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Background: Patients with type 2 diabetes mellitus are at an increased risk of adverse cardiovascular events compared to those without diabetes. The timing, relative to disease onset, and degree of glycemic control that reduces the risk of adverse cardiovascular events remains uncertain. Coronary microvascular dysfunction is prevalent in patients with type 2 diabetes mellitus and is linked to adverse cardiovascular events. We assessed the association between endothelial-dependent and endothelial-independent coronary microvascular dysfunction and glycemic control in patients presenting with chest pain and nonobstructive coronary disease at angiography., Methods: Patients presenting with chest pain and found to have non-obstructive CAD (stenosis < 40%) at angiography underwent an invasive assessment of endothelial-independent and endothelial -dependent microvascular function. Endothelial-independent microvascular function was assessed by comparing the coronary flow velocity, measured using a Doppler guidewire, in response to intracoronary infusion of adenosine to calculate the coronary flow reserve ratio in response to adenosine (CFRAdn Ratio). A CFRAdn Ratio ≤ 2.5 was considered abnormal. Endothelial-dependent microvascular function was assessed by measuring the percent change in coronary blood flow in response to intracoronary infusions of acetylcholine (%ΔCBFAch), and microvascular endothelial dysfunction defined as a %ΔCBFAch of ≤ 50%. Patients were classified by normal versus abnormal CFRAdn Ratio and %ΔCBFAch. Measurements of HbA1c and fasting serum glucose were obtained prior to catheterization and compared between groups., Results: Between 1993 and 2012, 1469 patients (mean age 50.4 years, 35% male) underwent coronary angiography and invasive testing for coronary microvascular dysfunction, of which 129 (8.8%) had type 2 diabetes. Fifty-one (39.5%) had an abnormal %ΔCBFAch and 49 (38.0%) had an abnormal CFRAdn Ratio. Conventional cardiovascular risk factors and cardiovascular or diabetic medication use did not vary significantly between groups. Females with an abnormal CFRAdn Ratio or abnormal %ΔCBFAch had a significantly higher HbA1c compared to patients with a normal CFRAdn Ratio or %ΔCBFAch respectively: HbA1c % (standard deviation) 7.4 (2.1) vs. 6.5 (1.1), p = 0.035 and 7.3 (1.9) vs. 6.4 (1.2), p = 0.022, respectively. Female patients with an abnormal CFRAdn Ratio had significantly higher fasting serum glucose concentrations compared to those with a normal CFRAdn Ratio: fasting serum glucose mg/dL (standard deviation) 144.4 (55.6) vs. 121.9 (28.1), p = 0.035. This was not observed in men. Amongst female diabetics, a higher HbA1c was significantly associated with any coronary microvascular dysfunction both in a univariate and multivariate analysis: odds ratio (95% confidence interval) 1.69 (1.01-2.86) p = 0.049; and a fasting serum glucose > 140 mg/dL was significantly associated with an abnormal CFRAdn Ratio, 4.28 (1.43-12.81)., Conclusion: Poor glycemic control is associated with coronary microvascular dysfunction amongst female diabetics presenting with chest pain and non-obstructive CAD. These findings highlight the importance of sex specific risk stratification models and treatment strategies when managing cardiovascular risk amongst diabetics. Further studies are required to identify additional risk prevention tools and therapies targeting microvascular dysfunction as an integrated index of cardiovascular risk.

Background: Coronary endothelial dysfunction (CED) is an early stage of atherosclerosis and is associated with adverse cardiovascular events. Inflammation may play a role in the development of endothelial dysfunction. To date no study has evaluated the relationship between C-reactive protein and CED. We aimed to determine if C-reactive protein is associated with CED., Methods: In 1016 patients (mean age 50.7±12.3 years, 34% male) presenting to the catheterization laboratory with chest pain and non-obstructive coronary artery disease, coronary vasoreactivity was assessed by measuring the percent change in coronary blood flow (%ΔCBF) and coronary artery diameter (%ΔCAD) in response to intracoronary acetylcholine. Plasma high sensitivity C-reactive protein (hs-CRP) was measured and patients were divided into 2 groups: hs-CRP≤3.0 mg/L (low-intermediate cardiovascular risk n=169) and 3 mg/L

The mechanisms responsible for late and very late stent thrombosis remain incompletely understood. This study aimed to evaluate the incidence and morphologic predictors of intrastent thrombus in patients after drug-eluting stent (DES) implantation using optical coherence tomography (OCT). A total of 208 patients with 262 DES who underwent follow-up OCT examination >6 months after DES implantation were included. The detailed vascular morphology including characteristics of neointima was analyzed. Thrombus was identified in 24 patients (11.5%) 11 months after DES implantation. Minimal lumen cross-sectional area was significantly smaller in the thrombus group than in the nonthrombus group (2.9 ± 1.7 vs 4.6 ± 2.0 mm(2); p <0.001). No difference was found in the frequency of uncovered or malapposed struts between the 2 groups. Thin-cap fibroatheroma (20.6% vs 0.1%; p <0.001) and heterogeneous neointima (22.2% vs 9.0%; p = 0.001) were more frequently detected in the thrombus group compared to the nonthrombus group. Second-generation DES showed lower incidence of thrombus, uncovered struts, and extrastent lumen compared with first-generation DES. In conclusion, the present OCT study revealed that smaller lumen cross-sectional area and neointimal morphology are important factors associated with intrastent thrombus. Second-generation DES demonstrated improved arterial healing and a lower incidence of intrastent thrombus compared with first-generation DES., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Coronary microvascular dysfunction (CMD) is linked to adverse cardiovascular events. Definitive diagnosis of CMD requires invasive provocative testing during angiography. We developed and tested a novel computerized T wave analysis tool to identify electrocardiographic signatures of CMD., Methods: 1552 patients underwent an invasive assessment of coronary microvascular function. Patients with interpretable pre-procedural ECGs were divided into 2 age and sex matched groups (n=261 in each group, 75% female): normal microvascular function, CFR>2.5 (CFR+), and abnormal microvascular function, CFR ≤ 2.5 (CFR-). ECGs were evaluated using a novel T wave program that quantified subtle changes in T wave morphology., Results: T wave repolarization parameters were significantly different between patients with normal and abnormal microvascular function. The top 3 features in males comprised of T wave area in V6 (CFR+: 10091.4 mV(2) vs. CFR-: 8152.3 mV(2), p<0.05); T1 Y-center of gravity in lead II (CFR+: 17.8 mV vs. CFR-: 22.4, p<0.005) and T Peak-T End in lead II (CFR+: 97.6 msec vs. CFR-: 91.1 msec, p<0.05). These could identify the presence of an abnormal CFR with 74 ± 0.2% accuracy. In females, the top 3 features were T wave right slope lead V6 (CFR+: -2489.1 mV/msec vs. CFR-: -2352.3 mV/msec, p<0.005); Amplitude in V6 (CFR+: 190.4 mV vs. 172.7 mV, p=0.05) and Y-center of gravity in lead V1 (CFR+: 33.3 vs. CFR-: 40.0, p=0.001). These features could identify the presence of an abnormal CFR with 67 ± 0.3% accuracy., Conclusion: Our data demonstrates that a computer-based repolarization measurement tool may identify electrocardiographic signatures of CMD., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objectives: This study assessed the prevalence of coronary microvascular abnormalities in patients presenting with chest pain and nonobstructive coronary artery disease (CAD)., Background: Coronary microvascular abnormalities mediate ischemia and can lead to an increased risk of cardiovascular events., Methods: Using an intracoronary Doppler guidewire, endothelial-dependent microvascular function was examined by evaluating changes in coronary blood flow in response to acetylcholine, whereas endothelial-independent microvascular function was examined by evaluating changes in coronary flow velocity reserve in response to intracoronary adenosine. Patients were divided into 4 groups depending on whether they had a normal (+) or abnormal (-) coronary blood flow (CBF) in response to acetylcholine (Ach) and a normal (+) or abnormal (-) coronary flow velocity reserve (CFR) in response to adenosine (Adn): CBFAch+, CFRAdn+ (n = 520); CBFAch-, CFRAdn+ (n = 478); CBFAch+, CFRAdn- (n = 173); and CBFAch-, CFRAdn- (n = 268)., Results: Two-thirds of all patients had some sort of microvascular dysfunction. Women were more prevalent in each group (56% to 82%). Diabetes was uncommon in all groups (7% to 12%), whereas hypertension and hyperlipidemia were relatively more prevalent in each group, although rates for most conventional cardiovascular risk factors did not differ significantly between groups. There were no significant differences in the findings of noninvasive functional testing between groups. In a multivariable analysis, age was the only variable that independently predicted abnormal microvascular function., Conclusions: Patients with chest pain and nonobstructive CAD have a high prevalence of coronary microvascular abnormalities. These abnormalities correlate poorly with conventional cardiovascular risk factors and are dissociated from the findings of noninvasive functional testing., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Despite a nonobstructive coronary angiogram, many patients may still have an abnormal coronary vasomotor response to provocation and to myocardial demand during stress. The ability of noninvasive stress tests to predict coronary vasomotor dysfunction in patients with nonobstructive coronary artery disease is unknown., Methods and Results: All patients with nonobstructive coronary artery disease who had invasive coronary vasomotor assessment and a noninvasive stress test (exercise ECG, stress echocardiography, or stress nuclear imaging) within 6 months of the cardiac catheterization with provocation at our institution were identified (n=376). Coronary vasomotor dysfunction was defined as a percentage increase in coronary blood flow of

Background: Smoking is a major risk factor for cardiovascular events. One of the potential mechanisms may be related to both coronary endothelial dysfunction and increased inflammatory response. The present study was designed to test the hypothesis that smoking is associated with epicardial coronary endothelial dysfunction and inflammation., Methods and Results: Coronary endothelial function in response to acetylcholine was assessed in 881 patients (115 current smokers and 766 nonsmokers, including 314 previous smokers). Smokers were significantly younger than nonsmokers (43+/-1 versus 51+/-1 years, P<0.0001), had more epicardial vasoconstriction in response to intracoronary acetylcholine (-19+/-2% versus -14+/-1% change in coronary artery diameter, P=0.03), and were more likely than nonsmokers to have epicardial endothelial dysfunction (46% versus 35%, P=0.005), but their microvascular endothelial function was intact. Smokers had higher white blood cell counts than nonsmokers (7.7+/-0.2 versus 6.6+/-0.1x10(9)/L, P<0.0001), higher myeloperoxidase (156+/-19 versus 89+/-8 ng/mL), higher lipoprotein-associated phospholipase A2 (242+/-12 versus 215+/-5 ng/mL), and higher levels of intracellular adhesion molecule (283+/-14 versus 252+/-5 ng/mL). There were no differences in the levels of C-reactive protein, fibrinogen, or vascular cell adhesion molecule between the groups., Conclusions: Young smokers are characterized by epicardial coronary endothelial dysfunction, preserved microvascular endothelial function, and increased levels of inflammatory biomarkers and oxidative stress. The present study provides further information regarding the potential mechanisms by which smoking contributes to cardiovascular events.

The purpose of this study was to determine the association between depression and coronary endothelial function and cardiac risk factors in men and women without obstructive coronary artery disease. Patients with no significant coronary artery disease who underwent invasive coronary endothelial function assessment with acetylcholine were studied. Men and women were divided into 2 groups: those with depression and those without. Endothelial function and risk factor profiles were compared between the 2 groups. Seven hundred fifty-nine patients were studied, 603 (79%) without depression and 156 (21%) with depression. Patients with depression were more likely to be women (71% vs 60%, p = 0.02), have greater body mass indexes (29.9 +/- 6.7 vs 28.2 +/- 5.9 kg/m(2), p = 0.002), and be diabetic (12% vs 6%, p = 0.02). Depressed patients also had higher levels of C-reactive protein (0.35 vs 0.30 mg/dl, p = 0.02). There was no difference in the change in coronary blood flow or diameter in response to acetylcholine between the 2 groups in men and women. In conclusion, the results of this study demonstrate that depression is not associated with coronary endothelial dysfunction in men and women without significant coronary artery disease. It is, however, associated with a cluster of cardiac risk factors that are linked to the progression of atherosclerotic disease.

Objective: The purpose of the current study was to determine whether lipoprotein-associated phospholipase A2 (Lp-PLA2) is associated with coronary endothelial dysfunction and is a predictor of endothelial dysfunction in humans., Methods and Results: Patients (172) with no significant coronary artery disease (<30% stenosis) undergoing assessment of coronary endothelial function were studied. Endothelial function was assessed by the change in coronary blood flow and coronary artery diameter in response to intracoronary acetylcholine. Plasma concentrations of Lp-PLA2 were measured, and patients were divided into tertiles. Patients in tertiles 2 and 3 had a significantly lower change in coronary blood flow (63.8+/-73.2 and 32.0+/-71.7 versus 78.4+/-73.2%; P<0.001) and greater epicardial coronary artery vasoconstriction (-14.1+/-14.7 and -23.3+/-25.1 versus -9.5+/-15.2% mean diameter change; P<0.001) in response to acetylcholine. Patients with coronary endothelial dysfunction had significantly higher serum concentrations of Lp-PLA2 than those with normal endothelial function (246.2+/-71.6 versus 209+/-56.7 ng/mL; P=0.001). The odds ratio for coronary endothelial dysfunction in patients with Lp-PLA2 in the highest tertile was 3.3 (95% CI, 1.6 to 6.6)., Conclusions: Lp-PLA2 is independently associated with coronary artery endothelial dysfunction and is a strong predictor of endothelial dysfunction in humans.

Objective: Atherosclerosis is a chronic and diffuse disease that affects all vascular beds. However, some vascular beds are more prone to atherosclerosis than others. Recent evidence suggests a role for the vasa vasorum in the atherosclerotic process. We hypothesized that there is a difference in adventitial vasa vasorum structure between the left internal thoracic artery and the coronary artery. Hence the current study was designed to characterize and compare the structure of the adventitial vasa vasorum in the left internal thoracic and coronary arteries., Methods: Samples of vessels were obtained from female crossbred domestic pigs maintained on a normal (n = 6) or high-cholesterol (n = 6) diet for 12 weeks. The samples were scanned with micro-computed tomography, and the tomographic images were reconstructed and analyzed to obtain lumen area, vessel wall area, vasa vasorum count, vasa vasorum density, mean diameter of first- and second-order vasa vasorum, and second-order/first-order vasa vasorum ratio., Results: Vasa vasorum density was significantly higher in the coronary arteries versus that seen in the left internal thoracic arteries in the normal group, as well as in the high-cholesterol group. The higher vasa vasorum density in the high-cholesterol group versus that in the normal group was significant for both vessels, being more pronounced in the left internal thoracic artery. Lumen area and second-order/first-order vasa vasorum ratio were higher in the high-cholesterol group than in the normal group only in the left internal thoracic artery., Conclusion: This study demonstrated that low vasa vasorum spatial density and higher lumen area observed in the left internal thoracic artery compared with that seen in the native coronary artery can be the structural background for the low incidence of atherosclerosis in this vessel.