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Our goal was to measure the association of CXCL5 and molecular phenotypes associated with coronary atherosclerosis severity in patients at least 65 years old. CXCL5 is classically defined as a proinflammatory chemokine, but its role in chronic inflammatory diseases, such as coronary atherosclerosis, is not well defined. We enrolled individuals who were at least 65 years old and undergoing diagnostic cardiac catheterization. Coronary artery disease (CAD) severity was quantified in each subject via coronary angiography by calculating a CAD score. Circulating CXCL5 levels were measured from plasma, and both DNA genotyping and mRNA expression levels in peripheral blood mononuclear cells were quantified via microarray gene chips. We observed a negative association of CXCL5 levels with CAD at an odds ratio (OR) of 0.46 (95% CI, 0.27–0.75). Controlling for covariates, including sex, statin use, hypertension, hyperlipidemia, obesity, self-reported race, smoking, and diabetes, the OR was not significantly affected [OR, 0.54 (95% CI, 0.31–0.96)], consistent with a protective role for CXCL5 in coronary atherosclerosis. We also identified 18 genomic regions with expression quantitative trait loci of genes correlated with both CAD severity and circulating CXCL5 levels. Our clinical findings are consistent with the emerging link between chemokines and atherosclerosis and suggest new therapeutic targets for CAD.

Objectives This multicenter pragmatic investigation assessed outcomes following clinical implementation of CYP2C19 genotype–guided antiplatelet therapy after percutaneous coronary intervention (PCI). Background CYP2C19 loss-of-function alleles impair clopidogrel effectiveness after PCI. Methods After clinical genotyping, each institution recommended alternative antiplatelet therapy (prasugrel, ticagrelor) in PCI patients with a loss-of-function allele. Major adverse cardiovascular events (defined as myocardial infarction, stroke, or death) within 12 months of PCI were compared between patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy. Risk was also compared between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy. Cox regression was performed, adjusting for group differences with inverse probability of treatment weights. Results Among 1,815 patients, 572 (31.5%) had a loss-of-function allele. The risk for major adverse cardiovascular events was significantly higher in patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy (23.4 vs. 8.7 per 100 patient-years; adjusted hazard ratio: 2.26; 95% confidence interval: 1.18 to 4.32; p = 0.013). Similar results were observed among 1,210 patients with acute coronary syndromes at the time of PCI (adjusted hazard ratio: 2.87; 95% confidence interval: 1.35 to 6.09; p = 0.013). There was no difference in major adverse cardiovascular events between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy (adjusted hazard ratio: 1.14; 95% confidence interval: 0.69 to 1.88; p = 0.60). Conclusions These data from real-world observations demonstrate a higher risk for cardiovascular events in patients with a CYP2C19 loss-of-function allele if clopidogrel versus alternative therapy is prescribed. A future randomized study of genotype-guided antiplatelet therapy may be of value.

Severe pulmonary regurgitation (PR) most commonly occurs as a sequelae of treatment of pulmonic stenosis or Tetralogy of Fallot with fewer cases of primary pulmonic valvular regurgitation. The amount of PR is influenced by valvular integrity, right ventricular (RV) size, and RV diastolic pressures. In chronic severe PR, the RV remodels to accommodate the regurgitant flow and RV stroke volume increases to maintain effective forward blood flow. Hemodynamic changes include a widened pulmonary artery (PA) pulse pressure and low PA diastolic pressures. As the amount of regurgitation increases, RV end diastolic pressure becomes elevated and systemic cardiac output is reduced, especially with exercise. "Ventricularization" of the PA pressure tracing, in which the contour of the PA pressure is similar to the contour of the RV pressure, is a specific but not sensitive finding in severe PR. © 2015 Wiley Periodicals, Inc.

Dual anti-platelet therapy with aspirin and a P2Y12 inhibitor is the standard of care for patients with acute coronary syndromes (ACS) and for patients undergoing percutaneous coronary intervention (PCI). Clopidogrel is associated with increased risk of high on-treatment platelet reactivity (HTPR) compared to ticagrelor and prasugrel. Investigators have therefore sought to "escalate" clopidogrel dosing to overcome HTPR to reduce ischemic/thrombotic events. In this review, we will summarize the evidence for dose escalation in the context of genetic determinants of resistance and platelet function data. We will review contemporary clinical trials that have sought to improve delivery of dual antiplatelet therapy to patients with coronary artery disease and discuss the potential of clopidogrel dose escalation in specific populations.

Aim: An algorithm that uses clinical factors and CYP2C19 genotype to guide P2Y12 inhibitor selection in high-risk patients undergoing percutaneous coronary intervention was implemented at our institution. We sought to evaluate use of this algorithm and identify which factors influenced P2Y12 inhibitor selection. Patients & methods: This retrospective cohort study included 264 patients receiving percutaneous coronary intervention from July–December 2012. Results: CYP2C19 genotype was obtained in 229 patients; of these, 30% were intermediate or poor metabolizers. CYP2C19 intermediate or poor metabolizer phenotype was among the strongest predictors for selecting prasugrel or ticagrelor as maintenance therapy (p < 0.001), and was the only significant predictor of a change in therapy (p < 0.001). Conclusion: These findings suggest that using CYP2C19 genotype to guide P2Y12 inhibitor selection is feasible. Original submitted 27 October 2014; revision submitted 19 December 2014

Aim: Determine whether using CYP2C19 genotype to optimize antiplatelet therapy selection is cost effective over the initial 30 days and 1-year following percutaneous coronary intervention. Materials & methods: A cost–effectiveness analysis compared 30-day and 1-year outcomes and cost across three treatment strategies (universal clopidogrel, universal prasugrel, genotype-guided) in a hypothetical cohort. Results: Base-case scenario results at 30 days indicated that the incremental cost per major cardiovascular or bleeding event avoided for genotype-guided treatment was US$8525 and US$42,198 compared with universal clopidogrel and prasugrel, respectively. Probabilistic sensitivity analysis demonstrated that genotype-guided treatment was cost effective over 30 days and 1 year in 62 and 70% of simulations, respectively. Conclusion: Implementing a CYP2C19 genotype-guided approach to antiplatelet therapy could have a positive economic impact by preventing readmissions following percutaneous coronary intervention.

The hemodynamic features of subacute aortic regurgitation include equalization of the left ventricular pressure and the aortic pressure during diastole, a mildly increased pulse pressure, and systemic hypotension. These findings are distinct from the hemodynamics of chronic aortic regurgitation.

We recently demonstrated that selective expression of the Rho GTPase-activating protein ARHGAP42 in smooth muscle cells (SMCs) controls blood pressure by inhibiting RhoA-dependent contractility, providing a mechanism for the blood pressure-associated locus within the ARHGAP42 gene. The goals of the current study were to identify polymorphisms that affect ARHGAP42 expression and to better assess ARHGAP42's role in the development of hypertension. Using DNase I hypersensitivity methods and ENCODE data, we have identified a regulatory element encompassing the ARHGAP42 SNP rs604723 that exhibits strong SMC-selective, allele-specific activity. Importantly, CRISPR/Cas9-mediated deletion of this element in cultured human SMCs markedly reduced endogenous ARHGAP42 expression. DNA binding and transcription assays demonstrated that the minor T allele variation at rs604723 increased the activity of this fragment by promoting serum response transcription factor binding to a cryptic cis-element. ARHGAP42 expression was increased by cell stretch and sphingosine 1-phosphate in a RhoA-dependent manner, and deletion of ARHGAP42 enhanced the progression of hypertension in mice treated with DOCA-salt. Our analysis of a well-characterized cohort of untreated borderline hypertensive patients suggested that ARHGAP42 genotype has important implications in regard to hypertension risk. Taken together, our data add insight into the genetic mechanisms that control blood pressure and provide a potential target for individualized antihypertensive therapies.

This pilot study examined the feasibility of outpatient screening and clopidogrel dose adjustment for patients with previous percutaneous coronary intervention and at least one CYP2C19 loss-of-function allele. After screening a total of 211 outpatients, 50 patients were enrolled in a crossover study comparing 30 days of standard dose (75 mg) to 30 days of high-dose clopidogrel (150 mg). Platelet function was assessed with the VerifyNow P2Y12 assay. In patients with CYP2C19*2, 150 mg daily of clopidogrel was associated with improved ADP-specific platelet inhibition (217 vs 258 P2Y12 reaction units, p = 0.01). Outpatient screening for CYP2C19 loss-of-function polymorphisms is feasible, and a strategy of clopidogrel dose escalation may improve platelet inhibition in appropriately selected patients.

Purpose The operational elements essential for establishing an inpatient pharmacogenetic service are reviewed, and the role of the pharmacist in the provision of genotype-guided drug therapy in pharmacogenetics programs at three institutions is highlighted. Summary Pharmacists are well positioned to assume important roles in facilitating the clinical use of genetic information to optimize drug therapy given their expertise in clinical pharmacology and therapeutics. Pharmacists have assumed important roles in implementing inpatient pharmacogenetics programs. This includes programs designed to incorporate genetic test results to optimize antiplatelet drug selection after percutaneous coronary intervention and personalize warfarin dosing. Pharmacist involvement occurs on many levels, including championing and leading pharmacogenetics implementation efforts, establishing clinical processes to support genotype-guided therapy, assisting the clinical staff with interpreting genetic test results and applying them to prescribing decisions, and educating other healthcare providers and patients on genomic medicine. The three inpatient pharmacogenetics programs described use reactive versus preemptive genotyping, the most feasible approach under the current third-party payment structure. All three sites also follow Clinical Pharmacogenetics Implementation Consortium guidelines for drug therapy recommendations based on genetic test results. Conclusion With the clinical emergence of pharmacogenetics into the inpatient setting, it is important that pharmacists caring for hospitalized patients are well prepared to serve as experts in interpreting and applying genetic test results to guide drug therapy decisions. Since genetic test results may not be available until after patient discharge, pharmacists practicing in the ambulatory care setting should also be prepared to assist with genotype-guided drug therapy as part of transitions in care.

The Updated Expert Consensus Statement [(1)][1] outlines the potential benefits of platelet function testing (PFT) or CYP2C19 genotyping to guide P2Y12 inhibitor therapy in high-risk patients treated with percutaneous coronary intervention (PCI). We would like to highlight a large cohort of patients

Clinical trials have shown that catheter-based renal denervation (RD), i.e. interruption of afferent and efferent sympathetic nerves supplying the kidney, can reduce systolic blood pressure (BP) by approximately 30 mm Hg. This technology is currently being tested as a therapeutic option for patients with resistant hypertension, a condition in which BP remains elevated despite adherence to a rational medication regimen. This novel treatment approach was developed on the basis of a wealth of animal and human research demonstrating the importance of the sympathorenal axis in the pathogenesis of hypertension. Sympathetic efferent signals to the kidneys raise BP by stimulating sodium retention and renin release, and the kidneys influence central sympathetic drive via afferent nerves. But as is true with many therapeutic advances, RD has shown benefit in clinical studies long before the mechanisms are fully understood. Additional research is needed to understand the contribution of afferent sympathetic nerve interruption to BP reductions observed with RD; to examine the degree and significance of re-innervation following RD; to elucidate factors that may lead to a lack of response to RD in some patients; to determine whether the modulation of the sympathetic nervous system via RD can have beneficial effects independent of BP reduction; and to develop methods to measure the effectiveness of RD in real time.

Abrupt onset of renal ischemia is associated with increased blood pressure (BP), but it is unknown whether BP remains elevated in patients with chronic severe atherosclerotic renal artery stenosis (RAS). Patients undergoing coronary angiography who had concurrent renal angiography were divided into 3 groups: severe (stenosis ≥70% diameter reduction), moderate (10%-69%), and minimal RAS. Aortic BP was measured at the time of angiography. Renal angiography was performed in 762 (5.4%) of 14,181 patients undergoing coronary angiography. The mean age was 62 ± 12 years, 52% were women, 93% had hypertension, and 42% had diabetes mellitus. Minimal, moderate, or severe RAS was found in 62%, 30%, and 9% of patients. Patients with minimal RAS were younger, less likely to have hypercholesterolemia or coronary artery disease, and had a lower creatinine than patients with severe RAS. Severe RAS was associated with a lower diastolic BP and mean BP and a higher pulse pressure (PP), but there was no difference in systolic BP or the number of antihypertensive medications between the 3 groups. The degree of RAS had a weak positive correlation with PP, a weak negative correlation with diastolic BP, and almost no correlation with systolic BP or mean BP. In multivariate linear regression analysis, there was an association between severity of RAS and PP but not with mean BP or systolic BP. In conclusion, PP, but not systolic BP, diastolic BP, mean BP, or number of antihypertensive medications, was elevated in patients with severe RAS.

To determine the ability of simple hemodynamic parameters obtained at the time of cardiac catheterization to predict in-hospital mortality following ST-elevation myocardial infarction (STEMI).Hemodynamic parameters measured at the time of primary percutaneous coronary intervention (PPCI) could potentially identify high-risk patients who would benefit from aggressive hemodynamic support in the Cardiac Catheterization laboratory.This is a retrospective single-center study of 219 consecutive patients with STEMI. Left ventricular end-diastolic pressure (LVEDP), systolic blood pressure (SBP), and aortic diastolic blood pressure were obtained after successful revascularization. The prognostic ability of LVEDP, pulse pressure, and SBP/LVEDP ratio were compared to major mortality risk scores.Patients had a mean age of 60 ±14 years, were predominantly white (73%), male (64%), with anterior wall infarcts in 39%. Comorbidities included diabetes mellitus (27%), heart failure (9%), and chronic kidney disease (7%). In-hospital mortality was 9%. Patients with SBP/LVEDP ≤ 4 had increased risk of in-hospital death (32% vs. 5.3%, P 0.0001), intra-aortic balloon pump (IABP) usage (51.6% vs. 9.6%, P 0.0001) and combined endpoint of death or IABP usage (58.1% vs. 13.3%, P 0.0001) compared to patients with SBP/LVEDP 4. The area under curve (AUC) for SBP/LVEDP ratio for in-hospital mortality (0.69) was more predictive than LVEDP (0.61, P = 0.04) or pulse pressure (0.55, P = 0.02) but similar to Shock Index (ratio of heart rate to SBP) and Modified Shock Index (ratio of HR to mean arterial pressure).An SBP/LVEDP ratio ≤ 4 identified a group of STEMI patients at high risk of in-hospital death. © 2017 Wiley Periodicals, Inc.

Without early revascularization, both inpatient and outpatient STEMIs have poor outcomes. Reasons for denying PCI for STEMI, however, remain uncertain. This single-center retrospective cohort study compares factors and outcomes associated with ineligibility for PCI between inpatients and outpatients following ST-elevation myocardial infarction (STEMI).A total of 1,759 STEMI patients between June 2009 and January 2015 were assessed. Individual medical records were reviewed to obtain reasons for PCI ineligibility for STEMI patients who did not receive reperfusion therapy.Compared to outpatients with STEMI (n = 1,688), inpatients (n = 71) were less likely to receive coronary angiography (60.6% vs 95.9%; P 0.001) or PCI (50.7% vs 80.9%; P 0.001), with longer ECG/door to first device activation times (97 [78, 131] vs 63 [49, 78] minutes; P 0.001). When coronary angiography was performed, however, similar rates of PCI and procedural success were seen in both groups. Principal contraindication for PCI was risk of bleeding within the inpatient population and complex coronary artery disease within the outpatient population. Total in-hospital mortality was higher in inpatient STEMIs compared to outpatients (42.2% vs 10.0%; P 0.001), but lower for patients eligible for PCI in both groups.Reasons for PCI ineligibility differ between inpatient and outpatient STEMIs. Inpatients have increased risks of bleeding, lower coronary angiography and PCI use, and higher in-hospital mortality. Especially for inpatients, specific PCI STEMI protocols that anticipate and overcome types of ineligibility and delay for cardiac catheterization may improve outcomes.

Background Chronic unilateral renal artery stenosis ( RAS ) causes accelerated atherosclerosis in apolipoprotein E–deficient (ApoE −/− ) mice, but effects of restoration of renal blood flow on aortic atherosclerosis are unknown. Methods and Results Male ApoE −/− mice underwent sham surgery (n=16) or had partial ligation of the right renal artery (n=41) with the ligature being removed 4 days later (D4 LR ; n=6), 8 days later (D8 LR ; n=11), or left in place for 90 days (chronic RAS ; n=24). Ligature removal at 4 or 8 days resulted in improved renal blood flow, decreased plasma angiotensin II levels, a return of systolic blood pressure to baseline, and increased plasma levels of neutrophil gelatinase associated lipocalin. Chronic RAS resulted in increased lipid staining in the aortic arch (33.2% [24.4, 47.5] vs 11.6% [6.1, 14.2]; P P LR group (22.7% [22.1, 32.7]), compared to sham‐surgery, but less than observed with chronic RAS . Lipid staining in the aortic arch was not increased in the D4 LR group, and lipid staining in the descending aorta was not increased in either the D8 LR or D4 LR groups. There was less macrophage expression in infrarenal aortic atheroma in the D4 LR and D8 LR groups compared to the chronic RAS group. Conclusions Restoration of renal blood flow at either 4 or 8 days after unilateral RAS had a beneficial effect on systolic blood pressure, aortic lipid deposition, and atheroma inflammation.

To determine the relationship between severity of stenosis and hemodynamic significance in calcified coronary arteries.Severity of stenosis is widely used to determine the need for revascularization but the effect of lesion calcification on hemodynamic significance is not well understood.Two hundred consecutive patients undergoing fractional flow reserve (FFR) testing of an intermediate coronary lesion with a pressure wire and intravenous infusion of adenosine were studied. Coronary calcium was quantified based upon radiopacities at the site of the stenosis on cineangiography using the method of Mintz et al. (0 = none or mild calcium, 1 = moderate calcium, 2 = severe calcium).Mean age was 61 ± 11 years, 66% were males, 87.5% had hypertension, 44.5% had diabetes, and 20.5% were current smokers. The mean coronary stenosis by quantitative coronary angiography was 60 ± 12% and the mean FFR was 0.83 ± 0.08. There were 109, 45, and 46 patients classified as Calcium Score of 0, 1, or 2, respectively. Compared to those with no/mild or moderate calcification, patients with severe coronary calcium were older and more likely to have chronic kidney disease and pulmonary disease. The correlation between angiographic severity and FFR decreased as lesion calcification increased [calcium score = 0 (RIn patients with heavily calcified coronary lesions, there was no association between angiographic stenosis and hemodynamic significance and FFR is needed to determine hemodynamic significance of intermediate lesions. © 2016 Wiley Periodicals, Inc.

Stress-induced cardiomyopathy has a wide variety of clinical presentations ranging from angina symptoms to cardiogenic shock, as well as an array of echocardiographic findings and etiologies. We present a unique case of severe biventricular dilation with cardiogenic shock but rapid recovery within 96 hrs. Severe biventricular stressinduced cardiomyopathy secondary to acute rheumatoid arthritis (RA) flare was diagnosed and the patient later regained full recovery after circulatory support and RA treatment.

Objective— Age-related aortic stiffness is an independent risk factor for cardiovascular diseases. Although oxidative stress is implicated in aortic stiffness, the underlying molecular mechanisms remain unelucidated. Here, we examined the source of oxidative stress in aging and its effect on smooth muscle cell (SMC) function and aortic compliance using mutant mouse models. Methods and Results— Pulse wave velocity, determined using Doppler, increased with age in superoxide dismutase 2 (SOD2) +/− but not in wild-type, p47phox −/− and SOD1 +/− mice. Echocardiography showed impaired cardiac function in these mice. Increased collagen I expression, impaired elastic lamellae integrity, and increased medial SMC apoptosis were observed in the aortic wall of aged SOD2 +/− versus wild-type (16-month-old) mice. Aortic SMCs from aged SOD2 +/− mice showed increased collagen I and decreased elastin expression, increased matrix metalloproteinase-2 expression and activity, and increased sensitivity to staurosporine-induced apoptosis versus aged wild-type and young (4-month-old) SOD2 +/− mice. Smooth muscle α-actin levels were increased with age in SOD2 +/− versus wild-type SMCs. Aged SOD2 +/− SMCs had attenuated insulin-like growth factor-1-induced Akt and Forkhead box O3a phosphorylation and prolonged tumor necrosis factor-α–induced Jun N-terminal kinase 1 activation. Aged SOD2 +/− SMCs had increased mitochondrial superoxide but decreased hydrogen peroxide levels. Finally, dominant-negative Forkhead box O3a overexpression attenuated staurosporine-induced apoptosis in aged SOD2 +/− SMCs. Conclusion— Mitochondrial oxidative stress over a lifetime causes aortic stiffening, in part by inducing vascular wall remodeling, intrinsic changes in SMC stiffness, and aortic SMC apoptosis.

We present a case of simultaneous occurrence of 2 rare congenital anomalies. A 57-year-old woman undergoing evaluation of dyspnea was found to have a single coronary artery and persistent left superior vena cava. The incidence of single coronary artery is 0.024% to 0.066% in the general population. Persistent left superior vena cava occurs in 0.3% of those without other congenital anomalies and in up to 5% when other anomalies are present. The likelihood of both anomalies occurring as a random event in 1 patient is approximately 1 in 10 million. Patient characteristics and data are presented, with a discussion on the epidemiology, incidence, diagnosis and pathologic implications of each anomaly.

The clinical impact of using CYP2C19 genotype to guide dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) remains unclear. This single center retrospective cohort study included 1193 PCI patients from 2012-14. CYP2C19 genotyping was recommended in high risk patients

Background The long-term benefits of coronary revascularization are proportional to the severity of underlying coronary artery disease (CAD). We sought to identify patients with a greater probability of severe CAD to target those who could receive the greatest benefit from revascularization. Methods We used multivariable logistic generalized estimating equations modeling to identify clinical factors associated with severe CAD in 83,490 patients, without prior bypass surgery, who underwent coronary angiography after presenting with non–ST-segment elevation acute coronary syndromes enrolled in CRUSADE. We then compared actual patterns of cardiac catheterization use relative to patients' probability of severe CAD in those who underwent catheterization and those who did not. Results Independent factors associated with severe CAD included older age, male sex, diabetes, no prior percutaneous coronary intervention, signs or history of heart failure, prior myocardial infarction, ST-segment depression, and family history of CAD. Cardiac catheterization rates were inversely related to the probability of severe CAD as estimated by the model. Conclusions There is a misalignment in the use of cardiac catheterization in patients with non–ST-segment elevation acute coronary syndromes relative to their predicted probability of severe CAD. The use of catheterization appears to target patients who would derive less benefit from revascularization. Further quality improvement efforts should promote appropriate use of cardiac catheterization procedures among patients with the greatest potential benefit.

Myocardial bridging is a congenital abnormality characterized by an intramyocardial course of a major epicardial coronary artery segment. Generally considered a benign condition, myocardial bridging has been associated with angina, acute myocardial infarction, and sudden death. Herein, we report a patient with an intramyocardial segment in the mid portion of the left anterior descending coronary artery with marked systolic compression. Single photon emission computed tomography with technetium-99m tetrofosmin done to evaluate an episode of chest pain showed a large predominantly fixed perfusion defect in the mid to apical anterior wall with partial reversibility. The patient’s chest pain did not recur and repeat single photon emission computed tomography imaging 14 days later with rest-redistribution thallium-201 showed normal myocardial perfusion. The overall clinical impression was that myocardial bridging resulted in severe transient anterior myocardial hypoperfusion. The literature on prevalence, diagnosis, use of perfusion imaging, and hemodynamic effects of myocardial bridging is reviewed.

The effect of the contrast agent iohexol on reference vessel size in patients with proximal left anterior descending disease is unknown. Quantitative coronary angiography and intravascular ultrasound were performed in 15 patients with atherosclerotic disease of the proximal left anterior descending. Mean proximal reference vessel diameter was 2.95 ± 0.59 mm with quantitative coronary angiography and 4.65 ± 0.66 mm with intravascular ultrasound ( P < .05). Intracoronary injection of iohexol resulted in a significant decrease in intravascular ultrasound-measured proximal reference vessel diameter from 4.65 ± 0.66 mm to 4.47 ± 0.68 mm ( P = .002). Vasoconstrictive response to iohexol in the proximal reference vessel ranged from −0.04 mm to 0.5 mm with a mean of 0.18 ± 0.16 mm. This study shows that iohexol can cause significant vasoconstriction of the proximal reference vessel in patients with severe disease involving the proximal left anterior descending.

Cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) exhibit potent cardiovascular protective effects in preclinical models, and promoting the effects of EETs has emerged as a potential therapeutic strategy for coronary artery disease (CAD). The relationship between circulating EET levels and CAD extent in humans, however, remains unknown. A panel of free (unesterified) plasma eicosanoid metabolites was quantified in 162 patients referred for coronary angiography, and associations with extent of CAD [no apparent CAD (N = 39), nonobstructive CAD (N = 51), and obstructive CAD (N = 72)] were evaluated. A significant relationship between free EET levels and CAD extent was observed (P = 0.003) such that the presence of obstructive CAD was associated with lower circulating EET levels. This relationship was confirmed in multiple regression analysis where CAD extent was inversely and significantly associated with EET levels (P = 0.013), and with a biomarker of EET biosynthesis (P < 0.001), independent of clinical and demographic factors. Furthermore, quantitative enrichment analysis revealed that these associations were the most pronounced compared with other eicosanoid metabolism pathways. Collectively, these findings suggest that the presence of obstructive CAD is associated with lower EET metabolite levels secondary to suppressed EET biosynthesis. Novel strategies that promote the effects of EETs may have therapeutic promise for patients with obstructive CAD.