Abstract 17182: Coronary Endothelial Dysfunction in Humans is Associated With Elevated Expression of Clonal Hematopoiesis of Indeterminate Potential

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Morsaleh Ganji ◽  
Terra Lasho ◽  
Takumi Toya ◽  
Ali Ahmed ◽  
Michel Corban ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Dna Methyltransferase ◽  
Early Stage ◽  
Gene Mutations ◽  
Control Group ◽  
Clonal Hematopoiesis ◽  
Cytokine Analysis ◽  
Coronary Endothelial Dysfunction

Introduction: Recent evidence has demonstrated that Clonal Hematopoiesis of Indeterminate Potential (CHIP) increases the risk of cardiovascular events. However, the exact role played by CHIP in early stages of coronary atherosclerosis, characterized by coronary endothelial dysfunction remains to be elucidated. Hypothesis: The current study was designed to test the hypothesis that the presence of CHIP in peripheral blood cells is associated with coronary endothelial dysfunction and increased levels of inflammatory markers. Methods: Next generation sequencing was used to detect mutations among patients who had coronary endothelial dysfunction and control group (normal coronary endothelial function). Endothelial dysfunction was defined by ≥ 20% decrease in coronary artery diameter or ≤50% increase in blood flow in response to acetylcholine injection compared to baseline. Plasma cytokine levels of Interleukin (IL)-6 and IL-8 were also assessed. Results: Clonal hematopoiesis relevant gene mutations were found in 1 out of 64 patients with normal endothelial function (1.5%) and 11 out of 119 cases in the endothelial dysfunction group (9.2%) (P = 0.04) with ASXL1 (Additional sex combs-like 1) being the most frequent gene (4.2%) mutated. Cytokine analysis demonstrated that mutations in ASXL1, DNMT3A (DNA methyltransferase 3A) and TET2 (Ten-eleven-translocation-2) in the endothelial dysfunction group were associated with increased levels of IL-6 and IL-8 (P = 0.001, P = 0.003; respectively). Conclusions: The current study supports a potential role for CHIP in mechanisms of coronary artery disease starting at early stage of atherosclerosis. Furthermore, enhanced expression levels of IL-6 and IL-8 seem to be related to mutations in DNMT3A, ASXL1 and TET2 genes, more than other gene mutations relevant CHIP.

scholarly journals Elevated expression of clonal hematopoiesis of indeterminate potential in patients with coronary endothelial dysfunction is associated with future cardiovascular events

2020 ◽  
Author(s):  
Morsaleh Ganji ◽  
Terra Lasho ◽  
Takumi Toya ◽  
Nadia Akhiyat ◽  
Changxin Shi ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Cardiovascular Events ◽  
Gene Mutations ◽  
Major Adverse Cardiovascular Events ◽  
Targeted Next Generation Sequencing ◽  
Clonal Hematopoiesis ◽  
Increased Risk ◽  
Elevated Expression ◽  
Regulator Genes ◽  
Coronary Endothelial Dysfunction

Abstract Aims We aimed to test the hypothesis that the presence of clonal hematopoiesis of indeterminate potential (CHIP) in peripheral blood cells is associated with coronary endothelial dysfunction, enhanced inflammatory markers, and major adverse cardiovascular events (MACE).Methods and results We compared targeted next generation sequencing (35 CHIP related genes) between patients with coronary endothelial dysfunction (n = 123) and controls (n=65). Coronary endothelial dysfunction was defined by ≥ 20% decrease in coronary artery diameter (CAD) or ≤ 50% increase in coronary blood flow (CBF) in response to acetylcholine injection compared to baseline. Plasma cytokine levels of Interleukin (IL)-6 and IL-8 were also assessed. Patients were subsequently followed for 12.2 ± 4.3 years. Clonal hematopoiesis relevant gene mutations were found in 1 individual in normal endothelial function group (1.5%) and 11 cases in endothelial dysfunction group (9.3%) (p = 0.04). Additionally, CHIP mutations were associated with an increased risk of MACE (OR = 4.08, P = 0.04). Mutations in ASXL1, DNMT3A and TET2 in the endothelial dysfunction group were also associated with increased levels of IL-6 and IL-8 (P = 0.001, P = 0.003; respectively).Conclusion The current study demonstrates a high frequency of CHIP in patients with coronary endothelial dysfunction as well as an association between mutations in three most common epigenetic regulator genes and increased levels of IL-6 and IL-8. Therefore it infers a probable relationship between CHIP, endothelial dysfunction and cardiovascular adverse events.

Coronary Artery Disease and Endothelial Dysfunction: Novel Diagnostic and Therapeutic Approaches

2020 ◽  
Vol 27 (7) ◽  
pp. 1052-1080 ◽  
Author(s):  
Evangelos Oikonomou ◽  
Gerasimos Siasos ◽  
Vasiliki Tsigkou ◽  
Evanthia Bletsa ◽  
Maria-Evi Panoilia ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Stable Coronary Artery Disease ◽  
Therapeutic Interventions ◽  
Therapeutic Approaches ◽  
Cardiovascular Prognosis ◽  
Ultrasound Evaluation ◽  
Artery Disease

Coronary artery disease is the leading cause of morbidity and mortality worldwide. The most common pathophysiologic substrate is atherosclerosis which is an inflammatory procedure that starts at childhood and develops throughout life. Endothelial dysfunction is associated with the initiation and progression of atherosclerosis and is characterized by the impaired production of nitric oxide. In general, endothelial dysfunction is linked to poor cardiovascular prognosis and different methods, both invasive and non-invasive, have been developed for its evaluation. Ultrasound evaluation of flow mediated dilatation of the branchial artery is the most commonly used method to assessed endothelial function while intracoronary administration of vasoactive agents may be also be used to test directly endothelial properties of the coronary vasculature. Endothelial dysfunction has also been the subject of therapeutic interventions. This review article summarizes the knowledge about evaluation of endothelial function in acute coronary syndromes and stable coronary artery disease and demonstrates the current therapeutic approaches against endothelial dysfunction.

scholarly journals Telomere Attrition and Clonal Hematopoiesis of Indeterminate Potential in Cardiovascular Disease

2021 ◽  
Vol 22 (18) ◽  
pp. 9867
Author(s):  
Yi-Chun Huang ◽  
Chao-Yung Wang
Keyword(s):  
Cardiovascular Disease ◽  
Dna Methyltransferase ◽  
Gene Mutations ◽  
Cvd Risk ◽  
Telomere Attrition ◽  
Clonal Hematopoiesis ◽  
Age Related ◽  
Cell Clones ◽  
Important Relationship ◽  
Increased Risk

Clinical evidence suggests that conventional cardiovascular disease (CVD) risk factors cannot explain all CVD incidences. Recent studies have shown that telomere attrition, clonal hematopoiesis of indeterminate potential (CHIP), and atherosclerosis (telomere–CHIP–atherosclerosis, TCA) evolve to play a crucial role in CVD. Telomere dynamics and telomerase have an important relationship with age-related CVD. Telomere attrition is associated with CHIP. CHIP is commonly observed in elderly patients. It is characterized by an increase in blood cell clones with somatic mutations, resulting in an increased risk of hematological cancer and atherosclerotic CVD. The most common gene mutations are DNA methyltransferase 3 alpha (DNMT3A), Tet methylcytosine dioxygenase 2 (TET2), and additional sex combs-like 1 (ASXL1). Telomeres, CHIP, and atherosclerosis increase chronic inflammation and proinflammatory cytokine expression. Currently, their epidemiology and detailed mechanisms related to the TCA axis remain incompletely understood. In this article, we reviewed recent research results regarding the development of telomeres and CHIP and their relationship with atherosclerotic CVD.

CD14+CD16++ “nonclassical” monocytes are associated with endothelial dysfunction in patients with coronary artery disease

2017 ◽  
Vol 117 (05) ◽  
pp. 971-980 ◽  
Author(s):  
Karol Urbanski ◽  
Dominik Ludew ◽  
Grzegorz Filip ◽  
Magdalena Filip ◽  
Agnieszka Sagan ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Mononuclear Cells ◽  
Vascular Dysfunction ◽  
Activation Markers ◽  
Mammary Arteries ◽  
No Bioavailability ◽  
Artery Disease

SummaryEndothelial dysfunction and inflammation are key mechanisms of vascular disease. We hypothesised that heterogeneity of monocyte subpopulations may be related to the development of vascular dysfunction in coronary artery disease (CAD). Therefore, we examined the relationships between monocyte subsets (CD14++CD16– “classical – Mon1”, CD14++CD16+ “intermediate – Mon2” and CD14+CD16++ “nonclassical – Mon3”), endothelial function and risk factor profiles in 130 patients with CAD undergoing coronary artery bypass grafting. This allowed for direct nitric oxide (NO) bioavailability assessment using isometric tension studies ex vivo (acetylcholine; ACh- and sodium- nitropruside; SNP-dependent) in segments of internal mammary arteries. The expression of CD14 and CD16 antigens and activation markers were determined in peripheral blood mononuclear cells using flow cytometry. Patients with high CD14+CD16++ “nonclassical” and low CD14++CD16- “classical” monocytes presented impaired endothelial function. High frequency of CD14+CD16++ “nonclassical” monocytes was associated with increased vascular superoxide production. Furthermore, endothelial dysfunction was associated with higher expression of activation marker CD11c selectively on CD14+CD16++ monocytes. Nonclassical and classical monocyte frequencies remained independent predictors of endothelial dysfunction when major risk factors for atherosclerosis were taken into account (β =0.18 p=0.04 and β =-0.19 p=0.03, respectively). In summary, our data indicate that CD14+CD16++ “nonclassical” monocytes are associated with more advanced vascular dysfunction measured as NO-bioavailability and vascular reactive oxygen species production.

Abstract 13062: Epicardial Fat Associates With Endothelial Dysfunction, but Not With Coronary Calcium Score: From the Elsa-brasil Cohort Study

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Karina P Martins ◽  
Sandhi Barreto ◽  
Daniel Bos ◽  
JESIANA PEDROSA ◽  
Douglas Mesquita ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cardiovascular Risk ◽  
Coronary Artery ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Cardiovascular Risk Factors ◽  
Subcutaneous Fat ◽  
Epicardial Fat ◽  
Fat Deposits ◽  
Multivariable Analyses

Introduction: Epicardial fat has been related to coronary artery disease (CAD) independent of visceral or subcutaneous fat. The mechanism responsible for this association has not yet been elucidated. Our objective was to evaluate the association between automatically measured epicardial fat volume (EFV), cardiovascular risk factors, coronary artery calcium (CAC) and endothelial function in participants of ELSA-Brasil. Methods and Results: The sample comprised 470 (mean age 55± 8y, 52.3% men) participants from ELSA-MG, one of the Investigation Centers of the cohort, who had valid computed tomography scans and endothelial function evaluated by peripheral arterial tonometry (PAT). The mean EFV was 111 (IQ 86-144) mL. CAC=0 was detected in 55% of participants. In the multivariable analyses between cardiovascular risk factors and EFV, the following associations were observed with higher EFV: female sex; and increased age, waist circumference and triglycerides (p <0.001 for all). In multivariable analyses, higher EFV remained associated with worse endothelial function - basal pulse amplitude (q2=1.22, CI95% 1.07-1.40, p=0.004; q3=1.50, CI95% 1.30-1.74, p<0.001; q4=1.50, CI95% 1.28-1.79, p<0.001) and PAT ratio (q2=0.87, CI95% 0.81-0.95, p<0.001; q3=0.86, CI95% 0.79-0.94, p<0.001; q4=0.80, CI95% 0.73-0.89, p<0.001), but not with CAC. Conclusions: Higher EFV was associated with impaired endothelial function, but not with higher CAC. Our results suggest that the mechanism by which epicardial fat deposits relates to CAD may be different from the pathway of CAC, which relates to calcified plaques. A possible mechanism may be through the enhancement of endothelial dysfunction, microvascular disease and predominantly lipidic non-calcified plaques.

Endothelial dysfunction is an independent factor responsible for vasospastic angina

2001 ◽  
Vol 101 (6) ◽  
pp. 707-713 ◽  
Author(s):  
Hiroki TERAGAWA ◽  
Masaya KATO ◽  
Junichi KUROKAWA ◽  
Togo YAMAGATA ◽  
Hideo MATSUURA ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Brachial Artery ◽  
Coronary Stenosis ◽  
Intima Media Thickness ◽  
Control Group ◽  
Test Results ◽  
Independent Factor ◽  
Atherosclerotic Changes ◽  
Significant Coronary Stenosis

In order to evaluate peripheral endothelial function in patients with vasospastic angina (VSA), we measured flow-mediated dilation (FMD) of the brachial artery in patients with VSA and compared it with FMD in patients without VSA. Endothelial dysfunction is considered one of the mechanisms underlying VSA. However, its exact role remains to be clarified. The study included 30 patients with positive spasm-provocational test results without evidence of significant coronary stenosis (VSA group) and 30 patients with negative spasm-provocational test results without evidence of significant coronary stenosis (control group). In each patient, brachial artery diameter responses to hyperemic flow and glyceryl trinitrate spray were measured using high-resolution ultrasound. The carotid intima-media thickness was also measured as a marker of systemic atherosclerosis. FMD was lower in the VSA group (4.8±0.5%) compared with the control group (9.4±0.7%, P < 0.0001). In the VSA group, FMD was not affected by coronary risk factors or the presence of atherosclerotic changes on coronary angiography. Glyceryl trinitrate-induced dilation did not differ between the two groups. The intima-media thickness was comparable between the VSA (0.85±0.04mm) and control groups (0.81±0.05mm). These findings indicated that peripheral endothelial function is impaired only in the VSA group, whereas the atherosclerotic changes were similar in the two groups. We conclude that endothelial dysfunction may be an independent factor responsible for the development of VSA.

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