Neutrophils and Circulating Inflammatory Biomarkers in Diabetes Mellitus and Heart Failure With Preserved Ejection Fraction

Abstract

Heart failure with preserved ejection fraction (HFpEF) is characterized by low-grade chronic inflammation, which could be exacerbated by type 2 diabetes mellitus (DM). We hypothesized that neutrophils in patients with DM and patients with HFpEF with/without DM contribute to low-grade inflammation through the release of pro-inflammatory cytokines. Venous blood was withdrawn from patients with DM (n = 22), HFpEF (n = 15), HFpEF with DM (n = 13), and healthy controls (CTL) (n = 21). Levels of circulating cytokines and in vitro cytokines released by isolated neutrophils were assessed by enzyme-linked immunosorbent assay. Compared with CTL, there was a significant decrease in circulating nitric oxide in patients with DM (p ≤0.001), HFpEF (p ≤0.05), and HFpEF with DM (p ≤0.001) up to 44%. Circulating soluble intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 levels increased (up to 2.5-fold and 1.9-fold, respectively; p ≤0.001) in patients with HFpEF and patients with HFpEF and DM, whereas soluble E-selectin only increased in patients with HFpEF and DM (1.4-fold, p ≤0.001). Circulating vascular endothelial growth levels were in and patients with DM were in patients with HFpEF with/without DM (up to p ≤0.001). Circulating and increased in with a of and in patients with HFpEF and patients with increased neutrophils release from HFpEF with DM p ≤0.001), and release from DM and HFpEF with DM and respectively; p ≤0.001). and vascular endothelial growth release from HFpEF neutrophils up to and from patients with DM and HFpEF release cytokines in pro-inflammatory the in patients with HFpEF and Heart failure with preserved ejection fraction (HFpEF) is characterized by low-grade chronic inflammation, which could be exacerbated by type 2 diabetes mellitus (DM). We hypothesized that neutrophils in patients with DM and patients with HFpEF with/without DM contribute to low-grade inflammation through the release of pro-inflammatory cytokines. Venous blood was withdrawn from patients with DM (n = 22), HFpEF (n = 15), HFpEF with DM (n = 13), and healthy controls (CTL) (n = 21). Levels of circulating cytokines and in vitro cytokines released by isolated neutrophils were assessed by enzyme-linked immunosorbent assay. Compared with CTL, there was a significant decrease in circulating nitric oxide in patients with DM (p ≤0.001), HFpEF (p ≤0.05), and HFpEF with DM (p ≤0.001) up to 44%. Circulating soluble intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 levels increased (up to 2.5-fold and 1.9-fold, respectively; p ≤0.001) in patients with HFpEF and patients with HFpEF and DM, whereas soluble E-selectin only increased in patients with HFpEF and DM (1.4-fold, p ≤0.001). Circulating vascular endothelial growth levels were in and patients with DM were in patients with HFpEF with/without DM (up to p ≤0.001). Circulating and increased in with a of and in patients with HFpEF and patients with increased neutrophils release from HFpEF with DM p ≤0.001), and release from DM and HFpEF with DM and respectively; p ≤0.001). and vascular endothelial growth release from HFpEF neutrophils up to and from patients with DM and HFpEF release cytokines in pro-inflammatory the in patients with HFpEF and Heart failure 2 ejection fraction which with ejection fraction preserved with preserved ejection fraction the and of and chronic the the and of and chronic failure of the of with the of the Heart of the Heart HFpEF is characterized by the of and type 2 diabetes mellitus that to low-grade chronic in of DM in patients with Heart failure with preserved ejection fraction and patients characterized by increased inflammation, increased and vascular failure with preserved ejection fraction is and is circulating to and in failure patients with preserved and ejection Heart pro-inflammatory and of in HFpEF with and HFpEF and a in with HFpEF circulating levels of which is with a of the of and of the to in patients with of in with Heart with of were to the in the of isolated neutrophils to release pro-inflammatory and cytokines in patients with and the of DM was a that patients with preserved ejection fraction with with DM of and healthy controls (CTL) were of patients with HFpEF and with HFpEF and DM were from the Heart the Heart of patients with DM with of and with were from the blood from patients and the was the was by the and the of the and and to the in the of were the and a in the and from the in pro-inflammatory and release in patients with failure and ejection Heart that in the the and significant and were by blood with DM of were by with with with Heart were patients were HFpEF with and of and assessed by the the and of and chronic the the and of and chronic failure of the of with the of the Heart of the Heart and of a of the Heart of Heart of the of Heart and of the of Heart by the Heart Heart of of and and Heart Heart patients were the of in failure with preserved ejection from in Heart Heart failure with preserved ejection with HFpEF DM and by patients with HFpEF were the of chronic chronic failure and were and Heart DM, and HFpEF with that 2 the were from blood were in blood and in with the blood of the of in were 2 to was to and and were and were isolated by by pro-inflammatory and release in patients with failure and ejection Heart blood were by and and was pro-inflammatory and release in patients with failure and ejection Heart was in vitro levels of nitric oxide and of vascular endothelial growth were by enzyme-linked immunosorbent levels of soluble intercellular adhesion molecule-1 vascular cell adhesion molecule-1 and soluble E-selectin were by a the were by by the neutrophils were in with and and were 2 with a neutrophils were and were were to and release by the of and and and were a of by a a by a were a of whereas were a a were and were significant p = = = = and a of = = = healthy DM = diabetes = = HFpEF = failure with preserved ejection = ejection = = = = and a of in a of in was significant in patients with/without HFpEF DM a significant in in and HFpEF the of in only a patients were with a of patients with DM and HFpEF with/without DM were were the significant circulating and the circulating levels of in with DM and HFpEF with DM a significant decrease in circulating levels of nitric oxide with to to to and to to a and the of decrease in circulating levels in HFpEF DM was significant with with HFpEF DM with DM and HFpEF and HFpEF DM a significant in circulating levels of to to to and to to a and 2.5-fold HFpEF with DM a significant of with to to and to to a and was a significant in soluble only in patients with HFpEF DM to to of circulating inflammation from CTL, DM, and HFpEF DM, was by and and by from DM whereas in patients with HFpEF with was only increased in HFpEF and increased in patients with DM and with and was in with increased in patients with HFpEF with DM with and was in with was increased in patients with DM and HFpEF with and and with and with = enzyme-linked immunosorbent 2 the circulating levels of pro-inflammatory and cytokines the Compared with CTL, circulating was patients with DM whereas was by in patients with HFpEF with/without DM to to to and to levels were increased in patients with DM, whereas were increased in patients with HFpEF with/without DM to to and to to a and with HFpEF DM a significant in circulating levels of to to and to to with HFpEF to a and We a significant of the circulating levels of the in patients with DM and HFpEF and HFpEF DM with to to to and to to a and pro-inflammatory to the and release of cytokines by of and We the of a with with a to the release of and by isolated neutrophils there was in release in patients with DM, in HFpEF and HFpEF DM, and a decrease in release by the neutrophils from patients with DM and HFpEF and HFpEF DM with neutrophils from of and the release of inflammation by neutrophils from CTL, DM, and HFpEF DM, were with 2 and released and were by release of and from neutrophils increased and HFpEF and release was whereas release was increased in patients with HFpEF DM, with release of from neutrophils was only by and was increased in HFpEF with and in HFpEF DM with and with with and with = enzyme-linked immunosorbent with increased the release of and by the neutrophils of CTL, patients with DM, and HFpEF DM, and only release Compared with CTL, neutrophils from patients with DM a release of by neutrophils from HFpEF and HFpEF DM a up to and to release with of neutrophils from patients with DM to release was in the was by and with from HFpEF and HFpEF DM to release in to a to release by up to with from patients with DM were neutrophils release by and and and neutrophils from patients with HFpEF release to neutrophils from a significant of the neutrophils from HFpEF DM to the release of which was increased by and with neutrophils from neutrophils from patients with DM were neutrophils release by release from neutrophils of patients with HFpEF was from a significant in the of the neutrophils from HFpEF DM to which was with neutrophils from the a decrease of circulating in patients with HFpEF with/without DM, with a of neutrophils to release We a significant of circulating in patients with DM which was in patients with HFpEF was a significant in circulating endothelial and in patients with whereas the in circulating pro-inflammatory and was in patients with HFpEF neutrophils from patients with were to release with HFpEF and DM a to and whereas neutrophils were in and DM in patients with a and of in HFpEF and endothelial nitric oxide and to the exacerbated by of and failure with preserved ejection in and in and failure with preserved ejection a of circulating in patients with DM and with the decrease in patients with HFpEF decrease in was in with a significant in the of the neutrophils from patients with HFpEF and HFpEF DM to release with a decrease in circulating in of endothelial growth in of and and in and neutrophils from circulating and release in the of of is in the the of release to a decrease in and endothelial growth in endothelial and in endothelial a decrease in circulating levels with decrease endothelial with the of the of soluble contribute to endothelial and in that a a in the of failure with preserved ejection a significant of in DM, and HFpEF and in HFpEF and HFpEF with that and release of and the and of endothelial adhesion and oxide endothelial oxide endothelial of adhesion and and in and in the and the of circulating by and to failure with preserved ejection and through endothelial We that in the of and DM, and were with pro-inflammatory and release in patients with failure and ejection Heart and that and a significant in and in the in and a significant in the circulating and a of the of the in inflammation and in patients with DM and HFpEF with the which that in was up to the of DM, by a the of in of type 2 a that circulating was increased with the of Circulating levels of cytokines and in patients with to failure to circulating levels of a decrease in release from the neutrophils from patients with DM, HFpEF with DM, and a neutrophils from healthy was was released with of and and the release of from is the to that neutrophils from patients with DM, and HFpEF DM release to a with CTL, that neutrophils to the of circulating in patients is to be from release by and of in the of DM pro-inflammatory and release was increased in patients with DM and HFpEF DM release was in isolated neutrophils from patients with HFpEF that neutrophils from HFpEF neutrophils from patients with HFpEF DM to release pro-inflammatory cytokines with to release of a of patients with and of HFpEF with the and of DM and the of was was a the the of the release in and cytokines was to a and is characterized by a significant decrease in circulating and release of pro-inflammatory and and cytokines by neutrophils is in patients with DM, and HFpEF DM with healthy a pro-inflammatory a in the and of and Heart failure 2 ejection fraction which with ejection fraction preserved with preserved ejection fraction the and of and chronic the the and of and chronic failure of the of with the of the Heart of the Heart HFpEF is characterized by the of and type 2 diabetes mellitus that to low-grade chronic in of DM in patients with Heart failure with preserved ejection fraction and patients characterized by increased inflammation, increased and vascular failure with preserved ejection fraction is and is circulating to and in failure patients with preserved and ejection Heart pro-inflammatory and of in HFpEF with and HFpEF and a in with HFpEF circulating levels of which is with a of the of and of the to in patients with of in with Heart with of were to the in the of isolated neutrophils to release pro-inflammatory and cytokines in patients with and the of DM was a that patients with preserved ejection fraction with with DM of and healthy controls (CTL) were of patients with HFpEF and with HFpEF and DM were from the Heart the Heart of patients with DM with of and with were from the blood from patients and the was the was by the and the of the and and to the in the of were the and a in the and from the in pro-inflammatory and release in patients with failure and ejection Heart that in the the and significant and were by blood with DM of were by with with with Heart were patients were HFpEF with and of and assessed by the the and of and chronic the the and of and chronic failure of the of with the of the Heart of the Heart and of a of the Heart of Heart of the of Heart and of the of Heart by the Heart Heart of of and and Heart Heart patients were the of in failure with preserved ejection from in Heart Heart failure with preserved ejection with HFpEF DM and by patients with HFpEF were the of chronic chronic failure and were and Heart DM, and HFpEF with that 2 the were from blood were in blood and in with the blood of the of in were 2 to was to and and were and were isolated by by pro-inflammatory and release in patients with failure and ejection Heart blood were by and and was pro-inflammatory and release in patients with failure and ejection Heart was in vitro levels of nitric oxide and of vascular endothelial growth were by enzyme-linked immunosorbent levels of soluble intercellular adhesion molecule-1 vascular cell adhesion molecule-1 and soluble E-selectin were by a the were by by the neutrophils were in with and and were 2 with a neutrophils were and were were to and release by the of and and and were a of by a a by a were a of whereas were a a were and were significant p = = = = and a of = = = healthy DM = diabetes = = HFpEF = failure with preserved ejection = ejection = = = = and a of in a was a that patients with preserved ejection fraction with with DM of and healthy controls (CTL) were of patients with HFpEF and with HFpEF and DM were from the Heart the Heart of patients with DM with of and with were from the blood from patients and the was the was by the and the of the and and to the in the of were the and a in the and from the in pro-inflammatory and release in patients with failure and ejection Heart that in the the and significant and were by blood with DM of were by with with with Heart were patients were HFpEF with and of and assessed by the the and of and chronic the the and of and chronic failure of the of with the of the Heart of the Heart and of a of the Heart of Heart of the of Heart and of the of Heart by the Heart Heart of of and and Heart Heart patients were the of in failure with preserved ejection from in Heart Heart failure with preserved ejection with HFpEF DM and by patients with HFpEF were the of chronic chronic failure and were and Heart DM, and HFpEF with that 2 the were from Venous blood were in blood and in with the blood of the of in were 2 to was to and and were and were isolated by by pro-inflammatory and release in patients with failure and ejection Heart blood were by and and was pro-inflammatory and release in patients with failure and ejection Heart was in vitro levels of nitric oxide and of vascular endothelial growth were by enzyme-linked immunosorbent levels of soluble intercellular adhesion molecule-1 vascular cell adhesion molecule-1 and soluble E-selectin were by a the were by by the neutrophils were in with and and were 2 with a neutrophils were and were were to and release by the of and and and were a of by a a by a were a of whereas were a a were and were significant p = = = healthy DM = diabetes = = HFpEF = failure with preserved ejection = ejection = = = = of in was significant in patients with/without HFpEF DM a significant in in and HFpEF the of in only a patients were with a of patients with DM and HFpEF with/without DM were were the significant circulating and the circulating levels of in with DM and HFpEF with DM a significant decrease in circulating levels of nitric oxide with to to to and to to a and the of decrease in circulating levels in HFpEF DM was significant with with HFpEF DM with DM and HFpEF and HFpEF DM a significant in circulating levels of to to to and to to a and 2.5-fold HFpEF with DM a significant of with to to and to to a and was a significant in soluble only in patients with HFpEF DM to to 2 the circulating levels of pro-inflammatory and cytokines the Compared with CTL, circulating was patients with DM whereas was by in patients with HFpEF with/without DM to to to and to levels were increased in patients with DM, whereas were increased in patients with HFpEF with/without DM to to and to to a and with HFpEF DM a significant in circulating levels of to to and to to with HFpEF to a and We a significant of the circulating levels of the in patients with DM and HFpEF and HFpEF DM with to to to and to to a and pro-inflammatory to the and release of cytokines by of and We the of a with with a to the release of and by isolated neutrophils there was in release in patients with DM, in HFpEF and HFpEF DM, and a decrease in release by the neutrophils from patients with DM and HFpEF and HFpEF DM with neutrophils from of and the release of inflammation by neutrophils from CTL, DM, and HFpEF DM, were with 2 and released and were by release of and from neutrophils increased and HFpEF and release was whereas release was increased in patients with HFpEF DM, with release of from neutrophils was only by and was increased in HFpEF with and in HFpEF DM with and with with and with = enzyme-linked immunosorbent with increased the release of and by the neutrophils of CTL, patients with DM, and HFpEF DM, and only release Compared with CTL, neutrophils from patients with DM a release of by neutrophils from HFpEF and HFpEF DM a up to and to release with of neutrophils from patients with DM to release was in the was by and with from HFpEF and HFpEF DM to release in to a to release by up to with from patients with DM were neutrophils release by and and and neutrophils from patients with HFpEF release to neutrophils from a significant of the neutrophils from HFpEF DM to the release of which was increased by and with neutrophils from neutrophils from patients with DM were neutrophils release by release from neutrophils of patients with HFpEF was from a significant in the of the neutrophils from HFpEF DM to which was with neutrophils from of in was significant in patients with/without HFpEF DM a significant in in and HFpEF the of in only a patients were with a of patients with DM and HFpEF with/without DM were were the significant circulating and the circulating levels of in with DM and HFpEF with DM a significant decrease in circulating levels of nitric oxide with to to to and to to a and the of decrease in circulating levels in HFpEF DM was significant with with HFpEF DM with DM and HFpEF and HFpEF DM a significant in circulating levels of to to to and to to a and 2.5-fold HFpEF with DM a significant of with to to and to to a and was a significant in soluble only in patients with HFpEF DM to to 2 the circulating levels of pro-inflammatory and cytokines the Compared with CTL, circulating was patients with DM whereas was by in patients with HFpEF with/without DM to to to and to levels were increased in patients with DM, whereas were increased in patients with HFpEF with/without DM to to and to to a and with HFpEF DM a significant in circulating levels of to to and to to with HFpEF to a and We a significant of the circulating levels of the in patients with DM and HFpEF and HFpEF DM with to to to and to to a and We pro-inflammatory to the and release of cytokines by of and We the of a with with a to the release of and by isolated neutrophils there was in release in patients with DM, in HFpEF and HFpEF DM, and a decrease in release by the neutrophils from patients with DM and HFpEF and HFpEF DM with neutrophils from with increased the release of and by the neutrophils of CTL, patients with DM, and HFpEF DM, and only release Compared with CTL, neutrophils from patients with DM a release of by neutrophils from HFpEF and HFpEF DM a up to and to release with of neutrophils from patients with DM to release was in the was by and with from HFpEF and HFpEF DM to release in to a to release by up to with from patients with DM were neutrophils release by and and and neutrophils from patients with HFpEF release to neutrophils from a significant of the neutrophils from HFpEF DM to the release of which was increased by and with neutrophils from neutrophils from patients with DM were neutrophils release by release from neutrophils of patients with HFpEF was from a significant in the of the neutrophils from HFpEF DM to which was with neutrophils from the a decrease of circulating in patients with HFpEF with/without DM, with a of neutrophils to release We a significant of circulating in patients with DM which was in patients with HFpEF was a significant in circulating endothelial and in patients with whereas the in circulating pro-inflammatory and was in patients with HFpEF neutrophils from patients with were to release with HFpEF and DM a to and whereas neutrophils were in and DM in patients with a and of in HFpEF and endothelial nitric oxide and to the exacerbated by of and failure with preserved ejection in and in and failure with preserved ejection a of circulating in patients with DM and with the decrease in patients with HFpEF decrease in was in with a significant in the of the neutrophils from patients with HFpEF and HFpEF DM to release with a decrease in circulating in of endothelial growth in of and and in and neutrophils from circulating and release in the of of is in the the of release to a decrease in and endothelial growth in endothelial and in endothelial a decrease in circulating levels with decrease endothelial with the of the of soluble contribute to endothelial and in that a a in the of failure with preserved ejection a significant of in DM, and HFpEF and in HFpEF and HFpEF with that and release of and the and of endothelial adhesion and oxide endothelial oxide endothelial of adhesion and and in and in the and the of circulating by and to failure with preserved ejection and through endothelial We that in the of and DM, and were with pro-inflammatory and release in patients with failure and ejection Heart and that and a significant in and in the in and a significant in the circulating and a of the of the in inflammation and in patients with DM and HFpEF with the which that in was up to the of DM, by a the of in of type 2 a that circulating was increased with the of Circulating levels of cytokines and in patients with to failure to circulating levels of a decrease in release from the neutrophils from patients with DM, HFpEF with DM, and a neutrophils from healthy was was released with of and and the release of from is the to that neutrophils from patients with DM, and HFpEF DM release to a with CTL, that neutrophils to the of circulating in patients is to be from release by and of in the of DM pro-inflammatory and release was increased in patients with DM and HFpEF DM release was in isolated neutrophils from patients with HFpEF that neutrophils from HFpEF neutrophils from patients with HFpEF DM to release pro-inflammatory cytokines with to release of a of patients with and of HFpEF with the and of DM and the of was was a the the of the release in and cytokines was to a and is characterized by a significant decrease in circulating and release of pro-inflammatory and and cytokines by neutrophils is in patients with DM, and HFpEF DM with healthy a pro-inflammatory a in the and of and the a decrease of circulating in patients with HFpEF with/without DM, with a of neutrophils to release We a significant of circulating in patients with DM which was in patients with HFpEF was a significant in circulating endothelial and in patients with whereas the in circulating pro-inflammatory and was in patients with HFpEF neutrophils from patients with were to release with HFpEF and DM a to and whereas neutrophils were in and DM in patients with a and of in HFpEF and endothelial nitric oxide and to the exacerbated by of and failure with preserved ejection in and in and failure with preserved ejection We a of circulating in patients with DM and with the decrease in patients with HFpEF decrease in was in with a significant in the of the neutrophils from patients with HFpEF and HFpEF DM to release with a decrease in circulating in of endothelial growth in of and and in and neutrophils from circulating and release in the of of is in the the of release to a decrease in and endothelial growth in endothelial and in endothelial a decrease in circulating levels with decrease endothelial with the of the of soluble contribute to endothelial and in that a a in the of failure with preserved ejection We a significant of in DM, and HFpEF and in HFpEF and HFpEF with that and release of and the and of endothelial adhesion and oxide endothelial oxide endothelial of adhesion and and in and in the and the of circulating by and to failure with preserved ejection and through endothelial We that in the of and DM, and were with pro-inflammatory and release in patients with failure and ejection Heart and that and a significant in and in the in and We a significant in the circulating and a of the of the in inflammation and in patients with DM and HFpEF with the which that in was up to the of DM, by a the of in of type 2 a that circulating was increased with the of Circulating levels of cytokines and in patients with to failure to circulating levels of a decrease in release from the neutrophils from patients with DM, HFpEF with DM, and a neutrophils from healthy was was released with of and and the release of from is the to that neutrophils from patients with DM, and HFpEF DM release to a with CTL, that neutrophils to the of circulating in patients is to be from release by and of in We the of DM pro-inflammatory and release was increased in patients with DM and HFpEF DM release was in isolated neutrophils from patients with HFpEF that neutrophils from HFpEF neutrophils from patients with HFpEF DM to release pro-inflammatory cytokines with to release of a of patients with and of HFpEF with the and of DM and the of was was a the the of the release in and cytokines was to a and cytokines. HFpEF is characterized by a significant decrease in circulating and release of pro-inflammatory and and cytokines by neutrophils is in patients with DM, and HFpEF DM with healthy a pro-inflammatory a in the and of and to the blood of to

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