorticoid Metabolism

Corticosteroids influence the development and function of the heart and its response to injury and pressure overload via actions on glucocorticoid (GR) and mineralocorticoid (MR) receptors. Systemic corticosteroid concentration depends largely on the activity of the hypothalamic–pituitary–adrenal (HPA) axis, but glucocorticoid can also be regenerated from intrinsically inert metabolites by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), selectively increasing glucocorticoid levels within cells and tissues. Extensive studies have revealed the roles for glucocorticoid regeneration by 11β-HSD1 in liver, adipose, brain and other tissues, but until recently, there has been little focus on the heart. This article reviews the evidence for glucocorticoid metabolism by 11β-HSD1 in the heart and for a role of 11β-HSD1 activity in determining the myocardial growth and physiological function. We also consider the potential of 11β-HSD1 as a therapeutic target to enhance repair after myocardial infarction and to prevent the development of cardiac remodelling and heart failure.

scholarly journals Vitamin D insufficiency is associated with impaired vascular endothelial and smooth muscle function and hypertension in young rats

2011 ◽  
Vol 589 (19) ◽  
pp. 4777-4786 ◽  
Author(s):  
Marianne Tare ◽  
Sarah J. Emmett ◽  
Harold A. Coleman ◽  
Con Skordilis ◽  
Darryl W. Eyles ◽  
...  
Keyword(s):  
Vitamin D ◽  
Smooth Muscle ◽  
Muscle Function ◽  
Vitamin D Insufficiency ◽  
Vascular Endothelial ◽  
Young Rats ◽  
Smooth Muscle Function

scholarly journals Left ventricular function and clinical heart failure after myocardial infarction revascularized with percutaneous coronary intervention - comparison between STEMI and NSTEMI in modern practice

2021 ◽  
Vol 22 (Supplement_1) ◽  
Author(s):  
A Radhakrishnan ◽  
H Sharma ◽  
S Brown ◽  
J May ◽  
N Zia ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Percutaneous Coronary Intervention ◽  
Coronary Intervention ◽  
Left Ventricular ◽  
Percutaneous Coronary ◽  
All Cause Mortality ◽  
St Elevation ◽  
Clinical Heart Failure

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Left ventricular systolic dysfunction (LVSD) is a common consequence of myocardial infarction (MI). Data from historic series identified LVSD in up to 60% of patients post-MI. However, in modern practice, with high-sensitivity cardiac biomarkers leading to early detection of MI and widespread use of early revascularization, the prevalence of LVSD in the acute phase of MI and its impact on subsequent clinical heart failure remains unknown. Purpose To ascertain the prevalence of LVSD on pre-discharge echocardiography and its impact on subsequent clinical heart failure after type 1 MI treated with percutaneous coronary intervention (PCI) in a UK tertiary cardiac centre. Methods A retrospective electronic patient records review of consecutive patients with type 1 MI treated with PCI between January 2016 - December 2017. Patients treated conservatively or with surgical revascularization were excluded. Results 1000 consecutive patients were identified and 948/1000 who had an inpatient echocardiogram prior to discharge were included in this analysis – 413 ST elevation MI (STEMI) and 535 non-ST elevation (NSTEMI). Median door to balloon time for STEMI was 42 minutes (IQR 28-79). Median time from symptom onset to intervention for NSTEMI was 3 days (IQR 1-6). LVSD was defined as left ventricular ejection fraction (LVEF) &lt;50% on transthoracic echocardiogram carried out during the hospital episode. LVSD was significantly more prevalent in patients with STEMI compared to NSTEMI (37.4% vs 17.3%, p &lt; 0.001). Median LVEF was significantly lower in the STEMI population (55%, IQR 45-60) compared to patients with NSTEMI (60%, IQR 54-65), p &lt; 0.001. However, rates of clinical heart failure at index presentation with MI did not vary significantly between STEMI and NSTEMI patients (6.1% vs 4.9%, p = 0.414). In stepwise multivariate regression models: age, peak troponin and previous coronary artery bypass grafting were predictors of LVEF, whereas LVEF and previous MI were predictors of clinical heart failure Patients with LVSD on pre-discharge echocardiography had significantly higher rates of 30-day readmission with heart failure (2.9% vs 0.7%, p = 0.017), 30-day all-cause mortality (6.1% vs 2%, p = 0.001), 30-day cardiac mortality (5.7% vs 1%, p &lt; 0.001) and 2-year all-cause mortality (5.7% vs 1.6%, p = 0.001). However, at 2-years, there was no difference in hospital readmission with heart failure (0.8% vs 0.3%, p = 0.276). There were no significant differences between STEMI and NSTEMI patients for these endpoints. Conclusions Early revascularisation with PCI has led to a reduction in the prevalence of early LVSD post-MI compared to historical data. However, the presence of LVSD remains a powerful predictor of adverse clinical outcomes. Despite lower rates of LVSD on pre-discharge echocardiography in patients with NSTEMI compared with STEMI, the incidence of subsequent clinical heart failure is similar. This however may be underestimated due to survival bias.

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