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Insulin resistance, endothelial function, angiogenic factors and clinical outcome in non-diabetic patients with chest pain without myocardial perfusion defects.

Westergren HU, Svedlund S, Momo RA, Blomster JI, Wåhlander K, Rehnström E, Greasley PJ, Fritsche-Danielson R, Oscarsson J, Gan LM - Cardiovasc Diabetol (2016)

Bottom Line: Furthermore, elevated HOMA-IR was associated with decreased levels of vascular endothelial growth factor D, stem cell factor and endocan as well as to increased level of interleukin-6.Global gene expression pathway analysis of whole blood cells showed that high HOMA-IR and impaired endothelial function were associated with upregulated pro-inflammatory pathways and down-regulated eukaryotic initiation factor-2 pathway.Increased systemic pro-inflammatory state and decreased levels of pro-angiogenic vascular growth factors may be important underlying molecular mechanisms.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden. helena.westergren@gu.se.

ABSTRACT

Background: Patients with angina-like symptoms without myocardial perfusion scintigram (MPS)-verified abnormality may still be at risk for cardiovascular events. We hypothesized that insulin resistance could play a role in this population even without diagnosed diabetes. We further explored physiological and blood biomarkers, as well as global gene expression patterns that could be closely related to impaired glucose homeostasis to deepen our mechanistic understanding.

Methods: A total of 365 non-diabetic patients with suspected myocardial ischemia referred to MPS were enrolled and followed up regarding event-free survival with a median time of 5.1 years. All patients underwent endothelial function assessment by reactive hyperemic index (RHI) using EndoPAT and extensive biomarker analysis. Whole blood global gene expression pathway analysis was performed in a subset of patients.

Results: Homeostasis model assessment of insulin resistance (HOMA-IR) added independent prognostic value in patients without myocardial perfusion defects. In a multivariable analysis, HOMA-IR was inversely associated with low RHI. Furthermore, elevated HOMA-IR was associated with decreased levels of vascular endothelial growth factor D, stem cell factor and endocan as well as to increased level of interleukin-6. Global gene expression pathway analysis of whole blood cells showed that high HOMA-IR and impaired endothelial function were associated with upregulated pro-inflammatory pathways and down-regulated eukaryotic initiation factor-2 pathway.

Conclusions: Insulin resistance measured by HOMA-IR is associated with endothelial dysfunction and confers independent prognostic information in non-diabetic patients with chest pain without myocardial perfusion defects. Increased systemic pro-inflammatory state and decreased levels of pro-angiogenic vascular growth factors may be important underlying molecular mechanisms.

No MeSH data available.


Related in: MedlinePlus

Global gene expression pathway analysis on patients without myocardial perfusion defects (n = 54). Red bars predict an overall increase in the activity of the pathway (activation) while blue bars indicate a prediction of an overall decrease in activity (deactivation/inhibition). White bars are those with a z-score which is zero or very close to zero. The overall activation/inhibition (deactivation) states of the pathways are predicted based on a Z-score algorithm. Z-score gives a statistical measure of the relationship of up and downregulated gene transcripts in the microarray data set with-respect-to a particular pathway. This Z-score is used to mathematically compare the microarray data set with the canonical pathway patterns. A pathway is predicted as activated or inhibited by comparing the expected pattern (up/downregulation of key genes in the pathway) if the pathway is activated against the actual pattern (up/downregulated key genes) in the microarray data set. If the actual pattern matches the expected pattern, the Z-score is positive (Z-score > ~2 = activated pathway) otherwise negative (Z-score <2 = inhibited pathway)
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Fig3: Global gene expression pathway analysis on patients without myocardial perfusion defects (n = 54). Red bars predict an overall increase in the activity of the pathway (activation) while blue bars indicate a prediction of an overall decrease in activity (deactivation/inhibition). White bars are those with a z-score which is zero or very close to zero. The overall activation/inhibition (deactivation) states of the pathways are predicted based on a Z-score algorithm. Z-score gives a statistical measure of the relationship of up and downregulated gene transcripts in the microarray data set with-respect-to a particular pathway. This Z-score is used to mathematically compare the microarray data set with the canonical pathway patterns. A pathway is predicted as activated or inhibited by comparing the expected pattern (up/downregulation of key genes in the pathway) if the pathway is activated against the actual pattern (up/downregulated key genes) in the microarray data set. If the actual pattern matches the expected pattern, the Z-score is positive (Z-score > ~2 = activated pathway) otherwise negative (Z-score <2 = inhibited pathway)

Mentions: The outcome of ‘limma’ gene expression analysis is moderated t-statistics with Bayesian-adjusted denominators that incorporate information across all genes [26]. The ‘limma’ result consisting of the probeset IDs and the log-fold expression values of gene transcripts were then analyzed using the IPA software. Differential expressed genes were characterized having an estimated fold-change >1.5, and the Benjamini and Hochberg’s method was used to control false discovery rate smaller than 0.05 [27]. Further analysis by PLS-DA produced lists of gene transcripts associated to HOMA-IR above median and RHI below median. Thereafter, we examined the canonical pathways enriched. IPA comparison analysis gene transcripts predict patients with high HOMA-IR and low RHI co-regulated signaling pathways. Worth mentioning is the activated pro-inflammatory pathways, dendritic cell maturation signaling, nuclear factor kappa B signaling and toll-like receptor signaling as well as inhibited eukaryotic initiation factor 2 (EIF2) signaling (Fig. 3).Fig. 3


Insulin resistance, endothelial function, angiogenic factors and clinical outcome in non-diabetic patients with chest pain without myocardial perfusion defects.

Westergren HU, Svedlund S, Momo RA, Blomster JI, Wåhlander K, Rehnström E, Greasley PJ, Fritsche-Danielson R, Oscarsson J, Gan LM - Cardiovasc Diabetol (2016)

Global gene expression pathway analysis on patients without myocardial perfusion defects (n = 54). Red bars predict an overall increase in the activity of the pathway (activation) while blue bars indicate a prediction of an overall decrease in activity (deactivation/inhibition). White bars are those with a z-score which is zero or very close to zero. The overall activation/inhibition (deactivation) states of the pathways are predicted based on a Z-score algorithm. Z-score gives a statistical measure of the relationship of up and downregulated gene transcripts in the microarray data set with-respect-to a particular pathway. This Z-score is used to mathematically compare the microarray data set with the canonical pathway patterns. A pathway is predicted as activated or inhibited by comparing the expected pattern (up/downregulation of key genes in the pathway) if the pathway is activated against the actual pattern (up/downregulated key genes) in the microarray data set. If the actual pattern matches the expected pattern, the Z-score is positive (Z-score > ~2 = activated pathway) otherwise negative (Z-score <2 = inhibited pathway)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4759743&req=5

Fig3: Global gene expression pathway analysis on patients without myocardial perfusion defects (n = 54). Red bars predict an overall increase in the activity of the pathway (activation) while blue bars indicate a prediction of an overall decrease in activity (deactivation/inhibition). White bars are those with a z-score which is zero or very close to zero. The overall activation/inhibition (deactivation) states of the pathways are predicted based on a Z-score algorithm. Z-score gives a statistical measure of the relationship of up and downregulated gene transcripts in the microarray data set with-respect-to a particular pathway. This Z-score is used to mathematically compare the microarray data set with the canonical pathway patterns. A pathway is predicted as activated or inhibited by comparing the expected pattern (up/downregulation of key genes in the pathway) if the pathway is activated against the actual pattern (up/downregulated key genes) in the microarray data set. If the actual pattern matches the expected pattern, the Z-score is positive (Z-score > ~2 = activated pathway) otherwise negative (Z-score <2 = inhibited pathway)
Mentions: The outcome of ‘limma’ gene expression analysis is moderated t-statistics with Bayesian-adjusted denominators that incorporate information across all genes [26]. The ‘limma’ result consisting of the probeset IDs and the log-fold expression values of gene transcripts were then analyzed using the IPA software. Differential expressed genes were characterized having an estimated fold-change >1.5, and the Benjamini and Hochberg’s method was used to control false discovery rate smaller than 0.05 [27]. Further analysis by PLS-DA produced lists of gene transcripts associated to HOMA-IR above median and RHI below median. Thereafter, we examined the canonical pathways enriched. IPA comparison analysis gene transcripts predict patients with high HOMA-IR and low RHI co-regulated signaling pathways. Worth mentioning is the activated pro-inflammatory pathways, dendritic cell maturation signaling, nuclear factor kappa B signaling and toll-like receptor signaling as well as inhibited eukaryotic initiation factor 2 (EIF2) signaling (Fig. 3).Fig. 3

Bottom Line: Furthermore, elevated HOMA-IR was associated with decreased levels of vascular endothelial growth factor D, stem cell factor and endocan as well as to increased level of interleukin-6.Global gene expression pathway analysis of whole blood cells showed that high HOMA-IR and impaired endothelial function were associated with upregulated pro-inflammatory pathways and down-regulated eukaryotic initiation factor-2 pathway.Increased systemic pro-inflammatory state and decreased levels of pro-angiogenic vascular growth factors may be important underlying molecular mechanisms.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden. helena.westergren@gu.se.

ABSTRACT

Background: Patients with angina-like symptoms without myocardial perfusion scintigram (MPS)-verified abnormality may still be at risk for cardiovascular events. We hypothesized that insulin resistance could play a role in this population even without diagnosed diabetes. We further explored physiological and blood biomarkers, as well as global gene expression patterns that could be closely related to impaired glucose homeostasis to deepen our mechanistic understanding.

Methods: A total of 365 non-diabetic patients with suspected myocardial ischemia referred to MPS were enrolled and followed up regarding event-free survival with a median time of 5.1 years. All patients underwent endothelial function assessment by reactive hyperemic index (RHI) using EndoPAT and extensive biomarker analysis. Whole blood global gene expression pathway analysis was performed in a subset of patients.

Results: Homeostasis model assessment of insulin resistance (HOMA-IR) added independent prognostic value in patients without myocardial perfusion defects. In a multivariable analysis, HOMA-IR was inversely associated with low RHI. Furthermore, elevated HOMA-IR was associated with decreased levels of vascular endothelial growth factor D, stem cell factor and endocan as well as to increased level of interleukin-6. Global gene expression pathway analysis of whole blood cells showed that high HOMA-IR and impaired endothelial function were associated with upregulated pro-inflammatory pathways and down-regulated eukaryotic initiation factor-2 pathway.

Conclusions: Insulin resistance measured by HOMA-IR is associated with endothelial dysfunction and confers independent prognostic information in non-diabetic patients with chest pain without myocardial perfusion defects. Increased systemic pro-inflammatory state and decreased levels of pro-angiogenic vascular growth factors may be important underlying molecular mechanisms.

No MeSH data available.


Related in: MedlinePlus