Myocardial Microvascular Inflammatory Endothelial Activation in Heart Failure With Preserved Ejection Fraction

Constantijn Franssen; Sophia Chen; Andreas Unger; H. Ibrahim Korkmaz; Gilles W. De Keulenaer; Carsten Tschoepe; Adelino F. Leite-Moreira; Rene Musters; Hans W. M. Niessen; Wolfgang A. Linke; Walter J. Paulus; Nazha Hamdani

doi:https://doi.org/10.1016/j.jchf.2015.10.007

Myocardial Microvascular Inflammatory Endothelial Activation in Heart Failure With Preserved Ejection Fraction

Constantijn Franssen, Sophia Chen, Andreas Unger, H. Ibrahim Korkmaz, Gilles W. De Keulenaer, Carsten Tschoepe, Adelino F. Leite-Moreira, Rene Musters, Hans W. M. Niessen, Wolfgang A. Linke, Walter J. Paulus, Nazha Hamdani

Research output: Contribution to journal › Article › Academic › peer-review

416 Citations (Scopus)

Abstract

OBJECTIVES: The present study investigated whether systemic, low-grade inflammation of metabolic risk contributed to diastolic left ventricular (LV) dysfunction and heart failure with preseved ejection fraction (HFpEF) through coronary microvascular endothelial activation, which alters paracrine signalling to cardiomyocytes and predisposes them to hypertrophy and high diastolic stiffness.

BACKGROUND: Metabolic risk is associated with diastolic LV dysfunction and HFpEF.

METHODS: We explored inflammatory endothelial activation and its effects on oxidative stress, nitric oxide (NO) bioavailability, and cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) signalling in myocardial biopsies of HFpEF patients and validated our findings by comparing obese Zucker diabetic fatty/Spontaneously hypertensive heart failure F1 hybrid (ZSF1)-HFpEF rats to ZSF1-Control (Ctrl) rats.

RESULTS: In myocardium of HFpEF patients and ZSF1-HFpEF rats, we observed the following: 1) E-selectin and intercellular adhesion molecule-1 expression levels were upregulated; 2) NADPH oxidase 2 expression was raised in macrophages and endothelial cells but not in cardiomyocytes; and 3) uncoupling of endothelial nitric oxide synthase, which was associated with reduced myocardial nitrite/nitrate concentration, cGMP content, and PKG activity.

CONCLUSIONS: HFpEF is associated with coronary microvascular endothelial activation and oxidative stress. These lead to a reduction of NO-dependent signalling from endothelial cells to cardiomyocytes, which can contribute to the high cardiomyocyte stiffness and hypertrophy observed in HFpEF.

Original language	English
Pages (from-to)	312-324
Number of pages	13
Journal	JACC-HEART FAILURE
Volume	4
Issue number	4
DOIs	https://doi.org/10.1016/j.jchf.2015.10.007
Publication status	Published - Apr 2016

Keywords

endothelium
heart failure
inflammation
nitric oxide
oxidative stress

Access to Document

https://doi.org/10.1016/j.jchf.2015.10.007

Cite this

Franssen, C., Chen, S., Unger, A., Korkmaz, H. I., De Keulenaer, G. W., Tschoepe, C., Leite-Moreira, A. F., Musters, R., Niessen, H. W. M., Linke, W. A., Paulus, W. J., & Hamdani, N. (2016). Myocardial Microvascular Inflammatory Endothelial Activation in Heart Failure With Preserved Ejection Fraction. JACC-HEART FAILURE, 4(4), 312-324. https://doi.org/10.1016/j.jchf.2015.10.007

@article{876bdf4e41404b2a891ef0b73cf676c8,

title = "Myocardial Microvascular Inflammatory Endothelial Activation in Heart Failure With Preserved Ejection Fraction",

abstract = "OBJECTIVES: The present study investigated whether systemic, low-grade inflammation of metabolic risk contributed to diastolic left ventricular (LV) dysfunction and heart failure with preseved ejection fraction (HFpEF) through coronary microvascular endothelial activation, which alters paracrine signalling to cardiomyocytes and predisposes them to hypertrophy and high diastolic stiffness.BACKGROUND: Metabolic risk is associated with diastolic LV dysfunction and HFpEF.METHODS: We explored inflammatory endothelial activation and its effects on oxidative stress, nitric oxide (NO) bioavailability, and cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) signalling in myocardial biopsies of HFpEF patients and validated our findings by comparing obese Zucker diabetic fatty/Spontaneously hypertensive heart failure F1 hybrid (ZSF1)-HFpEF rats to ZSF1-Control (Ctrl) rats.RESULTS: In myocardium of HFpEF patients and ZSF1-HFpEF rats, we observed the following: 1) E-selectin and intercellular adhesion molecule-1 expression levels were upregulated; 2) NADPH oxidase 2 expression was raised in macrophages and endothelial cells but not in cardiomyocytes; and 3) uncoupling of endothelial nitric oxide synthase, which was associated with reduced myocardial nitrite/nitrate concentration, cGMP content, and PKG activity.CONCLUSIONS: HFpEF is associated with coronary microvascular endothelial activation and oxidative stress. These lead to a reduction of NO-dependent signalling from endothelial cells to cardiomyocytes, which can contribute to the high cardiomyocyte stiffness and hypertrophy observed in HFpEF.",

keywords = "endothelium, heart failure, inflammation, nitric oxide, oxidative stress",

author = "Constantijn Franssen and Sophia Chen and Andreas Unger and Korkmaz, {H. Ibrahim} and {De Keulenaer}, {Gilles W.} and Carsten Tschoepe and Leite-Moreira, {Adelino F.} and Rene Musters and Niessen, {Hans W. M.} and Linke, {Wolfgang A.} and Paulus, {Walter J.} and Nazha Hamdani",

year = "2016",

month = apr,

doi = "https://doi.org/10.1016/j.jchf.2015.10.007",

language = "English",

volume = "4",

pages = "312--324",

journal = "JACC-HEART FAILURE",

issn = "2213-1779",

publisher = "Elsevier BV",

number = "4",

}

TY - JOUR

T1 - Myocardial Microvascular Inflammatory Endothelial Activation in Heart Failure With Preserved Ejection Fraction

AU - Franssen, Constantijn

AU - Chen, Sophia

AU - Unger, Andreas

AU - Korkmaz, H. Ibrahim

AU - De Keulenaer, Gilles W.

AU - Tschoepe, Carsten

AU - Leite-Moreira, Adelino F.

AU - Musters, Rene

AU - Niessen, Hans W. M.

AU - Linke, Wolfgang A.

AU - Paulus, Walter J.

AU - Hamdani, Nazha

PY - 2016/4

Y1 - 2016/4

N2 - OBJECTIVES: The present study investigated whether systemic, low-grade inflammation of metabolic risk contributed to diastolic left ventricular (LV) dysfunction and heart failure with preseved ejection fraction (HFpEF) through coronary microvascular endothelial activation, which alters paracrine signalling to cardiomyocytes and predisposes them to hypertrophy and high diastolic stiffness.BACKGROUND: Metabolic risk is associated with diastolic LV dysfunction and HFpEF.METHODS: We explored inflammatory endothelial activation and its effects on oxidative stress, nitric oxide (NO) bioavailability, and cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) signalling in myocardial biopsies of HFpEF patients and validated our findings by comparing obese Zucker diabetic fatty/Spontaneously hypertensive heart failure F1 hybrid (ZSF1)-HFpEF rats to ZSF1-Control (Ctrl) rats.RESULTS: In myocardium of HFpEF patients and ZSF1-HFpEF rats, we observed the following: 1) E-selectin and intercellular adhesion molecule-1 expression levels were upregulated; 2) NADPH oxidase 2 expression was raised in macrophages and endothelial cells but not in cardiomyocytes; and 3) uncoupling of endothelial nitric oxide synthase, which was associated with reduced myocardial nitrite/nitrate concentration, cGMP content, and PKG activity.CONCLUSIONS: HFpEF is associated with coronary microvascular endothelial activation and oxidative stress. These lead to a reduction of NO-dependent signalling from endothelial cells to cardiomyocytes, which can contribute to the high cardiomyocyte stiffness and hypertrophy observed in HFpEF.

AB - OBJECTIVES: The present study investigated whether systemic, low-grade inflammation of metabolic risk contributed to diastolic left ventricular (LV) dysfunction and heart failure with preseved ejection fraction (HFpEF) through coronary microvascular endothelial activation, which alters paracrine signalling to cardiomyocytes and predisposes them to hypertrophy and high diastolic stiffness.BACKGROUND: Metabolic risk is associated with diastolic LV dysfunction and HFpEF.METHODS: We explored inflammatory endothelial activation and its effects on oxidative stress, nitric oxide (NO) bioavailability, and cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) signalling in myocardial biopsies of HFpEF patients and validated our findings by comparing obese Zucker diabetic fatty/Spontaneously hypertensive heart failure F1 hybrid (ZSF1)-HFpEF rats to ZSF1-Control (Ctrl) rats.RESULTS: In myocardium of HFpEF patients and ZSF1-HFpEF rats, we observed the following: 1) E-selectin and intercellular adhesion molecule-1 expression levels were upregulated; 2) NADPH oxidase 2 expression was raised in macrophages and endothelial cells but not in cardiomyocytes; and 3) uncoupling of endothelial nitric oxide synthase, which was associated with reduced myocardial nitrite/nitrate concentration, cGMP content, and PKG activity.CONCLUSIONS: HFpEF is associated with coronary microvascular endothelial activation and oxidative stress. These lead to a reduction of NO-dependent signalling from endothelial cells to cardiomyocytes, which can contribute to the high cardiomyocyte stiffness and hypertrophy observed in HFpEF.

KW - endothelium

KW - heart failure

KW - inflammation

KW - nitric oxide

KW - oxidative stress

U2 - https://doi.org/10.1016/j.jchf.2015.10.007

DO - https://doi.org/10.1016/j.jchf.2015.10.007

M3 - Article

C2 - 26682792

SN - 2213-1779

VL - 4

SP - 312

EP - 324

JO - JACC-HEART FAILURE

JF - JACC-HEART FAILURE

IS - 4

ER -