Circ Res.2003;93:e98-e103 R2 이홍주

HMG-CoA reductase inhibitors (statins) - beneficial therapeutic effects in patients at risk for cardiovascular events - Long-term treatment → ↓ cardiovascular death, MI, stroke - in patients with and without hypercholesterolemia - potentially more rapid effects than seen in the large lipid-lowering trials

Several studies - effects of statins within months on endothelial function in hypercholesterol N Engl J Med. 1995;332:488–493 N Engl J Med. 1995;332:481–487 - treatment was initiated within 1 to 7 days after the ACS onset → outcomes were measured after several months : benefit from statins Am J Cardiol. 2000;86:1293–1298 JAMA. 2001;285:1711–1718 statin therapy per se? or relatively early initiation of therapy? whether statins lead to acute benefits within days in these unstable patients? - statin effects on endothelial function of the forearm within 3 days to 1 month J Am Coll Cardiol. 2001;37:1351–1358 Circulation. 2001;104:376–379 whether statins exert beneficial effects on the coronary vasculature in patients that occur even earlier?

vascular endothelium : pathogenesis of atherosclerosis. → predicting adverse cardiac events and mortality in patients with and without manifested atherosclerosis Object potentially rapid effect of the HMG-CoA reductase inhibitor pravastatin within 24 hours on coronary endothelial function and coronary blood flow reserve in patients presenting with stable angina pectoris.

M Acethylcholine

27, middle-aged, white patients coronary angiography due to stable angina pectoris exclusion criteria treatment with statins LVEF < 55% BP > 150/90 mm Hg ACS 3VD or left main disease revascularization procedures within the last 8 weeks significant valvular heart disease any liver disease renal insufficiency (Cr > 2.0 mg/dL) severe disease at present or in the past history of drug or alcohol abuse, or gravidity Measurements : before and 24 hours after treatment

Prospective double-blind : placebo or pravastatin 40 mg once placebo-controlled Randomized monocenter study

≥ 1 coronary vessel without limiting stenosis (luminal diameter reduction ≤ 50%) fasting overnight IU heparin and 500 mg ASA IV routine diagnostic coronary angiography coronary luminal diameter : quantitative angiography(mm) blood flow velocity : Doppler velocimetry(mL/min) average peak velocity X cross-sectional area(πr 2 ) X 0.5 coronary blood flow reserve = average peak velocity after adenosine average peak velocity at baseline Measurements : LAD - 21 patients LCX - 4 patients RCA - 2 patients

15-minute equilibration period resting measurements acetylcholine infusion : 0.01mol/L → coronary angiography 0.1mol/L → coronary angiography 1mol/L → coronary angiography interval with saline infusion adenosine infusion : 15g/min → Doppler velocimetry → coronary angiography (1 mol/L estimated final intracoronary conc.) interval with saline infusion nitroglycerin infusion : 200g/min → coronary angiography (15 mol/L estimated final intracoronary conc.)

Drug administration : through the inner lumen of the over-the wire catheter with an infusion pump at a flow rate of 1 mL/min over 3 minutes Nitroglycerin 15 mol/L 1 mol/L

non-ionic contrast medium iopromide Biplane cineangiograms automated edge-detection software system mean luminal diameter of the target vessel - at a segment proximal to the infusion catheter(control segment) - at the tip of the Doppler wire before and after nitroglycerin infusion before and after adenosine - in 3 subsequent vessel segments distal to the Doppler wire before and after administration of each successive dose of acetylcholine

compared before and after treatment Mean+SE : continuous data two-tailed Student’s t test or by ANOVA followed by post-hoc comparisons using the Newman-Keuls procedure : continuous variables chi-squared test : Categorical variables P < 0.05 : statistical significance SPSS 10.0 software package (SPSS)

40mg/d 138+9mg/dL TABLE 1. Patient Characteristics and Baseline Data

TABLE 2. Changes in Serum Concentrations, HR, and BP Levels 24 Hours After Treatment With Pravastatin (40 mg/d) or Placebo (After 24hrs)

Fig 1. Changes in coronary luminal diameter in response to increasing doses of acetylcholine before and 24 hours after treatment with pravastatin or placebo. P=0.58 P=0.69 P=0.85 P=0.04 P=0.03 P=0.33 M Acethylcholine

TABLE 3. Changes in Coronary Vessel Luminal Diameter and CBF Before and 24 Hours After Treatment With Pravastatin (40 mg/d) or Placebo P=0.81P=0.64

TABLE 3. Changes in Coronary Vessel Luminal Diameter and CBF Before and 24 Hours After Treatment With Pravastatin (40 mg/d) or Placebo P=0.76 P=0.55 P=0.91 P=0.70

Statin treatment improves endothelium-dependent coronary vasomotion within 24 hours in the absence of significant cholesterol reduction