scholarly journals Mechanism of the Switch from NO to H2O2 in Endothelium-Dependent Vasodilation in Diabetes

2021 ◽  
Author(s):  
Cody Juguilon ◽  
Zhiyuan Wang ◽  
Yang Wang ◽  
Anurag Jamaiyar ◽  
Molly Enrick ◽  
...  
Keyword(s):  
Coronary Arteries ◽  
Ex Vivo ◽  
Contrast Echocardiography ◽  
Microvascular Dysfunction ◽  
Coronary Microvascular Dysfunction ◽  
Early Event ◽  
Paramagnetic Resonance ◽  
Artery Disease ◽  
Synthase Inhibitor

Coronary microvascular dysfunction is prevalent among diabetics and is correlated with cardiac mortality. Compromised endothelial-dependent dilation (EDD) is an early event in the progression of diabetes, but the mechanisms remain incompletely understood. Nitric oxide (NO) is the major endothelium-dependent vasodilatory metabolite in the healthy coronary circulation, but switches to hydrogen peroxide (H2O2) in coronary artery disease (CAD) patients. Because diabetes is a major risk factor for CAD we hypothesized that a similar switch from NO-to-H2O2 occurs in diabetes. Methods: Vasodilation was measured ex vivo in isolated coronary arteries from wild type (WT) and microRNA-21 (miR-21) null mice fed chow or high fat and sugar diet, and LepR null (db/db) mice using myography. Myocardial blood flow (MBF), blood pressure, and heart rate were measured in vivo using contrast echocardiography and a solid-state pressure sensor catheter. RNA from coronary arteries, endothelial cells and hearts were analyzed via qPCR for gene expression and protein expression was assessed via Western-Blot analyses. Superoxide was detected via electron paramagnetic resonance (EPR). Results: 1) Ex vivo coronary EDD and in vivo MBF was impaired in diabetes. 2) L-NAME (NO-synthase inhibitor) inhibited ex vivo coronary EDD and in vivo MBF in WT, while PEG-catalase (H2O2 scavenger) inhibited diabetic EDD ex vivo and MBF in vivo. 5) miR-21 deficiency blocked the NO-to-H2O2 switch and prevented diabetic vasodilation impairments. 6) Diabetic mice displayed increased serum NO and H2O2, upregulated mRNA expression of Sod1, Sod2, iNos, and Cav-1, and downregulated Pgc-1α. Deficiency of miR-21 reversed these changes. 7) miR-21 deficiency increased PGC1α, PPARα and eNOS protein and reduced detection of endothelial superoxide. Conclusions: Diabetics exhibit an NO-to-H2O2 switch in the mediator of EDD coronary dilation, which contributed to microvascular dysfunction and is mediated by miR-21. This study represents the first mouse model recapitulating the NO-to-H2O2 switch seen in CAD patients.

Abstract 17248: The Role of microRNA-21 in Regulating the Coronary Microcirculation in Diabetes

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Cody Juguilon ◽  
Zhiyuan Wang ◽  
James Gadd ◽  
Vahagn A Ohanyan ◽  
Anurag Jamaiyar ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Quantitative Polymerase Chain Reaction ◽  
Contrast Echocardiography ◽  
Microvascular Dysfunction ◽  
Coronary Microvascular Dysfunction ◽  
Diabetic Mice ◽  
Coronary Vasodilation ◽  
Nitric Oxide Synthase Inhibitor ◽  
Genetic Profiling ◽  
Synthase Inhibitor

Introduction: Coronary microvascular dysfunction is prevalent among diabetics and intersects with deficits in endothelial-dependent vasodilation. These deficits occur early in the progression of the disease, but the mechanisms remain incompletely understood. Nitric oxide (NO) is the major endothelial-dependent mediator of vasodilation in the healthy coronary circulation, but the mediator switches to hydrogen peroxide (H 2 O 2 ) in coronary artery disease (CAD) patients. Diabetes is a risk factor for CAD, so we hypothesized that a similar switch would occur. Methods: Coronary arteries were isolated and endothelial-dependent vasodilation was assessed using myography. Quantitative polymerase chain reaction (qPCR) was performed for gene expression analysis and myocardial blood flow (MBF) was measured by contrast echocardiography. Results: Nitric oxide synthase inhibitor (L-NAME) inhibited vasodilation in wild type (WT) mice, but the H 2 O 2 scavenger (PEG-catalase) had no effect. In contrast, vasodilation in diabetic mice was blunted by PEG-catalase, but not L-NAME. This suggests that the mediator of coronary vasodilation switched from NO to H 2 O 2 in diabetes. Importantly, we found that microRNA-21 (miR-21) is upregulated in diabetes and the deficiency modulates the mediator switch from NO to H 2 O 2 in diabetic mice. Conclusions: The switch in the mediator of coronary vasodilation from NO to H2O2 contributes to microvascular dysfunction in diabetes and miR-21 regulates this switch. Further genetic profiling will elucidate the pathways and mechanisms converging with miR-21 to regulate microvascular function in diabetes. This is the first mouse model that recapitulates the switch in mediator of coronary vasodilation from NO to H 2 O 2 seen in CAD patients.

scholarly journals Plasma Lipidomic Patterns in Patients with Symptomatic Coronary Microvascular Dysfunction

Metabolites ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 648
Author(s):  
Jonathan R. Lindner ◽  
Brian P. Davidson ◽  
Zifeng Song ◽  
Claudia S. Maier ◽  
Jessica Minnier ◽  
...  
Keyword(s):  
Risk Factors ◽  
High Resolution Mass Spectrometry ◽  
Contrast Echocardiography ◽  
Microvascular Dysfunction ◽  
Carbon Chain ◽  
Elderly Subjects ◽  
Coronary Microvascular Dysfunction ◽  
Metabolic Demand ◽  
Long Chain Fatty Acid ◽  
Artery Disease

Coronary microvascular dysfunction (MVD) is a syndrome of abnormal regulation of vascular tone, particularly during increased metabolic demand. While there are several risk factors for MVD, some of which are similar to those for coronary artery disease (CAD), the cause of MVD is not understood. We hypothesized that MVD in symptomatic non-elderly subjects would be characterized by specific lipidomic profiles. Subjects (n = 20) aged 35–60 years and referred for computed tomography coronary angiography (CTA) for chest pain but who lacked obstructive CAD (>50% stenosis), underwent quantitative regadenoson stress-rest myocardial contrast echocardiography (MCE) perfusion imaging for MVD assessment. The presence of MVD defined by kinetic analysis of MCE data was correlated with lipidomic profiles in plasma measured by liquid chromatography and high-resolution mass spectrometry. Nine of twenty subjects had evidence of MVD, defined by reduced hyperemic perfusion versus other subjects (beta-value 1.62 ± 0.44 vs. 2.63 ± 0.99 s−1, p = 0.009). Neither the presence of high-risk but non-obstructive CAD on CTA, nor CAD risk factors were different for those with versus without MVD. Lipidomic analysis revealed that patients with MVD had lower concentrations of long-carbon chain triacylglycerols and diacylglycerols, and higher concentrations of short-chain triacylglycerols. The diacylglycerol containing stearic and linoleic acid classified all participants correctly. We conclude that specific lipidomic plasma profiles occur in MVD involving saturated long-chain fatty acid-containing acylglycerols that are distinctly different from those in non-obstructive CAD. These patterns could be used to better characterize the pathobiology and potential treatments for this condition.

scholarly journals Coronary microvascular dysfunction after long-term diabetes and hypercholesterolemia

2016 ◽  
Vol 311 (6) ◽  
pp. H1339-H1351 ◽  
Author(s):  
Oana Sorop ◽  
Mieke van den Heuvel ◽  
Nienke S. van Ditzhuijzen ◽  
Vincent J. de Beer ◽  
Ilkka Heinonen ◽  
...  
Keyword(s):  
Coronary Arteries ◽  
High Fat Diet ◽  
Microvascular Dysfunction ◽  
Coronary Microvascular Dysfunction ◽  
Atherosclerotic Plaques ◽  
No Donor ◽  
Vasoconstrictor Response ◽  
Artery Disease

Coronary microvascular dysfunction (CMD) has been proposed as an important component of diabetes mellitus (DM)- and hypercholesterolemia-associated coronary artery disease (CAD). Previously we observed that 2.5 mo of DM and high-fat diet (HFD) in swine blunted bradykinin (BK)-induced vasodilation and attenuated endothelin (ET)-1-mediated vasoconstriction. Here we studied the progression of CMD after 15 mo in the same animal model of CAD. Ten male swine were fed a HFD in the absence (HFD, n = 5) or presence of streptozotocin-induced DM (DM + HFD, n = 5). Responses of small (∼300-μm-diameter) coronary arteries to BK, ET-1, and the nitric oxide (NO) donor S-nitroso- N-acetylpenicillamine were examined in vitro and compared with those of healthy (Normal) swine ( n = 12). Blood glucose was elevated in DM + HFD (17.6 ± 4.5 mmol/l) compared with HFD (5.1 ± 0.4 mmol/l) and Normal (5.8 ± 0.6 mmol/l) swine, while cholesterol was markedly elevated in DM + HFD (16.8 ± 1.7 mmol/l) and HFD (18.1 ± 2.6 mmol/l) compared with Normal (2.1 ± 0.2 mmol/l) swine (all P < 0.05). Small coronary arteries showed early atherosclerotic plaques in HFD and DM + HFD swine. Surprisingly, DM + HFD and HFD swine maintained BK responsiveness compared with Normal swine due to an increase in NO availability relative to endothelium-derived hyperpolarizing factors. However, ET-1 responsiveness was greater in HFD and DM + HFD than Normal swine (both P < 0.05), resulting mainly from ETB receptor-mediated vasoconstriction. Moreover, the calculated vascular stiffness coefficient was higher in DM + HFD and HFD than Normal swine (both P < 0.05). In conclusion, 15 mo of DM + HFD, as well as HFD alone, resulted in CMD. Although the overall vasodilation to BK was unperturbed, the relative contributions of NO and endothelium-derived hyperpolarizing factor pathways were altered. Moreover, the vasoconstrictor response to ET-1 was enhanced, involving the ETB receptors. In conjunction with our previous study, these findings highlight the time dependence of the phenotype of CMD.

Abstract 16233: Systemic Arterial Pulsatility Index is a Potential Metric for Microvascular Dysfunction

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Douglas Sawch ◽  
Benjamin Ruth ◽  
Sula Mazimba ◽  
Jamieson M Bourque ◽  
Kenneth C Bilchick ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Coronary Artery Disease ◽  
Pulsatility Index ◽  
Microvascular Dysfunction ◽  
Suspected Coronary Artery Disease ◽  
Continuous Variable ◽  
Coronary Microvascular Dysfunction ◽  
Chi Square ◽  
Artery Disease ◽  
Fatal Myocardial Infarction

Introduction: Coronary microvascular dysfunction is associated with both atherosclerosis and heart failure (HF). We aimed to evaluate the prognostic value of global coronary flow reserve (CFR) and systemic arterial pulsatility index, a metric of ventricular-arterial coupling, (SAPi = [systemic systolic pressure-systemic diastolic pressure]/pulmonary capillary wedge pressure) in patients with known or suspected coronary artery disease. Methods: This was a retrospective analysis at an academic tertiary care center for patients who underwent right heart catheterization (RHC) and positron emission tomography (PET) imaging within a 6 month period. Global CFR was evaluated with PET imaging and SAPi was calculated using cardiac hemodynamics from RHC. Patients were evaluated for endpoints of non-fatal myocardial infarction, revascularization, and death. Cox proportional hazards regression modeling was used to examine the associations between CFR & SAPi with death and other adverse cardiovascular events. Results: Among 74 patients with complete imaging and hemodynamic data (mean age 64.23 ± 11.18 years, 54.67% female) the mean SAPi was 4.87 ± 3.09 and CFR was 52.95 ± 16.17. Increased SAPi as a continuous variable trended towards decreased mortality [HR: 0.814 (95% CI 0.663-1.016, chi square 3.31, p=.07).] Increased CFR as a continuous variable was significantly associated with decreased mortality [HR: 0.964 (95% CI 0.936-0.993, chi square 6.03, p<0.05). Neither were associated with non-fatal myocardial infarction or early revascularization. There was a weak trend toward correlation between SAPi and CFR (r=0.19, p=0.11). Conclusions: SAPi a hemodynamic marker of ventricular arterial coupling was weakly associated with CFR. On the other hand, CFR was significantly associated with death in patients with known or suspected coronary artery disease. Future work is needed to assess the correlation between SAPi and coronary microvascular dysfunction.

scholarly journals Elevated C-reactive protein levels and coronary microvascular dysfunction in patients with coronary artery disease

2005 ◽  
Vol 26 (20) ◽  
pp. 2099-2105 ◽  
Author(s):  
Fabrizio Tomai ◽  
Flavio Ribichini ◽  
Anna S. Ghini ◽  
Valeria Ferrero ◽  
Giuseppe Andò ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Microvascular Dysfunction ◽  
Coronary Microvascular Dysfunction ◽  
C Reactive Protein ◽  
Protein Levels ◽  
Reactive Protein ◽  
Artery Disease

Abstract 14277: Serum Nt-prob-type Natriuretic Peptide is Associated With Coronary Microvascular Dysfunction in Patients With Angina and Non-obstructive Coronary Artery Disease

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Ali Ahmad ◽  
Jaskanwal D Sara ◽  
Michel T Corban ◽  
Takumi Toya ◽  
Ilke Ozcan ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Natriuretic Peptide ◽  
Obstructive Coronary Artery Disease ◽  
Inverse Correlation ◽  
Microvascular Dysfunction ◽  
Coronary Microvascular Dysfunction ◽  
Flow Reserve ◽  
Artery Disease ◽  
And Gender

Title: Serum NT-proB-type Natriuretic Peptide is associated with Coronary Microvascular Dysfunction in Patients with Angina and Non-obstructive Coronary Artery Disease Authors: Ali Ahmad, MD, Jaskanwal D. Sara, MBChB, Michel T. Corban, MD, Takumi Toya, MD, Ilke Özcan, MD, Lilach O. Lerman, MD PhD, Amir Lerman, MD Introduction: Coronary microvascular dysfunction (CMD) is prevalent in patients with heart failure with preserved ejection fraction. Subclinical ischemia and myocardial fibrosis in CMD might raise filling pressure, a hallmark of HFpEF, which induces secretion of NT-proB-type natriuretic peptide (NTpro-BNP). We sought to explore the relationship between CMD and NT-proBNP. Methods: We studied 698 patients with signs and/or symptoms of ischemia and with non-obstructive CAD (<40% angiographic stenosis) who underwent invasive CMD evaluation and had NT-proBNP checked within 6 weeks. CMD was defined as coronary flow reserve (CFR) (hyperemic flow/baseline flow as measured by the doppler wire) of ≤2.5 in response to intracoronary adenosine injection. Results: Overall mean age was 52.8±12.2 years, and women represented 69% of the patients. Log NT-proBNP showed a modest inverse correlation with CFR (Pearson’s R = -0.22, P<0.0001; Figure 1 ), which remained significant after adjusting for age and gender (Standardized ß coefficient = -0.14; P = 0.001). Patients with CMD had higher levels of NT-proBNP than those without (82 [44-190] vs. 62 (33-130], P <0.0001; Figure 2) . Conclusion: Declining coronary microvascular function is correlated with higher NT-proBNP levels. Patients with CMD had higher levels of NT-proBNP, a marker of elevated LV pressure, contributing to the possible role of CMD in early HFpEF pathophysiology. Keywords: Coronary microvascular dysfunction, NT-proBNP

Imaging of microvascular disease

2021 ◽  
pp. 481-494
Author(s):  
Paolo G. Camici ◽  
Ornella Rimoldi
Keyword(s):  
Myocardial Ischaemia ◽  
Imaging Techniques ◽  
Microvascular Disease ◽  
Microvascular Dysfunction ◽  
Microvascular Function ◽  
Coronary Microvascular Dysfunction ◽  
Maximal Increase ◽  
Asymptomatic Subjects ◽  
Coronary Microvascular Function

Beside obstructive disease of the epicardial coronary arteries dysfunction of the coronary microvasculature has emerged in the past 20 years as an additional mechanism of myocardial ischaemia. The coronary microvasculature cannot be directly visualized in vivo, therefore, both invasive and non-invasive techniques, have been developed to assess parameters that depend directly on coronary microvascular function. Studies at the microcirculatory level entail the use of vasodilators to obtain near-maximal vasodilation. The ratio of the maximal increase of blood flow above its resting value the coronary flow reserve (CFR) allows to gain an insight into the integrated circulatory function. The diagnostic accuracy of imaging techniques can be exploited to detect impairments of myocardial perfusion in asymptomatic subjects with cardiovascular risk factors. The assessment of the coronary microvascular function has provided novel details on the pathophysiological role of coronary microvascular dysfunction in the development of myocardial ischaemia bearing also important prognostic implications.

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