Abstract 13292: A Novel Reproducible Noninvasive Imaging Approach to Quantify Nitric Oxide-mediated Coronary Endothelial Function in Humans

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Micaela Iantorno ◽  
Allison G Hays ◽  
Sahar Soleimanifard ◽  
Angela Steinberg ◽  
Michael Schar ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Endothelial Function ◽  
Coronary Blood Flow ◽  
Repeated Measures ◽  
Healthy Subjects ◽  
Cine Mri ◽  
Isometric Handgrip ◽  
Coronary Endothelial Function ◽  
The Impact

Endothelial release of nitric oxide (NO) is a defining characteristic of non-diseased vascular tissue. Healthy coronary arteries respond to endothelial-dependent stressors with vasodilatation but those with endothelial dysfunction respond with paradoxical vasoconstriction. The combination of new non-invasive 3T coronary MRI methods and isometric handgrip exercise (IHE), has been suggested as a means to noninvasively quantify coronary endothelial function (CEF). However, IHE may trigger neural, neuro-hormonal and other vasoreactive responses; thus, it is unknown whether the IHE-induced coronary response is, in fact, primarily mediated by NO. Furthermore, it is not known whether the MRI-IHE test is reproducible over time.To test the hypothesis that the IHE-induced coronary response is NO-mediated, we performed MRI-IHE studies before and during the infusion of monomethyl-L-arginine (L-NMMA, 0.3mg/kg/min), a NO synthase inhibitor in 8 healthy subjects. To study reproducibility we performed 2 MRI-IHE studies ~8 weeks apart in 8 coronary artery disease (CAD) patients and 9 healthy subjects. Changes from rest to IHE in coronary cross-sectional area (%CSA) and coronary blood flow (%CBF) were measured with cine MRI. L-NMMA completely blocked coronary vasodilation during IHE (%CSA change 15.4%±2.8% with placebo vs -1.6%±1.3% with L-NMMA; p<0.0001) and the normal increase in coronary blood flow (%CBF change 50.2%±6.7% with placebo vs -2.1%±6.7% with L-NMMA; p< 0.0001). Moreover, there was a strong correlation between repeated measures for %CSA change with IHE at the two exams (R=0.91, p<0.0001) and %CBF change with IHE (R=0.80; p<0.001). Bland-Altman analysis and intra-class correlation coefficients for %CSA and %CBF change with IHE (0.90 and 0.80, respectively) indicated good agreement and little variability between repeated measures. In summary the coronary response to IHE is largely mediated by endothelial-derived NO and is reproducible over several weeks. Thus MRI-IHE is a noninvasive, reproducible tool to assess CEF, arguably the first to noninvasively measure macro- and micro-vascular NO-mediated coronary responses. This noninvasive tool may be useful in future studies of the impact of interventions on CAD pathogenesis.

scholarly journals Randomized Trial of Anti-inflammatory Medications and Coronary Endothelial Dysfunction in Patients With Stable Coronary Disease

2021 ◽  
Vol 8 ◽  
Author(s):  
Allison G. Hays ◽  
Michael Schär ◽  
Gabriele Bonanno ◽  
Shenghan Lai ◽  
Joseph Meyer ◽  
...  
Keyword(s):  
Endothelial Function ◽  
Primary Endpoint ◽  
Low Dose ◽  
Critical Role ◽  
Isometric Handgrip ◽  
Coronary Endothelial Function ◽  
Markers Of Inflammation ◽  
Anti Inflammatory ◽  
Stable Cad ◽  
The Impact

Aims: Inflammation plays a critical role in the pathogenesis of coronary artery disease (CAD), however the impact of anti-inflammatory therapies to reduce those processes which promote atherosclerosis in CAD patients is unknown. We aimed to test the hypothesis that anti-inflammatory approaches improve impaired coronary endothelial function (CEF), a driver of coronary atherosclerosis, in stable CAD patients.Methods and Results: We performed a single-center, randomized, placebo-controlled, double-blinded trial to assess whether low dose methotrexate (MTX), low dose colchicine (LDC), and/or their combination (MTX+LDC), improves CEF using non-invasive MRI measures in patients with stable CAD (N = 94). The primary endpoint was the MRI-detected change in coronary cross-sectional area from rest to isometric handgrip exercise (IHE), a predominantly nitric oxide-dependent endothelial dependent stressor. Coronary and systemic endothelial endpoints, and serum inflammatory markers, were collected at baseline, 8 and 24 weeks. Anti-inflammatory study drugs were well-tolerated. There were no significant differences in any of the CEF parameters among the four groups (MTX, LDC, MTX+LDC, placebo) at 8 or 24 weeks. Serum markers of inflammation and systemic endothelial function measures were also not significantly different among the groups.Conclusion: This is the first study to examine the effects of the anti-inflammatory approaches using MTX, LDC, and/or the combination in stable CAD patients on CEF, a marker of vascular health and the primary endpoint of the study. Although these anti-inflammatory approaches were relatively well-tolerated, they did not improve coronary endothelial function in patients with stable CAD.Clinical Trial Registration:www.clinicaltrials.gov, identifier: NCT02366091.

scholarly journals Coronary vasomotor responses to isometric handgrip exercise are primarily mediated by nitric oxide: a noninvasive MRI test of coronary endothelial function

2015 ◽  
Vol 308 (11) ◽  
pp. H1343-H1350 ◽  
Author(s):  
Allison G. Hays ◽  
Micaela Iantorno ◽  
Sahar Soleimanifard ◽  
Angela Steinberg ◽  
Michael Schär ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Function ◽  
Handgrip Exercise ◽  
Isometric Handgrip ◽  
Cross Sectional ◽  
Coronary Endothelial Function ◽  
Cell Release ◽  
Isometric Handgrip Exercise ◽  
Translational Strategies ◽  
Synthase Inhibitor

Endothelial cell release of nitric oxide (NO) is a defining characteristic of nondiseased arteries, and abnormal endothelial NO release is both a marker of early atherosclerosis and a predictor of its progression and future events. Healthy coronaries respond to endothelial-dependent stressors with vasodilatation and increased coronary blood flow (CBF), but those with endothelial dysfunction respond with paradoxical vasoconstriction and reduced CBF. Recently, coronary MRI and isometric handgrip exercise (IHE) were reported to noninvasively quantify coronary endothelial function (CEF). However, it is not known whether the coronary response to IHE is actually mediated by NO and/or whether it is reproducible over weeks. To determine the contribution of NO, we studied the coronary response to IHE before and during infusion of NG-monomethyl-l-arginine (l-NMMA, 0.3 mg·kg−1·min−1), a NO-synthase inhibitor, in healthy volunteers. For reproducibility, we performed two MRI-IHE studies ∼8 wk apart in healthy subjects and patients with coronary artery disease (CAD). Changes from rest to IHE in coronary cross-sectional area (%CSA) and diastolic CBF (%CBF) were quantified. l-NMMA completely blocked normal coronary vasodilation during IHE [%CSA, 12.9 ± 2.5 (mean ± SE, placebo) vs. −0.3 ± 1.6% (l-NMMA); P < 0.001] and significantly blunted the increase in flow [%CBF, 47.7 ± 6.4 (placebo) vs. 10.6 ± 4.6% (l-NMMA); P < 0.001]. MRI-IHE measures obtained weeks apart strongly correlated for CSA ( P < 0.0001) and CBF ( P < 0.01). In conclusion, the normal human coronary vasoactive response to IHE is primarily mediated by NO. This noninvasive, reproducible MRI-IHE exam of NO-mediated CEF promises to be useful for studying CAD pathogenesis in low-risk populations and for evaluating translational strategies designed to alter CAD in patients.

The Impact of Peripheral Nerve Stimulation on Coronary Blood Flow and Endothelial Function

2015 ◽  
Vol 29 (6) ◽  
pp. 527-533 ◽  
Author(s):  
Anthony C. Camuglia ◽  
Mistre Alemayehu ◽  
Andrew McLellan ◽  
Sabrina Wall ◽  
Nour Abu-Romeh ◽  
...  
Keyword(s):  
Blood Flow ◽  
Endothelial Function ◽  
Peripheral Nerve ◽  
Coronary Blood Flow ◽  
Nerve Stimulation ◽  
Peripheral Nerve Stimulation ◽  
The Impact

Disruption of TRPV1-mediated coupling of coronary blood flow to cardiac metabolism in diabetic mice: role of nitric oxide and BK channels

2012 ◽  
Vol 303 (2) ◽  
pp. H216-H223 ◽  
Author(s):  
Giacinta Guarini ◽  
Vahagn A. Ohanyan ◽  
John G. Kmetz ◽  
Daniel J. DelloStritto ◽  
Roslin J. Thoppil ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Coronary Blood Flow ◽  
Cardiac Metabolism ◽  
Bk Channels ◽  
Bk Channel ◽  
Transient Receptor Potential Vanilloid ◽  
Trpv1 Channels ◽  
Channel Dependent

We have previously shown transient receptor potential vanilloid subtype 1 (TRPV1) channel-dependent coronary function is compromised in pigs with metabolic syndrome (MetS). However, the mechanisms through which TRPV1 channels couple coronary blood flow to metabolism are not fully understood. We employed mice lacking TRPV1 [TRPV1(−/−)], db/db diabetic, and control C57BKS/J mice to determine the extent to which TRPV1 channels modulate coronary function and contribute to vascular dysfunction in diabetic cardiomyopathy. Animals were subjected to in vivo infusion of the TRPV1 agonist capsaicin to examine the hemodynamic actions of TRPV1 activation. Capsaicin (1–100 μg·kg−1·min−1) dose dependently increased coronary blood flow in control mice, which was inhibited by the TRPV1 antagonist capsazepine or the nitric oxide synthase (NOS) inhibitor N-nitro-l-arginine methyl ester (l-NAME). In addition, the capsaicin-mediated increase in blood flow was attenuated in db/db mice. TRPV1(−/−) mice exhibited no changes in coronary blood flow in response to capsaicin. Vasoreactivity studies in isolated pressurized mouse coronary microvessels revealed a capsaicin-dependent relaxation that was inhibited by the TRPV1 inhibitor SB366791 l-NAME and to the large conductance calcium-sensitive potassium channel (BK) inhibitors iberiotoxin and Penetrim A. Similar to in vivo responses, capsaicin-mediated relaxation was impaired in db/db mice compared with controls. Changes in pH (pH 7.4–6.0) relaxed coronary vessels contracted to the thromboxane mimetic U46619 in all three groups of mice; however, pH-mediated relaxation was blunted in vessels obtained from TRPV1(−/−) and db/db mice compared with controls. Western blot analysis revealed decreased myocardial TRPV1 protein expression in db/db mice compared with controls. Our data reveal TRPV1 channels mediate coupling of myocardial blood flow to cardiac metabolism via a nitric oxide-dependent, BK channel-dependent pathway that is corrupted in diabetes.

Isometric handgrip training does not improve flow-mediated dilation in subjects with normal blood pressure

2007 ◽  
Vol 112 (7) ◽  
pp. 403-409 ◽  
Author(s):  
Cheri L. Mcgowan ◽  
Andrew S. Levy ◽  
Neil Mccartney ◽  
Maureen J. Macdonald
Keyword(s):  
Blood Pressure ◽  
Endothelial Function ◽  
Internal Control ◽  
Repeated Measures ◽  
Flow Mediated Dilation ◽  
Normal Blood Pressure ◽  
Isometric Handgrip ◽  
Repeated Measures Design ◽  
Artery Flow ◽  
Maximal Effort

Isometric HG (handgrip) training lowers resting arterial BP (blood pressure), yet the mechanisms are elusive. In the present study, we investigated improved systemic endothelial function as a mechanism of arterial BP modification following isometric HG training in normotensive individuals. This study employed a within-subject repeated measures design primarily to assess improvements in BA FMD (brachial artery flow-mediated dilation; an index of endothelium-dependent vasodilation), with the non-exercising limb acting as an internal control. Eleven subjects performed four 2-min unilateral isometric HG contractions at 30% of maximal effort, three times per week for 8 weeks. Pre-, mid- and post-training resting ABP and BA FMD (exercised arm and non-exercised arm) were measured via automated brachial oscillometry and ultrasound respectively. BA FMD (normalized to the peak shear rate experienced in response to the reactive hyperaemic stimulus) remained unchanged [exercised arm, 0.029±0.003 to 0.026±0.003 to 0.029±0.004%/s−1 (pre- to mid- to post-training respectively); non-exercised arm, 0.023±0.003 to 0.023±0.003 to 0.024±0.003%/s−1 (pre- to mid- to post-training respectively); P=0.22]. In conclusion, improved systemic endothelial function is unlikely to be responsible for lowering arterial BP in this population.

Abstract WP322: Inhaled Nitric Oxide Augments Cerebral Blood Flow in Healthy Subjects

Stroke ◽  
2018 ◽  
Vol 49 (Suppl_1) ◽  
Author(s):  
Christopher G Favilla ◽  
Rodrigo M Forti ◽  
Ahmad Zamzam ◽  
John A Detre ◽  
Michael T Mullen ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Healthy Subjects ◽  
Inhaled Nitric Oxide

scholarly journals Impact of Visual Field Testing on Intraocular Pressure Change Trends in Healthy People and Glaucoma Patients

2020 ◽  
Vol 2020 ◽  
pp. 1-6 ◽  
Author(s):  
Mengwei Li ◽  
Bingxin Zheng ◽  
Qi Wang ◽  
Xinghuai Sun
Keyword(s):  
Intraocular Pressure ◽  
Visual Field ◽  
Repeated Measures ◽  
Healthy Subjects ◽  
Open Angle Glaucoma ◽  
Field Testing ◽  
Automated Perimetry ◽  
Open Angle ◽  
Standard Automated Perimetry ◽  
The Impact

Purpose. To compare the impact of visual field (VF) testing on intraocular pressure (IOP) change trends between healthy subjects and glaucoma patients. Methods. We recruited healthy volunteer subjects who did not have previous ocular diseases and open-angle glaucoma patients who were medically controlled well. IOP in both eyes of each participant was measured by using a noncontact tonometer at five time points: before, immediately after (0 minute), and 10, 30, and 60 minutes after the standard automated perimetry. Repeated measures ANOVA was used to analyze the effect of VF testing on IOP change trends in healthy and glaucoma eyes. Results. Forty healthy subjects (80 eyes) and 31 open-angle glaucoma patients (62 eyes) were included for the study. The baseline IOP of healthy and glaucoma eyes was 16.11 ± 3.01 mmHg and 15.78 ± 3.57 mmHg, respectively. After the VF testing, the IOP in healthy eyes was decreased by 1.5% at 0 minute, 6.5% at 10 minutes (P<0.001), 6.6% at 30 minutes (P<0.001), and 7.0% at 1 hour (P<0.001), indicating that this reduction was sustained for at least 1 hour. However, the IOP in glaucoma eyes was increased by 12.7% at 0 minute (P<0.001) and, then, returned towards initial values 1 hour after the VF testing. Conclusions. IOP change trends after VF field testing between healthy subjects and glaucoma patients were quite different. VF testing led to a mild and relatively sustained IOP decrease in healthy subjects, whereas IOP in open-angle glaucoma patients tended to significantly increase immediately after VF testing and, then, returned to pretest values after 1 hour. These findings indicate that the factors of VF testing should be considered in the clinical IOP measurements.

4313Evolocumab rapidly reverses impaired coronary endothelial function in six weeks in people living with HIV and in patients with dyslipidemia

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
T Leucker ◽  
G Gerstenblith ◽  
M Schar ◽  
T Brown ◽  
S Jones ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Endothelial Function ◽  
Highly Active Antiretroviral Therapy ◽  
Cholesterol Metabolism ◽  
Clinical Manifestations ◽  
People Living With Hiv ◽  
Isometric Handgrip ◽  
Coronary Endothelial Function ◽  
Pcsk9 Inhibition ◽  
Living With Hiv

Abstract Background/Introduction Proprotein convertase subtilisin/kexin type 9 (PCSK9) is well recognized for its importance in cholesterol metabolism. Elevated levels are associated with increased cardiovascular risk and inhibition with PCSK9 antibodies lowers cardiovascular events in patients with known coronary disease. PCSK9 levels are also elevated in people living with HIV (PLWH), and we previously reported that increased PCSK9 in PLWH is associated with impaired coronary endothelial function (CEF), a major driver for the development, progression, and clinical manifestations of coronary artery disease. Purpose Here we investigate the hypothesis that PCSK9 inhibition improves impaired CEF in PLWH and in patients with dyslipidemia (DL). Methods Cine 3T MRI was used to noninvasively measure CEF, assessed as the change in coronary cross-sectional area (CSA) from rest to isometric handgrip exercise (IHE), a known endothelial-dependent vasodilator. Eight HIV+ subjects on stable highly active antiretroviral therapy and with undetectable HIV RNA (mean age 53±9 yrs, LDLC 98±18 mg/dL, 38% on statins) and ten patients with dyslipidemia (DL) without HIV receiving evolocumab for clinical reasons (mean age 56±10 yrs, LDLC 130±28 mg/dL, 50% on statins) underwent MRI studies before and six weeks following the initiation of evolocumab 420 mg. MRI readers were blinded to group and timepoint. MRI data are presented as mean±SD for % change rest vs IHE. Results Prior to evolucumab, resting CSA in the two groups did not differ and IHE did not induce normal coronary vasodilation in either group; mean stress-induced CSA changes were −2.1±6.4% in HIV (p=0.27) and −0.6±4.1% in DL (p=0.46). Notably, CEF significantly improved following six weeks of evolocumab with IHE-induced CSA changes of 7.6±5.7% (p=0.006) and 5.0±3.6% (p=0.002) in the HIV and DL groups, respectively. The %-LDLC reduction with evolocumab was profound and comparable in the HIV and DL groups, 73±5% and 60±6% (p=0.19 HIV vs. DL). There was no significant correlation between the extents of LDLC reduction and of CEF improvement in either of these modest sized groups. Conclusion PCSK9 inhibition with evolocumab significantly improves abnormal coronary endothelial function after only six weeks in HIV+ people with normal LDLC and in HIV- people with DL. To our knowledge, these data represent the earliest (6 weeks) evidence for improvement in human coronary artery health by PCSK9 inhibition. Acknowledgement/Funding Amgen provided the PCSK9 monoclonal antibody (evolocumab) for this study.

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