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 journalArticleAcademicpeer-review

422 Citations (Scopus)


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 languageEnglish
Pages (from-to)312-324
Number of pages13
Issue number4
Publication statusPublished - Apr 2016


  • endothelium
  • heart failure
  • inflammation
  • nitric oxide
  • oxidative stress

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