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 ◽  
...  

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.

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Micaela Iantorno ◽  
Allison G Hays ◽  
Sahar Soleimanifard ◽  
Angela Steinberg ◽  
Michael Schar ◽  
...  

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.


2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
T Leucker ◽  
G Gerstenblith ◽  
M Schar ◽  
T Brown ◽  
S Jones ◽  
...  

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.


2015 ◽  
Vol 308 (11) ◽  
pp. H1343-H1350 ◽  
Author(s):  
Allison G. Hays ◽  
Micaela Iantorno ◽  
Sahar Soleimanifard ◽  
Angela Steinberg ◽  
Michael Schär ◽  
...  

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.


2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
C Montalto ◽  
G Crimi ◽  
F Fortuni ◽  
A Mandurino Mirizzi ◽  
L Piatti ◽  
...  

Abstract Background Prasugrel was superior to clopidogrel in the setting of acute coronary syndromes (ACS) and recent data highlighted its possible role in the setting of complex percutaneous coronary intervention (PCI). Nonetheless, evidence supporting its use in high bleeding risk population are lacking. Purpose The aim of this post-hoc subgroup analysis was to evaluate the impact of prasugrel administration in elderly patients undergoing complex PCI for ACS. A primary composite endpoint of composite of mortality, myocardial infarction, disabling stroke and re-hospitalization for cardiovascular causes or bleeding within one year and secondary endpoints of all-cause mortality and any bleeding at 1 year were analyzed. Methods In the multicenter Elderly ACS 2 Study 1,443 patients aged >74 y were randomly assigned to receive low-dose prasugrel (5 mg) or clopidogrel (75 mg) and were prospectively followed for 1 year (Table 1). Complex PCI was defined if ≥3 lesions were treated, if ≥3 stents were deployed, or if any bifurcation, trifurcation, chronic total obstruction or moderate-to-severe calcified lesions were treated. Results Patients undergoing complex PCI (n=607) did not experience worse outcome, as compared to those with simpler PCI, in terms of primary endpoint (p=0.21, Figure 1A). Furthermore, in this subgroup, no significant difference was observed with prasugrel vs clopidogrel with regard to the primary endpoint (HR 1.17; CI 0.819–1.67; p=0.39, Figure 1A), all-cause death and bleeding (Figure 1C and 1D). No significant interaction was observed between treatment and PCI complexity (interaction p=0.34). Table 1 Overall Non-complex PCI Complex PCI p value Age (y) 80.60±4.46 80.00 [77.00, 84.00] 80.00 [77.00, 83.00] 0.215 STE-ACS 595 (41.2) 272 (32.5) 323 (53.4) <0.001 Diabetes mellitus 253 (17.5) 159 (19.0) 94 (15.5) 0.104 LVEF 48.27±9.59 49.08±9.55 47.26±9.54 0.002 Total number of diseased vessels 2.29±1.06 2.22±1.06 2.38±1.05 0.005 Previous Myocardial Infarction 274 (19.0) 171 (20.4) 103 (17.0) 0.122 Randomized to prasugrel 713 (49.4) 404 (48.2) 404 (48.2) 0.307 Data are expressed as mean ± SD or [IQR] and count/valid %). Figure 1 Conclusions In elderly patients presenting with ACS low-dose prasugrel was comparable to clopidogrel in terms of all-cause mortality and any bleeding at 1 year. Acknowledgement/Funding None


2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Qin Yang ◽  
Cheuk-Man Yu ◽  
Guo-Wei He ◽  
Malcolm John Underwood

Vascular endothelium plays a critical role in the control of blood flow by producing vasoactive factors to regulate vascular tone. Ion channels, in particular, K+channels and Ca2+-permeable channels in endothelial cells, are essential to the production and function of endothelium-derived vasoactive factors. Impairment of coronary endothelial function occurs in open heart surgery that may result in reduction of coronary blood flow and thus in an inadequate myocardial perfusion. Hyperkalemic exposure and concurrent ischemia-reperfusion during cardioplegic intervention compromise NO and EDHF-mediated function and the impairment involves alterations of K+channels, that is,KATPandKCa, and Ca2+-permeable TRP channels in endothelial cells. Pharmacological modulation of these channels during ischemia-reperfusion and hyperkalemic exposure show promising results on the preservation of NO and EDHF-mediated endothelial function, which suggests the potential of targeting endothelial K+and TRP channels for myocardial protection during cardiac surgery.


Author(s):  
Ramesh Araganji ◽  
Manjunath S. Somannavar ◽  
Sunil S. Vernekar ◽  
Avinash Kavi ◽  
Matthew K. Hoffman ◽  
...  

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15584-e15584
Author(s):  
A. Reichle ◽  
A. Lugner ◽  
C. Ott ◽  
F. Klebl ◽  
M. Vogelhuber ◽  
...  

e15584 Background: An angiostatic approach was used to assess the impact of anti-inflammatory therapy in combination with metronomic low-dose chemotherapy. Methods: A randomized multi-institutional phase II trial was designed to select metronomic chemotherapy (arm A: capecitabine 1 g orally twice daily for 14 days with one week break until tumor progression) or combined anti-inflammatory/angiostatic treatment (arm B: capecitabine as mentioned above plus etoricoxib 60 mg orally, day 1+, and pioglitazone 60 mg orally, day 1+) for further evaluation. Patients with refractory or progressive disease following any first-line therapy except capecitabine or frail were eligible. According to the one stage design, a sample size of 64 patients was calculated for the primary objective, improvement of response rate. Results: As similar response rates were observed (arm A/B 15/14%) after the accrual of 42 patients, the study was closed (n=20 (A), n=22 (B); median age 69 years (range 46 to 86ys); frail A/B n=9/11). Median progression- free survival for arm A/B was 3.0/2.9 months (P=0.878), and overall survival 5.0/6.1 months (P=0.778). In both treatment arms a significant decline of serum C-reactive protein (CRP) levels was observed within the first 4 to 6 weeks on treatment, A/B P= 0.01/0.04, respectively. CRP response > 50% from baseline was associated with a significantly improved overall survival in arm A/B (3.1 versus 11.0 months, P= 0.023/ 3.3 versus 7.1 months, P= 0.078) indicating an impact of inflammation-control on survival. WHO grade 3 (no grade 4) toxicities were reported in arm A/B in 20% and 23%, respectively, mostly due to hand-foot-syndrome. Conclusions: Metronomic low- dose chemotherapy in gastric cancer may induce anti-inflammatory response, but the chosen additional anti-inflammatory approach neither has impact on tumor-associated inflammation nor on response or survival rate. In a historical comparison, CRP-responder have similar outcome as patients treated with combination chemotherapy in first-line. No significant financial relationships to disclose.


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