Changes In Coronary Artery Diameter Research Articles

Abstract 14428: The Effect of Menopause on Coronary Blood Flow in Females Presenting With Angina and Non-Obstructive Coronary Artery Disease

Introduction: Changes in coronary artery diameter (CAD) and coronary blood flow (CBF) in reaction to acetylcholine are important surrogates of endothelial health, and abnormalities in these parameters might represent early atherosclerosis. Menopause is associated with an increased risk of coronary artery disease, yet the role of menopause on the endothelium is not well described. Hypothesis: The vasodilatory response of the endothelium to acetylcholine (Ach) decreases after menopause. Methods: A total of 1271 (42% pre-menopausal) females with angina and non-obstructive coronary artery disease (<50% angiographic stenosis) that underwent coronary reactivity study were enrolled. A doppler wire was positioned and incremental Ach doses were injected (10 -6 , 10 -5 , and 10 -4 mol/L). CBF was then calculated from CAD and doppler-derived flow velocity. Comparisons between the pre-and post-menopause groups were performed. Results: Mean age of the pre-menopausal group was 44±10 years, while that of the post-menopausal 59±9 years. Pre-menopausal females had higher baseline CAD as compared to post-menopausal females (2.22 [1.90; 2.65] vs. 2.20 [1.85; 2.55] mm, P=0.03). However, this difference was nullified with subsequent doses of Ach (Figure 1A&B ). Pre-menopausal females had a higher baseline CBF than post-menopausal females (32.1 [21.7; 44.9] vs. 29.2 [19.8; 42.0] mL/min; P=0.01). This difference progressively increased with successive doses of Ach (10 -4 :49.5 [30.3; 77.0] vs. 41.7 [24.4; 69.0] mL/min; P=0.0002), revealing a greater microvascular vasodilatory response in pre-menopausal females (Cumulative %ΔCBF after highest dose= 60 [2.6; 122] vs 45 [-4; 98], P=0.002) ( Figure 1C&D ). Conclusions: Premenopausal females have greater sensitivity of the microvascular endothelium to Ach compared to post-menopausal, suggesting a possible role for estrogen in mediating the effect of stress on the microvasculature through the endothelium.

Abstract 13735: Coronary Endothelial Dysfunction Plays Important Roles on Development of Acute Coronary Syndrome and Fatal Cardiovascular Events During Long-term Follow-up Over 10 Years

Introduction: Although coronary endothelial dysfunction is thought to affect coronary atherothrombogenic processes, there has been little practical evidence for the relationship between clinical evolution of fatal or non-fatal acute coronary syndrome (ACS) and coronary endothelial dysfunction. Hypothesis: We assessed hypothesis that coronary endothelial dysfunction has clinical impacts on development of ACS and fatal cardiovascular events. Methods: Coronary endothelial dysfunction was practically graded by the flow-mediated endothelium-dependent reactive changes in coronary artery diameter (CFMD) to infusion of adenosine triphosphate (ATP ; 50μg) into the normal left coronary artery using quantitative coronary arteriography in 150 patients with stable coronary artery disease. The enrolled patients were categorized into tertile groups according to the values of CFMD, and we prospectively followed-up major adverse clinical cardiac events including ACS and cardiovascular death. Results: For a mean follow-up period of 132 months (range; 120 to 144) with complete follow-up, the patients in the lower third with severe coronary endothelial dysfunction (Group-L) more frequently developed ACS than those in the middle third with mild coronary endothelial dysfunction (Group-M) plus those in the higher third without coronary endothelial dysfunction (Group-H) [Group-L versus Group-M plus Group-H: 15(30%) versus 5(10%) plus 0(0%), p<0.001, by Kaplan-Meier analysis]. Majority of the patients who resulted in cardiovascular death belonged to Group-L, [6(12%) versus 1(2%) plus 0(0%), p=0.014]. Cox hazard proportional model analyses indicated that severe coronary endothelial dysfunction was the strong predictor for future ACS (hazard ratio=7.53, 95%confidential interval; 1.78-12.25, p<0.001) and future cardiovascular death (hazard ratio=13.50, 95%confidential interval; 1.55-25.25, p=0.005). Conclusions: This is the novel and longest follow-up investigation that demonstrates coronary endothelial dysfunction plays important roles on development of ACS and fatal cardiovascular events and therefore the strategies based on status of coronary endothelial dysfunction are required to prevent major adverse ischemic cardiac events.

Prevalence of myocardial bridging associated with coronary endothelial dysfunction in patients with chest pain and non-obstructive coronary artery disease.

Myocardial bridging (MB), characterised by the epicardial coronary vessel diving into the myocardium, is present in up to one third of adults and is associated with angina and acute coronary syndromes. MB is accompanied by altered blood flow mechanics and regional changes in wall sheer stress. The purpose of this study was to determine the association between myocardial bridging and coronary endothelial dysfunction. Patients presenting with chest pain and found to have non-obstructive CAD (stenosis <40%) on angiography underwent an invasive assessment of epicardial and microvascular endothelial function. Epicardial endothelial function was assessed by measuring the percent change in coronary artery diameter in response to intracoronary infusions of acetylcholine (%ΔCADAch). Epicardial endothelial dysfunction was defined as a %ΔCADAch of <-20%. Microvascular endothelial function was assessed by the percent change in coronary blood flow in response to intracoronary infusions of acetylcholine (%ΔCBFAch), and microvascular endothelial dysfunction was defined as a %ΔCBFAch of <50%. MB was diagnosed angiographically by identifying the characteristic reduction in minimal luminal diameter during systole. Patients were divided into those with and those without MB, and the frequency of epicardial endothelial dysfunction and microvascular endothelial dysfunction was compared between patients with versus those without MB. Between 1993 and 2012, 1,469 patients (mean age 50.4 years, 35% male) underwent coronary angiography and invasive testing of endothelial function. Two hundred and eight (14.2%) patients were found to have MB in the LAD. Patients with any MB had a significantly higher frequency of endothelial dysfunction within the mid and/or distal vessel segment compared to patients without MB (60.1% vs 50.4%, p=0.012). In multivariate analyses, mid and/or distal vessel MB was a significant predictor of mid and/or distal vessel epicardial endothelial dysfunction (OR 1.44, 95% CI: 1.04-2.00, p=0.029) and of microvascular endothelial dysfunction (OR 1.34, 95% CI: 1.00-1.82, p=0.050). MB co-localises with epicardial endothelial dysfunction and is significantly associated with microvascular endothelial dysfunction in symptomatic patients with non-obstructive CAD, supporting its potential role as a mechanism for angina in symptomatic patients with MB.

Strong Relationship Between Vascular Function in the Coronary and Brachial Arteries.

Early detection of coronary artery dysfunction is of paramount cardiovascular clinical importance, but a noninvasive assessment is lacking. Indeed, the brachial artery flow-mediated dilation test only weakly correlated with acetylcholine-induced coronary artery function ( r=0.36). However, brachial artery flow-mediated dilation methodologies have, over time, substantially improved. This study sought to determine if updates to this technique have improved the relationship with coronary artery function and the noninvasive indication of coronary artery dysfunction. Coronary artery and brachial artery function were assessed in 28 patients referred for cardiac catheterization (61±11 years). Coronary artery function was determined by the change in artery diameter with a 1.82 μg/min intracoronary acetylcholine infusion. Based on the change in vessel diameter, patients were characterized as having dysfunctional coronary arteries (>5% vasoconstriction) or relatively functional coronary arteries (<5% vasoconstriction). Brachial artery function was determined by flow-mediated dilation, adhering to current guidelines. The acetylcholine-induced change in vessel diameter was smaller in patients with dysfunctional compared with relatively functional coronary arteries (-11.8±4.6% versus 5.8±9.8%, P<0.001). Consistent with this, brachial artery flow-mediated dilation was attenuated in patients with dysfunctional compared with relatively functional coronaries (2.9±1.9% versus 6.2±4.2%, P=0.007). Brachial artery flow-mediated dilation was strongly correlated with the acetylcholine-induced change in coronary artery diameter ( r=0.77, P<0.0001) and was a strong indicator of coronary artery dysfunction (receiver operator characteristic=78%). The current data support that updates to the brachial artery flow-mediated dilation technique have strengthened the relationship with coronary artery function, which may now provide a clinically meaningful indication of coronary artery dysfunction.

Chronic inhibition of lipoprotein-associated phospholipase A2 does not improve coronary endothelial function: A prospective, randomized-controlled trial

AimsLipoprotein-associated phospholipase A2 (Lp-PLA2), a novel biomarker for vascular inflammation, is associated with coronary endothelial dysfunction (CED) and independently predicts cardiovascular events. The current study aimed to determine whether darapladib, an orally administered Lp-PLA2 inhibitor, improved CED. Methods and resultsFifty-four patients with CED were enrolled in a double-blinded randomized placebo-controlled trial, and were randomized to receive oral darapladib, 160mg daily, or placebo. Coronary angiography and invasive coronary endothelial function assessment were performed at baseline and post-6months of treatment. Primary endpoints were change in coronary artery diameter and coronary blood flow in response to acetylcholine. Additionally, Lp-PLA2 activity was measured at baseline and on follow-up to evaluate for adherence and drug effect. Fifty-four patients were randomized to placebo (n=29) and darapladib (n=25). Mean age in darapladib group was 55.2.±11.7years vs. 54.0±10.5years (p=0.11). On follow-up, there was no significant difference in the percent response to acetylcholine of coronary artery diameter in treatment vs. placebo group (+3 (IQR −9, 15) vs. +3 (−12, 19); p=0.87) or coronary blood flow (−5 (IQR −24, 54) vs. 39 (IQR −26, 67); p=0.41). There was significant reduction in Lp-PLA2 activity in the treatment arm vs. placebo (−76 (IQR −113, −52) vs. −7(−21, −7); p<0.001). DiscussionLp-PLA2 inhibition with darapladib did not improve coronary endothelial function, despite significantly reduced Lp-PLA2 activity with darapladib. This study suggests endogenous Lp-PLA2 may not play a primary role in coronary endothelial function in humans. Clinicaltrials.gov IdentifierNCT01067339

Sex-Specific Genetic Variants are Associated With Coronary Endothelial Dysfunction.

BackgroundEndothelial dysfunction is an early stage of atherosclerosis. Single‐nucleotide polymorphisms (SNPs) have been associated with vascular dysfunction, cardiac events, and coronary artery remodeling. We aimed to detect SNPs associated with endothelial dysfunction and determine whether these associations are sex specific.Methods and ResultsSix hundred forty‐three subjects without significant obstructive coronary artery disease underwent invasive coronary endothelial function assessment. We collected data from 1536 SNPs that had previously been associated with vasoreactivity, angiogenesis, inflammation, artery calcification, atherosclerotic risk factors, insulin resistance, hormone levels, blood coagulability, or with coronary heart disease. Coronary vascular reactivity was assessed by the percent change in coronary artery diameter ≤ −20% after an intracoronary bolus injection of acetylcholine on invasive coronary physiology study. SNPs significantly associated with coronary epicardial endothelial dysfunction were ADORA1,KCNQ1, and DNAJC4 in the whole cohort, LPA, MYBPH, ADORA3, and PON1 in women and KIF6 and NFKB1 in men (P<0.01).ConclusionsWe have identified several significant SNPs that are associated with an increased risk of coronary endothelial dysfunction. These associations appear to be sex specific and may explain gender‐related differences in development of atherosclerosis.

Coronary endothelial function in patients with obstructive sleep apnea

Obstructive sleep apnea (OSA) has been associated with increased risk for cardiovascular events, possibly mediated by endothelial dysfunction. The current study evaluates the association between invasive coronary endothelial dysfunction and OSA in patients with nonobstructive coronary atherosclerosis. All patients who had undergone both polysomnography and an invasive coronary vasomotor study at the Mayo Clinic, Rochester, Minnesota, from January 1997 to August 2011 were identified (n=143). OSA was defined as an apnea-hypopnea index of 5 or higher. Three endpoints of coronary endothelial function - percentage change in coronary artery diameter at the mid and distal left anterior descending artery to intracoronary acetylcholine and percentage change in coronary blood flow to intracoronary acetylcholine - were assessed. Differences between patients with OSA (n=102) and those without OSA (n=41) were evaluated using multivariate analysis of variance. Follow-up mortality data were collected and Kaplan-Meier curves were plotted to evaluate differences in mortality between patients with and without OSA. Patients with OSA were more likely to have hypertension compared with patients without OSA. OSA was not significantly associated with coronary endothelial dysfunction on univariate analysis (P=0.23) and after adjustment for hypertension (P=0.19). Similarly, there was no significant difference in coronary endothelial function in patients who had oxygen desaturation of less than 90% during polysomnography (P=0.42). There was a trend toward higher mortality in patients with OSA compared with those without OSA, but this did not reach statistical significance (5 vs. 0% at 10 years, P=0.25). The current study suggests that OSA is not an independent risk factor for coronary endothelial dysfunction in patients with early coronary atherosclerosis. Adverse coronary outcomes in patients with OSA may be independent of coronary endothelial dysfunction.

Evaluation of coronary microvascular function in patients with vasospastic angina

To investigate endothelium-dependent and -independent coronary microvascular functions in patients with vasospastic angina (VSA). Thirty-six patients with VSA (30 men and 6 women; mean age, 58 years) were enrolled in this study. VSA was defined as ≥ 90% narrowing of the epicardial coronary arteries on angiography performed during a spasm provocation test, presence of chest pain, and/or ST-segment deviation on an electrocardiogram (ECG). Patients (n = 36) with negative spasm provocation test results and those matched for age and sex were enrolled as a control group (nonVSA group). Low-dose acetylcholine (ACh; 3 μg/min) was infused into the left coronary ostium for 2 min during the spasm provocation test. Following the spasm provocation test, nitroglycerin (0.2 mg) was administered intracoronally. Coronary blood flow (was calculated from quantitative angiography and Doppler flow velocity measurements, and the coronary flow reserve was calculated as the ratio of coronary flow velocity after injection of adenosine triphosphate (20 μg) to the baseline value. Changes in the coronary artery diameter in response to ACh and nitroglycerin infusion were expressed as percentage changes from baseline measurements. Body mass index was significantly lower in the VSA group than in the nonVSA group. The frequency of conventional coronary risk factors and the rate of statin use were similar between the 2 groups. The left ventricular ejection fraction as evaluated by echocardiography was similar between the 2 groups. The duration of angina was 9 ± 2 mo. The results of blood chemistry analysis were similar between the 2 groups. Low-dose ACh did not cause coronary spasms. The change in coronary artery diameter in response to ACh was lower in the VSA group (-1.4% ± 9.3%) than in the nonVSA group (3.1% ± 6.5%, P < 0.05), whereas nitroglycerin-induced coronary artery dilatation and coronary blood flow increase in response to ACh or coronary flow reserve did not differ significantly between the 2 groups. These findings suggest that microvascular coronary function may be preserved despite endothelial dysfunction of the epicardial coronary arteries in patients with VSA.

Abstract 9941: Prior Myocardial Infarction is Associated with Endothelial Dysfunction in Women with Microvascular Coronary Dysfunction

Background: Patients with signs and symptoms of ischemia but no obstructive coronary artery disease (CAD) often have microvascular coronary dysfunction (MCD). MCD is associated with an elevated risk of myocardial infarction (MI), yet the pathophysiological mechanism(s) are not well understood. We compared endothelial-dependent and endothelial-independent pathways in women with MCD with and without a prior history of MI. Methods: 67 women with persistent chest pain, clinical evidence of myocardial ischemia, and no obstructive CAD by angiography, underwent clinically-ordered coronary reactivity testing, which included infusion of intracoronary acetylcholine (ACH), adenosine and nitroglycerin to determine percent change in coronary artery diameter and flow. History of prior MI was obtained through supervised, self-reported questionnaire and confirmed with medical record evidence of elevated troponin when available. Data were analyzed using a Wilcoxon signed-rank test. Results: Overall 10 (15%) women (51±12 years) had a history of MI (4 confirmed by available medical records) and 57 (55±9 years) had no prior MI (No-MI). There were no group differences in rates of age, hypertension, dyslipidemia, body mass index, smoking history, family history of heart disease, or diabetes (data not shown). Intracoronary ACH response (endothelial-dependent pathway) was significantly lower in the group with prior MI compared to no-prior MI group (figure). Measurements of coronary flow reserve with adenosine infusion and coronary vasodilation with nitroglycerin infusion (both endothelial-independent pathways) were not different between groups. Conclusions: Prior MI in women with MCD is associated with endothelial dysfunction. Future study should consider coronary endothelial dysfunction as a MCD treatment target in women with a history of MI and no obstructive CAD.

Relationship Between Bilirubin Concentration, Coronary Endothelial Function, and Inflammatory Stress in Overweight Patients

Bilirubin has antioxidant properties and may protect against atherosclerosis and coronary heart disease (CHD). Further, in patients with metabolic syndrome, hyperbilirubinemia is associated with attenuation of insulin resistance. The aim of the present study was to determine the relationship between serum bilirubin concentration and coronary endothelial function in overweight patients. The study population consisted of 107 patients without CHD who underwent coronary flow studies. Vascular reactivity was examined by intra-coronary administration of papaverine and nitroglycerin. Coronary endothelial function was evaluated by assessing the change in coronary artery diameter to papaverine [percent change in flow-mediated dilatation (%FMD)] and nitroglycerin (%NTG). Serum total bilirubin, high-sensitivity C-reactive protein (hs-CRP), high density lipoprotein-cholesterol (HDL-C), fasting plasma glucose and immunoreactive insulin levels were also measured, and the homeostasis model assessment insulin resistance (HOMA-IR) index was calculated. Patients were divided into two groups according to body mass index (BMI): an overweight group (BMI ≥ 25; n = 36) and a normal weight group (BMI < 25; n = 71). In the overweight group, univariate analysis revealed that log-transformed total bilirubin was positively correlated with %FMD and HDL-C (r = 0.38, p< 0.05; r = 0.30, p < 0.05, respectively) and was inversely correlated with log-transformed hs-CRP and HOMA-IR (r = -0.45, p < 0.01; r = -0.45, p< 0.05, respectively). Multivariate analysis revealed that log-transformed hs-CRP was the only independent predictor of log-transformed total bilirubin (p< 0.05). These results suggest that a high bilirubin level was associated with favorable coronary endothelial function in overweight patients. Further, the anti-inflammatory effects of bilirubin may mediate this effect.

Impaired coronary microvascular endothelial function in men with metabolic syndrome

To assess coronary endothelial function of conduit and resistance vessels in patients with metabolic syndrome (MS). Seventy-eight men (mean age, 57 years) with chest pain and angiographically normal coronary arteries were included in the study. Patients with coronary spastic angina were excluded. Changes in coronary artery diameter and coronary blood flow (CBF) in response to acetylcholine (ACh) were determined using quantitative coronary angiography and Doppler velocity measurements. Coronary flow reserve was calculated as the ratio of coronary blood velocity after adenosine triphosphate infusion relative to baseline values. Patients were divided into two groups based on the presence or absence of MS. There were 24 patients in the MS group (31%). The increase in CBF in response to ACh infusion was impaired in the MS group (P < 0.0001) compared to the non-MS group, whereas changes in coronary artery diameter in response to ACh infusion did not differ between the two groups. Multivariate regression analysis revealed that MS was a significant factor associated with the lesser change in CBF induced by ACh infusion at 30 μg/min (P < 0.0001, r(2) = 0.46). Coronary endothelial dysfunction was present at the level of resistance vessels but not conduit vessels in the MS patients included in our study.

Long-term follow-up of acute changes in coronary artery diameter caused by Kawasaki disease: risk factors for development of stenotic lesions

To investigate the long-term outcome of initially dilated/aneurysmatic coronary arteries in Kawasaki disease (KD) and to define risk factors for significant myocardial ischemia during follow-up, we retrospectively followed all pediatric patients with proven acute coronary changes due to KD in our institution. Since 1981, 38 children have been identified with coronary changes due to KD. The median age was 1.2 years (0.1-12.8). In 37 patients therapy with intravenous immunoglobulin was initiated within 9 days (1-30) after the beginning of KD. All received aspirin and three additionally received steroids. Median follow-up was 8.5 years (0.5-24.8). We defined two groups: A aneurysm/ectasia of the coronary artery < or =5.0 mm (n = 23) and B aneurysm size >5.0 mm (n = 15). During follow-up, all coronary aneurysms of group A regressed to normal size, whereas in 14 patients of group B (93%) the aneurysms persisted or even increased in size. Four patients of group B developed severe coronary stenosis at the proximal and/or distal end of the aneurysm and needed an intervention (endovascular balloon dilation and stent implantation (n = 2) or bypass surgery (n = 2)) after a median time interval of 9.8 years (1.0-15.6) after KD. They all had ECG changes preceding the intervention about 1 year in advance. Maximum aneurysm size >5 mm was a statistical significant predictive risk factor for myocardial ischemia. After KD, patients with a coronary aneurysm size >5.0 mm need close follow-up assessments because of an elevated risk for the development of coronary stenotic lesions. In case of new and even unspecific ECG changes, coronary imaging modalities (angiography, MRI) have to be considered. Therapy options vary from percutaneous catheter interventions to bypass surgery and have to be selected individually for each patient.

The Interaction Between Coronary Endothelial Dysfunction, Local Oxidative Stress, and Endogenous Nitric Oxide in Humans

In vitro and animal studies suggest that oxidative stress is associated with endothelial dysfunction. We tested whether local oxidative stress and nitric oxide (NO) bioavailability in the coronary circulation is associated with coronary endothelial dysfunction in humans. Blood samples were obtained simultaneously from the left main coronary artery and the coronary sinus for measurement of F2-isoprostanes, myeloperoxidase, nitrotyrosine, and superoxide dismutase in 20 patients without significant coronary disease. Afterward, coronary blood flow and the vascular response to intracoronary acetylcholine and NG-monomethyl-L-arginine (L-NMMA) were assessed. The gradient of isoprostanes between the arterial levels and coronary sinus correlated with the change in coronary artery diameter in response to acetylcholine (r=-0.79, P<0.0001). Isoprostanes net production across the left anterior descending artery territory correlated with a decrease in superoxide dismutase activity (r=0.66, P=0.002) and decrease in coronary artery diameter in response to L-NMMA (rs=0.48, P<0.05). Myeloperoxidase and nitrotyrosine gradients were similar in patients with endothelial dysfunction and controls. The effect of L-NMMA was similar in both groups. We conclude that coronary endothelial dysfunction in humans is characterized by local enhancement of oxidative stress without a decrease in basal NO release. This study supports the hypothesis that local oxidative stress has a role in reduction of NO bioavailability in humans with coronary endothelial dysfunction.

Smoking Is Associated With Epicardial Coronary Endothelial Dysfunction and Elevated White Blood Cell Count in Patients With Chest Pain and Early Coronary Artery Disease

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. 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. 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.

Lipoprotein-Associated Phospholipase A 2 and Cardiovascular Risk

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an enzyme that circulates in blood, bound mainly to LDL particles (80%) but also to HDL particles (20%). It has been shown to be a risk factor for cardiovascular disease, and it is believed to form bioactive lipid mediators resulting in vascular inflammation. At the same time, Lp-PLA2 is implicated in the degradation of the platelet-activating factor (PAF), a potent mediator of inflammation (this is why this enzyme is also known as platelet-activating factor acetylhydrolase [PAF-AH]), a function that would lead to cardioprotection. See page 106 In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology , Yang and colleagues provide new evidence that Lp-PLA2 is an independent correlate of coronary endothelial-dependent dysfunction in a sample of 172 patients with no significant coronary artery disease (<30% stenosis) undergoing diagnostic coronary angiography.1 Microvascular and epicardial endothelial-dependent dysfunction were assessed as change in coronary blood flow and change in coronary artery diameter in response to intracoronary acetylcholine, respectively. After adjustment for relevant …

Impaired Coronary Endothelium–Dependent Vasodilation Is Associated With Microalbuminuria in Patients With Type 2 Diabetes and Angiographically Normal Coronary Arteries

OBJECTIVE—Microalbuminuria and impaired endothelium-dependent vasodilation are both predictors for cardiac events in patients with type 2 diabetes. The aim of the study was to evaluate whether microalbuminuria correlated with coronary endothelium–dependent vasodilation. RESEARCH DESIGN AND METHODS—We evaluated 84 patients (47 men, mean age 50.5 ± 5.9 years) with type 2 diabetes for 9.4 ± 3.4 years, without angiographic coronary stenosis and without major cardiovascular risk factors or other confounding factors, for endothelium investigation. Quantitative coronary angiography was used to assess coronary artery response to cold pressor testing, used to assess endothelium-dependent vasodilation, and to isosorbide dinitrate (endothelium-independent vasodilation). RESULTS—Endothelium-dependent vasodilation differed in the patients with and without microalbuminuria (changes in coronary artery diameter during cold pressor testing: −15.0 ± 1.9% vs. −10.2 ± 1.3%, respectively, P &amp;lt; 0.05) and correlated with urinary albumin excretion rate (r = −0.39, P = 0.003), diastolic blood pressure (r = 0.29, P &amp;lt; 0.01), and left ventricular mass index (r = −0.24, P &amp;lt; 0.05). Independent predictors for endothelium-dependent vasodilation were urinary albumin excretion rate (β −0.04 [95% CI −0.07 to −0.01], P &amp;lt; 0.005) and left ventricular mass index (−0.26 [−0.49 to −0.05], P &amp;lt; 0.05). Endothelium-independent vasodilation was similar in both groups. CONCLUSIONS—Type 2 diabetic patients with microalbuminuria have a more severely impaired coronary endothelium–dependent vasodilation than those with normoalbuminuria. These data suggest a common pathophysiological process for both coronary vasomotor abnormalities and microalbuminuria.

Effects of sumatriptan and eletriptan on diseased epicardial coronary arteries

Triptans are contraindicated in patients with known or suspected coronary artery disease (CAD); however, few studies have evaluated triptans in patients with obstructive CAD to quantify the vasoconstrictive effect on diseased coronary vessels. Patients undergoing percutaneous transluminal coronary angioplasty for symptomatic single-vessel CAD were randomised to one of three parallel cohorts to receive (1) 6 mg intravenously (IV) infused eletriptan plus subcutaneous (SC) placebo, (2) IV infused placebo plus 6 mg SC sumatriptan or (3) IV infused placebo plus SC placebo, as simultaneous administrations in a double-blind manner. Serial arteriograms, hemodynamic indices, electrocardiography and triptan plasma concentrations were obtained. . Fifteen minutes after triptan challenge, median (95% confidence interval) changes in coronary artery diameter (CADM) at the focal point of the stenosed segment were: dilation of 2.6% (-5.0, 11.4), eletriptan 6 mg IV (n = 18); constriction of 6.8% (-12.6, 0.4), sumatriptan 6 mg SC (n = 17), and constriction of 4.5% (-7.0, 7.9), placebo (n = 10). One patient had angiographic evidence of a new thrombus at the stenosis site, necessitating termination of study infusion and successful stenting of the lesion. There was no correlation between effects on CADM and triptan concentration, or between hemodynamic or electrocardiograph changes and the presence (n = 13) or absence (n = 33) of chest pain. Triptans had very little effect on diseased epicardial coronary arteries in a small group of angina sufferers with established CAD. Results should be interpreted cautiously since there may be instances where even modest triptan-associated epicardial constriction is sufficient to precipitate myocardial ischemia in patients with severe obstructive CAD.

Hormone Replacement Therapy and Coronary Endothelial Function in Postmenopausal Women

Dr Singh raises some excellent points, and we appreciate his comments. For the sake of brevity, we did not include the number of patients taking progesterone alone. Eighty-two patients took estrogen alone, and 19 took a combined estrogen plus progesterone preparation. However, we did note that concurrent administration of progesterone was not significantly associated with a change in the coronary blood flow or the coronary artery diameter response to acetylcholine or the coronary velocity reserve response to adenosine. Dr Singh's second point is an important one in that calcium channel blockers can affect vasomotor tone. For brevity, we did not include these data in our article. However, there was no significant difference in the rate of calcium channel blocker use between premenopausal and postmenopausal women (P=.52). The rates were also similar between postmenopausal women who were not receiving HRT compared with those who were (P=.17) and compared with those who had received HRT for more than 2 years (P=.20). Furthermore, there was no evidence of an interaction between calcium channel blocker use and any of the 3 comparisons (premenopausal vs post-menopausal, HRT vs no HRT, and HRT for more than 2 years vs no HRT) with regard to percent change in coronary blood flow in response to acetylcholine, percent change in coronary artery diameter in response to acetylcholine, or coronary velocity reserve response to adenosine: all interaction tests yielded P>.20. Dr Singh's final point is interesting. Age certainly could contribute to the observed differences, and it is possible that estrogen has different physiological effects in postmenopausal compared with premenopausal women. Recent animal study data from researchers at the Medical College of Georgia show that, when the activity of nitric oxide synthase that produces nitric oxide is blocked, the administration of estrogen causes not vasodilation but vasoconstriction.1White RE, HanG, Fulton D, Barman S. Dual and opposite effects of estrogen on coronary arteries mediated by type 1 (N) nitric oxide synthase via nitric oxide and superoxide. Presented at the American Heart Association Second International Conference on Women, Heart Disease, and Stroke; Orlando, Fla; February 16-19, 2005.Google Scholar Theoretically, since nitric oxide production is reduced in older women, giving postmenopausal women estrogen might, in this context, be expected to have detrimental cardiovascular effects, as seen in trials such as the Heart and Estrogen/progestin Replacement Study (HERS) and the Women's Health Initiative. Obviously, the physiology of HRT remains incompletely understood, and further study is needed to elucidate the different effects of estrogen on young vs older coronary arteries. Hormone Replacement Therapy and Coronary Endothelial Function in Postmenopausal WomenMayo Clinic ProceedingsVol. 80Issue 6PreviewTo the Editor: I read with interest the article by Halligan et al1 about the effects of long-term hormone replacement therapy (HRT) on coronary endothelial function in postmenopausal women that was published in the December 2004 issue of the Mayo Clinic Proceedings. Although the authors reached interesting conclusions, a few discrepancies should be addressed. Full-Text PDF

Long-term effect of combined vitamins e and c on coronary and peripheral endothelial function

ObjectivesWe tested whether long-term administration of antioxidant vitamins C and E improves coronary and brachial artery endothelial function in patients with coronary artery disease (CAD). BackgroundEndothelial function is a sensitive indicator of vascular health. Oxidant stress and oxidized low-density lipoprotein (LDL) impair endothelial function by reducing nitric oxide bioavailability in the artery wall. MethodsWe randomly assigned 30 subjects with CAD to combined vitamin E (800 IU per day) and C (1,000 mg per day) or to placebos in a double-blind trial. Coronary artery endothelial function was measured as the change in coronary artery diameter to acetylcholine infusions (n = 18 patients), and brachial artery endothelial function was assessed by flow-mediated dilation (n = 25 patients) at baseline and six months. Plasma markers of oxidant stress (oxidized LDL and autoantibodies) were also measured. ResultsPlasma alpha-tocopherol (p < 0.001) and ascorbic acid (p < 0.02) increased with active therapy. Compared to placebo, there was no improvement in coronary and brachial endothelial vasomotor function over six months. Although vitamins C and E tended to reduce F2-isoprostanes (p = 0.065), they failed to alter oxidized LDL or autoantibodies to oxidized LDL. ConclusionsLong-term oral vitamins C and E do not improve key mechanisms in the biology of atherosclerosis or endothelial dysfunction, or reduce LDL oxidation in vivo.

Coronary endothelial dysfunction is not rapidly reversible with ascorbic acid

In humans with cardiovascular risk factors, increased vascular production of superoxide anion may contribute to endothelial dysfunction by its reacting with nitric oxide and reducing its biological activity. High concentrations of ascorbic acid scavenge superoxide anion and restore normal endothelium-dependent vasodilation in humans with cardiovascular risk factors. To investigate the contribution of increased superoxide anion to endothelial dysfunction in atherosclerotic coronary arteries, we examined the effect of sequential infusions of ascorbic acid (final concentration 0.1, 1.0, and 10 mmol/L) or placebo on coronary endothelial function in 26 subjects referred for cardiac catheterization to evaluate coronary artery disease. Coronary vasomotor function was evaluated using intracoronary agonist infusion, quantitative angiography, and intracoronary Doppler measurements. At baseline, endothelium-dependent vasodilation of epicardial arteries and coronary microvessels was impaired to an equivalent extent in the ascorbic acid and placebo groups. Sequential ascorbic acid infusions had no effect on the acetylcholine-induced change in coronary artery diameter (−11±8, −12±10, and −9±9%) compared with the effect of placebo (−14±13, −16±10, and −13±9%) infusions ( p=0.98). Similarly, the changes in coronary blood flow during acetylcholine infusions were equivalent during ascorbic acid (51±44, 67±66, and 62±52%) and placebo (61±104, 55±93, and 50±69%) infusions ( p=0.63). Ascorbic acid also had no effect on the dilator response to intracoronary nitroglycerin ( p=0.19). These data argue against an important role for superoxide-mediated “inactivation” of nitric oxide or another rapidly reversible form of oxidative stress as a mechanism of coronary endothelial dysfunction in patients with coronary atherosclerosis.