Efficacy of mineralocorticoid receptor antagonism in the acute myocardial infarction phase: eplerenone versus spironolactone

Fraccarollo, Daniela; Galuppo, Paolo; Sieweke, Jan‐Thorben; Napp, L. Christian; Grobbecker, Paul; Bauersachs, Johann

doi:10.1002/ehf2.12053

Cited by 16 publications

(12 citation statements)

References 36 publications

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“…MI was induced by permanent left coronary artery ligation (17, 18) in age- and gender-matched mice. In brief, mice were anesthetized with 1.8% isoflurane in a 100% oxygen mix, intubated, and ventilated using a ventilator (MiniVent mouse ventilator model 845; Harvard Apparatus, Holliston, MA, USA) with the tidal volume adjusted on the basis of body weight (10 µl/g body weight).…”

Section: Methodsmentioning

confidence: 99%

“…Pvan software (Millar Instruments) was used to analyze all pressure-volume loop data recorded at steady state and during the injection of hypertonic saline for the calibration of parallel conductance volume ( V p ). Left ventricle (LV) volume was calculated for each mouse from conductance volume corrected by the relative V p (17, 18). …”

Section: Methodsmentioning

confidence: 99%

“…Tissue images were recorded with a cooled digital camera (DS-5Mc; Nikon) with a magnification ×200 and analyzed using SigmaScan Pro 5.0 image analysis software (Systat Software, San Jose, CA, USA). Collagen content was expressed as a percentage of the area of each image (17, 18). …”

Section: Methodsmentioning

confidence: 99%

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The glucocorticoid receptor in monocyte‐derived macrophages is critical for cardiac infarct repair and remodeling

et al. 2017

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Cell- and tissue-specific actions of glucocorticoids are mediated by the glucocorticoid receptor. Here, we demonstrate that the glucocorticoid receptor (GR) in macrophages is essential for cardiac healing after myocardial infarction. Compared with GRflox (wild-type controls), GRLysMCre mice that lacked GR in myeloid cells showed increased acute mortality as a result of cardiac rupture. Seven days after left coronary artery ligation, GRLysMCre mice exhibited worse cardiac function and adverse remodeling associated with impaired scar formation and angiogenic response to ischemic injury. Inactivation of GR altered the functional differentiation/maturation of monocyte-derived macrophages in the infarcted myocardium. Mechanistically, CD45+/CD11b+/Ly6G−/F4/80+ macrophages isolated from GRLysMCre infarcts showed deregulation of factors that control inflammation, neovascularization, collagen degradation, and scar tissue formation. Moreover, we demonstrate that cardiac fibroblasts sorted from the ischemic myocardium of GRLysMCre mice compared with cells isolated from injured GRflox hearts displayed higher matrix metalloproteinase 2 expression, and we provide evidence that the macrophage GR regulates myofibroblast differentiation in the infarct microenvironment during the early phase of wound healing. In summary, GR signaling in macrophages, playing a crucial role in tissue-repairing mechanisms, could be a potential therapeutic target during wound healing after ischemic myocardial injury.—Galuppo, P., Vettorazzi, S., Hövelmann, J., Scholz, C.-J., Tuckermann, J. P., Bauersachs, J., Fraccarollo, D. The glucocorticoid receptor in monocyte-derived macrophages is critical for cardiac infarct repair and remodeling.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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The glucocorticoid receptor in monocyte‐derived macrophages is critical for cardiac infarct repair and remodeling

et al. 2017

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“…A macrophage‐specific knockout for the mineralocorticoid receptor (MR) protects mice against cardiac fibrosis induced by hypertensive deoxy‐corticosterone acetate plus high salt intake . Furthermore, MR antagonism, especially by the selective MR antagonist eplerenone, skewed the monocyte/macrophage population towards higher numbers of healing‐promoting Ly6C low cells …”

Section: Immune Mechanisms In Heart Failure Pathophysiologymentioning

confidence: 99%

The innate immune system in chronic cardiomyopathy: a European Society of Cardiology (ESC) scientific statement from the Working Group on Myocardial Function of the ESC

Frantz

Falcão-Pires

Balligand

et al. 2018

European J of Heart Fail

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Activation of the immune system in heart failure (HF) has been recognized for over 20 years. Initially, experimental studies demonstrated a maladaptive role of the immune system. However, several phase III trials failed to show beneficial effects in HF with therapies directed against an immune activation. Preclinical studies today describe positive and negative effects of immune activation in HF. These different effects depend on timing and aetiology of HF. Therefore, herein we give a detailed review on immune mechanisms and their importance for the development of HF with a special focus on commonalities and differences between different forms of cardiomyopathies. The role of the immune system in ischaemic, hypertensive, diabetic, toxic, viral, genetic, peripartum, and autoimmune cardiomyopathy is discussed in depth. Overall, initial damage to the heart leads to disease specific activation of the immune system whereas in the chronic phase of HF overlapping mechanisms occur in different aetiologies.

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“…However, there are also several studies that demonstrated no changes in serum inflammatory markers . Comparing the available mineralocorticoid receptor antagonists for treatment of HF, eplerenone showed superior efficacy during acute MI compared to spironolactone, which was associated with monocyte maturation and enhanced neovascularization . Blockade of T‐cell co‐stimulation through abatacept, which is already used for the treatment of rheumatoid arthritis, results in a significant delay in progression and decreased severity of cardiac function, which was associated with inhibition of cardiac infiltration and activation of T cells and macrophages as well as more production of IL‐10 …”

Section: Available Treatment Options To Modulate Immune Responses In mentioning

confidence: 99%

Immune mechanisms in heart failure

Zhang

Bauersachs

Langer

2017

European J of Heart Fail

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198

134

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Elevated levels of circulating pro-inflammatory biomarkers in patients with both ischaemic and non-ischaemic heart failure (HF) correlate with disease severity and prognosis. Experimental studies have shown activation of immune response mechanisms in the heart to provoke cardiac adverse remodelling and cause left ventricular dysfunction. Consequently, most of the clinical trials targeting elements of the immune response in HF attempted to modulate the inflammatory response. Surprisingly, clinical studies targeting immune effectors were either neutral or even increased pre-specified clinical endpoints, and some studies resulted in worsening of HF. This review discusses immune mediators involved in the pathogenesis and progression of HF and potential therapeutic applications targeting inflammation in HF. Besides more obvious settings featuring immune activation such as inflammatory or ischaemic cardiomyopathy, the relevance of immune activation in acute or chronic HF of other origins, including volume overload or valvular heart disease, is highlighted. Understanding how cell-specific and molecular mechanisms of the immune response interfere with cardiac remodelling in HF may open new avenues to design biomarkers or druggable targets.

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Efficacy of mineralocorticoid receptor antagonism in the acute myocardial infarction phase: eplerenone versus spironolactone

Cited by 16 publications

References 36 publications

The glucocorticoid receptor in monocyte‐derived macrophages is critical for cardiac infarct repair and remodeling

The glucocorticoid receptor in monocyte‐derived macrophages is critical for cardiac infarct repair and remodeling

The innate immune system in chronic cardiomyopathy: a European Society of Cardiology (ESC) scientific statement from the Working Group on Myocardial Function of the ESC

Immune mechanisms in heart failure

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