Best, Patricia J.M.

Background: In women with low to intermediate risk of coronary artery disease (CAD), prognostic detection strategies have been controversial. We present the follow-up data of the SMART trial in peri/postmenopausal women at low to intermediate risk of CAD. Objectives: To determine the value of contrast stress echocardiography (CSE), stress electrocardiogram (sECG), and serum biomarkers for prediction of cardiovascular events (CE) in peri/postmenopausal women at low to intermediate risk of CAD. Materials and Methods: From January 2004 to August 2007, 400 peri/postmenopausal women were prospectively enrolled. All women had detailed risk factor assessment, and underwent simultaneous CSE (Definity ® , Lantheus Medical Imaging) and sECG. Laboratories included brain natriuretic peptide (BNP), atrial natriuretic peptide, endothelin, and high sensitivity C-reactive protein. Wall motion score index was based on a 16-segment model. Abnormal CSE was defined as new or worsening wall motion abnormality at stress, while abnormal sECG was ≥1 mm horizontal/downsloping ST segment depression/elevation (80 mseconds duration). Self-reported outcome data were collected from a mailed Women's Heart Clinic Questionnaire. CE outcomes included all-cause mortality, nonfatal myocardial infarction (MI), heart failure, chest pain hospitalization or development of typical angina (CP), and revascularization (REVASC). Adjusted Cox proportional hazard ratios (HR; 95% confidence intervals) were reported. Results: A total of 366 women (54.4 ± 5.5 years, Framingham risk 6.5% ± 4.4%) completed simultaneous CSE and sECG. Forty-two (11.5%) had abnormal CSE, while sECG was abnormal in 22 (6%) women. Follow-up (4.4 ± 1.2 years) was available in 315/366 (86%) women (78% exercise-CSE, 22% dobutamine-CSE). In those who completed follow-up, CSE was abnormal in 33 women (10.5%) and sECG was abnormal in 21 (6.7%). In 33 women with abnormal CSE, sECG was abnormal in 7 (21.2%) and normal in 26 (79%), p = 0.0004. CE occurred in 27 (8.6%) women: 8 all-cause mortality, 2 nonfatal MI, 13 CP, and 4 REVASC. CE occurred in 21% versus 7% of women with abnormal versus normal CSE, p = 0.014 and 38% versus 6% of women with abnormal versus normal sECG, p < 0.0001. Rest BNP was higher in women with CE versus those without ( p = 0.018). Abnormal sECG and abnormal CSE were associated with CE, while only abnormal sECG was an independent predictor of CE (adjusted HR 10.3 [1.9–61.4], p = 0.007). Of the laboratory results, only BNP was associated with CE (adjusted HR 2.9 [1.1–7.3], p = 0.028). Conclusions: sECG and rest BNP were independent predictors of subsequent CE within 5 years in peri/postmenopausal women at low to intermediate risk of CAD.

Background: The coronary computed tomography angiography features of acute spontaneous coronary artery dissection, an important cause of acute coronary syndrome in young women, have not been assessed. Methods: The “Virtual” Multicenter Mayo Clinic Spontaneous Coronary Artery Dissection Registry was established in 2010 and includes retrospective and prospective patient data. Retrospective assessment of acute coronary computed tomography angiography images was performed for 14 patients (16 vessels) who had images performed within two days of invasive coronary angiography diagnosis of acute spontaneous coronary artery dissection. Results: Four pertinent diagnostic coronary features of acute spontaneous coronary artery dissection were observed in order of prevalence: 1) abrupt luminal stenosis (64%); 2) intramural hematoma (50%); 3) tapered luminal stenosis (36%); and 4) dissection (14%). Additional findings include epicardial fat stranding (42%), coronary tortuosity (29%), and coronary bridge (14%). Fifty percent of patients had myocardial hypoperfusion in the myocardial distribution of the dissected coronary artery. Conclusions: We define key coronary computed tomography angiography features of acute spontaneous coronary artery dissection, the most common of which are abrupt luminal stenosis and intramural hematoma. Importantly, intramural hematoma appears similar to noncalcified atherosclerotic plaque, emphasizing the importance of invasive coronary angiography for acute diagnosis of spontaneous coronary artery dissection until the sensitivity and specificity of coronary computed tomography angiography is better understood.

In experimental hypercholesterolemia, endothelium-dependent relaxations decrease, as does endothelial immunoreactivity for nitric oxide (NO) synthase (NOS; eNOS) in coronary arteries. Systemic levels of NO also decrease with concomitant elevations in systemic circulating levels of endothelin (ET)-1. Chronic treatment of hypercholesterolemic pigs with ET-receptor antagonists increases circulating NO and improves endothelium-dependent relaxations. Mechanisms causing these increases are not known. Therefore, experiments were designed to test the hypothesis that chronic administration of ET-receptor antagonists to hypercholesterolemic pigs increases NO production through increases in NOS activity. Female juvenile pigs were fed a 2% cholesterol atherogenic diet and were randomly allocated to receive no treatment (controls), a selective ET A -receptor antagonist (ABT-624), or a combined ET A + ET B -receptor antagonist (RO-48-5695) daily for 12 wk. After 12 wk, endothelial cells from thoracic aorta were prepared for measurement of eNOS mRNA or eNOS activity. Total cholesterol, low-density-lipoprotein cholesterol, and concentrations of ET-1 were significantly higher in all three groups at 12 wk compared with baseline levels. Circulating plasma-oxidized products of NO (NOx) increased with ET-receptor blockade. NOS mRNA was similar among groups. Total and Ca-dependent NOS activity was significantly higher in aortic endothelial cells from the ET A + ET B -treated pigs compared with those treated with ET A antagonist alone. These results suggest that changes in systemic NOx after chronic inhibition of ET A + ET B receptors in hypercholesterolemia may result from posttranscriptional changes in NOS.

Objectives Percutaneous coronary intervention (PCI) for acute coronary syndromes frequently fails to restore myocardial perfusion despite establishing epicardial vessel patency. Endothelin-1 (ET-1) is a potent vasoconstrictor, and its expression is increased in atherosclerosis and after PCI. In this study, we aim to define the role of endothelin in regulating coronary microvascular blood flow and myocardial perfusion following PCI in patients with non-ST elevation acute coronary syndromes (NSTACS), by assessing whether adjunctive therapy with a selective endothelin A (ETA) receptor antagonist acutely improves postprocedural coronary microvascular blood flow. Methods In a randomised, double-blinded, placebo-controlled trial, 23 NSTACS patients were enrolled to receive an intracoronary infusion of placebo (n=11) or BQ-123 (n=12) immediately before PCI. Post-PCI coronary microvascular blood flow and myocardial perfusion were assessed by measuring Doppler-derived average peak velocity (APV), and cardiac biomarker levels were quantified. Results Compared with the placebo group, APV was significantly higher in the drug group immediately after PCI (30 (20, 37) vs 19 (9, 26) cm/s; p=0.03). Hyperaemic APV, measured post-adenosine administration, was higher in the BQ-123 group, but the difference did not achieve statistical significance (56 (48, 72) vs 46 (34, 64) cm/s; p=0.090). Maximum coronary flow reserve postprocedure was not different between the two groups (2.1 (1.6, 2.3) vs 2.5 (1.8, 3.0)). Per cent change in creatine kinase isoenzyme MB from the time of PCI to 8 and 16 hours post-PCI was significantly lower in the drug group compared with the placebo group (−17 (−26, −10) vs 26 (−15, 134); p=0.02 and −17 (−38, 14) vs 107 (2, 446); p=0.007, respectively). Conclusions Endothelin is a mediator of microvascular dysfunction during PCI in NSTACS, and adjunctive selective ETA antagonist may augment myocardial perfusion during PCI. Trial registration number NCT00586820; Results.

Background Endothelial dysfunction is an early stage of atherosclerosis. Single‐nucleotide polymorphisms ( SNP s) have been associated with vascular dysfunction, cardiac events, and coronary artery remodeling. We aimed to detect SNP s associated with endothelial dysfunction and determine whether these associations are sex specific. Methods and Results Six hundred forty‐three subjects without significant obstructive coronary artery disease underwent invasive coronary endothelial function assessment. We collected data from 1536 SNP s 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. SNP s significantly associated with coronary epicardial endothelial dysfunction were ADORA 1 , KCNQ 1 , and DNAJC 4 in the whole cohort, LPA , MYBPH , ADORA 3 , and PON 1 in women and KIF 6 and NFKB 1 in men ( P <0.01). Conclusions We have identified several significant SNP s 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.

Introduction Apical ballooning syndrome (ABS) is typically associated with an antecedent stressful situation. Affected patients have been reported to have higher frequencies of premorbid affective disorders. We hypothesised that patients with ABS would have elevated levels of neuroticism (tendency to experience negative affect) and greater vulnerability to stress. Methods In this cross-sectional study, all active participants in the Mayo Clinic ABS prospective follow-up registry were invited to complete the third edition of the NEO Personality Inventory (NEO-PI-3). The NEO-PI-3 is the universally accepted measure of the ‘Five-Factor Model’ of personality. Inventory responses were scored using the NEO-PI-3 computer program and the data were compared with US normative sample used in standardisation of the inventory. Significance was set at 0.0014 to account for multiple comparisons. Results Of 106 registry participants approached, 53 completed the inventory. There was no difference in age, gender, time from ABS diagnosis, type of antecedent stressor (emotional, physical or none) or severity of initial illness between the responders and non-responders. Responders had mean Neuroticism T-scores of 48.0±10.6 (95% CI 45.1 to 50.9); p=0.18, when compared with the normal mean of 50. There was also no significant difference in the facet scale of Vulnerability: 46.9±8.4 (44.6 to 49.2), p=0.038, at α=0.0014. Conclusions Contrary to our hypothesis, patients with ABS do not manifest higher levels of neuroticism and do not have greater vulnerability to stress than the general population. These findings have implications for the clinicians’ perception of, and approach to, patients with ABS.

Hypercholesterolemia (HC) is characterized by increased circulating 8- epi-prostaglandin-F2α(isoprostane), a vasoconstrictor, marker, and mediator of increased oxidative stress, whose vascular effects might be augmented in HC. Anesthetized pigs were studied in vivo with electron beam computed tomography after a 12-wk normal ( n = 8) or HC ( n = 8) diet. Mean arterial pressure (MAP), single-kidney perfusion, and glomerular filtration rate (GFR) were quantified before and during unilateral intrarenal infusions of U46619 (10 ng · kg−1· min−1) or isoprostane (1 μg · kg−1· min−1). Basal renal perfusion and function were similar, and isoprostane infusion elevated its systemic levels similarly in normal and HC (333 ± 89 vs. 366 ± 48 pg/ml, respectively, P < 0.01 vs. baseline). Both drugs markedly and comparably decreased cortical perfusion and GFR in both groups, whereas medullary perfusion decreased significantly only in HC. Moreover, MAP increased significantly only in HC (+9 ± 3 and +11 ± 3 mmHg, respectively, P≤ 0.05). Hence, in HC, renal functional responses to high-dose isoprostane are largely similar to normal, but the systemic circulation exhibits augmented sensitivity to pathophysiological levels of isoprostane and U46619 , which may potentially play a role in development of hypertension and vascular injury associated with increased oxidative stress.