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

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.

Coronary endothelial function

The assessment of coronary endothelial function has profound importance in terms of diagnostic and prognostic significance in patients with both obstructive and non-obstructive coronary artery disease. Endothelial dysfunction may take place in both epicardial coronary arteries as well as in the coronary microcirculation. Epicardial coronary endothelial dysfunction can be detected in the catheterization laboratory with abnormal vascular responses to endothelial-dependent physiological or pharmacological stimuli, and is characteristically a precursor to the initial processes of atherosclerotic coronary disease. This chapter discusses coronary endothelial physiology, the prevalence of endothelial dysfunction, how to evaluate coronary endothelial function, and the prognosis for patients with endothelial dysfunction.

Abstract 458: Chronic Inhibition of Protein Kinase C Improves Coronary Endothelial Function in the Setting of Diabetes and Hypoxia

Background: Both Diabetes (DM) and hypoxia/re-oxygenation (H/R) upregulate protein kinase C (PKC), resulting in coronary endothelial dysfunction. We hypothesized that chronic inhibition of PKC protects coronary endothelial function against DM and H/R injury. Methods: Genetically modified obesity and type-2 diabetic mice (female) were orally treated with or without selective PKCα/β inhibitor ruboxistaurin (10μg/g) for 4 weeks (n = 6/group). Coronary small arteries (70-110 μm in diameter) were then dissected from the harvested heart of mice. The isolated vessels were subjected to 60-min of hyperkalemic cardioplegic hypoxia (15°C) and then reperfused with oxygenated Krebs-Henseleit buffer for 60 minutes. At the end of 60-min re-oxygenation, all vessels was pretreated with endothelin-1 and then the responses to endothelium-dependent vasodilators, adenosine-diphosphate (ADP) and substance P were examined. Results: PKCα/β inhibition significantly improved the recovery of coronary endothelial function in the small coronary arteries of diabetic mice showing increased relaxation response to ADP and substance P in dose-dependent manner compared with the DM control (no-pretreatment alone) (*p<0.05). Conclusion: Chronic inhibition of PKC significantly improved the recovery of coronary endothelial function against a period of cardiolpegic H/R in the diabetic microvasculature. These data suggest that the PKC inhibitor ruboxistaurin represents a novel potential therapeutic for coronary endothelial dysfunctionin patients with DM following cardioplegic ischemia and reperfusion.

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

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.