Italy called Limone sul Garda live approximately 40 carriers with a naturally occurring variant of apolipoprotein A-I known as ApoA-I Milano. Individuals with ApoA-I Milano are characterized by very low levels of highdensity lipoprotein cholesterol (HDL-C) (10-30 mg/dL [0.25-0.78 mmol/L]), apparent longevity, 1 and much less atherosclerosis than expected for their HDL-C levels. 2 The ApoA-I Milano protein differs from native ApoA-I in that cysteine is substituted at position 173 for arginine allowing disulfide-linked dimer formation. Recombinant ApoA-I Milano has been formulated in a complex with a naturally occurring phospho-lipid to mimic the properties of nascent HDL (ETC-216, Esperion Therapeutics, Ann Arbor, Mich). Studies in mice and rabbits with experimental ath-Author Affiliations and Financial Disclosures are listed at the end of this article.
Background-Coronary vascular dysfunction has been linked to atherosclerosis and adverse cardiovascular outcomes in men, but these relationships have not been firmly established in women. Methods and Results-As part of the Women's Ischemia Syndrome Evaluation (WISE) sponsored by the National Heart, Lung, and Blood Institute, 163 women referred for clinically indicated coronary angiography underwent coronary reactivity assessment with quantitative coronary angiography and intracoronary Doppler flow before and after intracoronary administration of acetylcholine, adenosine, and nitroglycerin and were then followed up for clinical outcomes. History of hypertension was present in 61%, dyslipidemia in 54%, diabetes in 26%, and current tobacco use in 21% of women enrolled. Seventy-five percent had no or only mild epicardial coronary artery disease (CAD). Over a median follow-up of 48 months, events occurred in 58 women. On bivariate analysis, women with an event had significantly less change in coronary cross-sectional area (⌬CSA) in response to acetylcholine (Pϭ0.0006) and nitroglycerin (Pϭ0.04). In addition, women with abnormal coronary dilator response to acetylcholine had less time free from cardiovascular events (Pϭ0.004). In multivariable analysis, after controlling for age, hypertension, diabetes, dyslipidemia, tobacco use, and CAD severity, %⌬CSA with acetylcholine (Pϭ0.001) independently predicted events. When the outcome was restricted to only death, myocardial infarction, congestive heart failure, and stroke, %⌬CSA with acetylcholine remained a significant predictor (Pϭ0.006).
Conclusions-In
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