Beneficial Effects of Cholesterol-Lowering Therapy on the Coronary Endothelium in Patients with Coronary Artery Disease
Charles B. Treasure, M.D., J. Larry Klein, M.D., William S. Weintraub, M.D., J. David Talley, M.D., Michael E. Stillabower, M.D., Andrzej S. Kosinski, Ph.D., Jian Zhang, M.S., Stephen J. Boccuzzi, Ph.D., John C. Cedarholm, M.D., and R. Wayne Alexander, M.D., Ph.D.
Background Impaired endothelium-mediated relaxation contributesto vasospasm and myocardial ischemia in patients with coronaryartery disease. We hypothesized that cholesterol-lowering therapywith the 3-hydroxy-3-methylglutaryl–coenzyme A reductaseinhibitor lovastatin could improve endothelium-mediated responsesin patients with coronary atherosclerosis.
Methods In a randomized, double-blind, placebo-controlled trial,we studied coronary endothelial responses in 23 patients randomlyassigned to either lovastatin (40 mg twice daily; 11 patients)or placebo (12 patients) plus a lipid-lowering diet (AmericanHeart Association Step 1 diet). Patients were studied 12 daysafter randomization and again at 51/2 months. These patientshad total cholesterol levels ranging from 160 to 300 mg perdeciliter (4.1 to 7.8 mmol per liter) and were undergoing coronaryangioplasty. At the initial and follow-up studies, patientsreceived serial intracoronary infusions (in a coronary arterynot undergoing angioplasty) of acetylcholine to assess endothelium-mediatedvasodilatation. The responses of the coronary vessels were analyzedwith quantitative angiography.
Results The patients in the placebo and lovastatin groups hadsimilar responses to acetylcholine at a mean of 12 days of therapy(expressed as the percentage of change in diameter in responseto acetylcholine doses of 10-9 M, 10-8 M, 10-7 M, and 10-6 M).In the placebo group, the respective mean (±SE) changeswere 1±2, 0±2, -2±4, and -19±4 percent;in the lovastatin group, they were -2±2, -4±4,-12±5, and -16±7 percent (P =0.32). (coronary-arteryconstriction is reflected by negative numbers.) The responsesto acetylcholine in the placebo group after a mean of 5.5 monthsof therapy were -3±3, -1±2, -8±4, and -18±5percent, respectively; there was significant improvement inthe lovastatin group, which had responses of 3±3, 3±3,0±2, and 0±3 percent (P = 0.004).
Conclusions Cholesterol lowering with lovastatin significantlyimproved endothelium-mediated responses in the coronary arteriesof patients with atherosclerosis. Such improvement in the localregulation of coronary arterial tone could potentially relieveischemic symptoms and signal the stabilization of the atheroscleroticplaque.
Cholesterol-lowering therapy has been associated with a decreasedrisk of ischemic coronary events and with angiographically detectableregression of atherosclerosis.1,2,3,4,5 However, regressionof atherosclerosis as assessed by angiography has been slightas compared with clinical outcomes, which have been substantiallyimproved.3,4 This important effect on clinical outcomes maybe related to improved function of the coronary endothelium.
The endothelium is intimately involved in the pathogenesis ofatherosclerosis.6 Oxidative modification of low-density lipoprotein(LDL) cholesterol by the endothelium is thought to be an importantstep in the initiation of atherosclerosis.7 Oxidized LDL cholesterolimpairs endothelium-mediated relaxation in isolated arterialsegments.8 Hypercholesterolemia and atherosclerosis impair endothelium-mediatedvasodilator responses in animal models9 and humans.10 This lossof endothelium-mediated vasodilatation is thought to be involvedin the pathogenesis of myocardial ischemia.11 In hypercholesterolemicanimal models, the return to a normal diet only partially restoresthe morphologic features of the vessel, but it reestablishesnormal endothelium-mediated relaxation.9
We hypothesized that aggressive lipid-lowering therapy couldimprove the function of coronary-artery endothelium in patientswith coronary atherosclerosis. We investigated this hypothesisin a multicenter, double-blind, placebo-controlled substudyof the Lovastatin Restenosis Trial.12
Methods
Population of Patients
This prospective, randomized, double-blind, placebo-controlledstudy evaluated the short-term (12-day) and longer-term (51/2-month)effects on coronary endothelial vasodilator function of a lipid-loweringdiet and treatment with lovastatin (Mevacor, Merck, Rahway,N.J.; 40 mg twice daily) or placebo. The responses to acetylcholine,an endothelium-dependent vasodilator, and to nitroglycerin,an endothelium-independent vasodilator, were assessed in 23of 404 patients who gave informed consent and were randomizedin the Lovastatin Restenosis Trial.12 Briefly, patients includedin the Lovastatin Restenosis Trial were 30 to 81 years old,had a clinical requirement for coronary angioplasty at a nonoccludedsite and a total serum cholesterol concentration ranging from160 to 300 mg per deciliter (4.1 to 7.8 mmol per liter), andhad not previously been treated with lipid-lowering medications.Patients with secondary hypercholesterolemia, hypertriglyceridemia,insulin-dependent diabetes mellitus, liver or renal disease,previous coronary angioplasty, coronary bypass surgery (withinthe past six months), or myocardial infarction (within the pastmonth) were excluded from the study.
Diagnostic coronary cineangiograms of patients in the LovastatinRestenosis Trial were reviewed to determine the patients' suitabilityfor this substudy. Patients with unstable angina, stenosis ofthe left main coronary artery, stenosis of >50 percent inat least two of the three major coronary arteries, proximaldiameter of the study vessel of less than 2 mm, a left ventricularejection fraction below 30 percent, or a combination of thesefeatures were excluded from the study. In every case, the vesselstudied was the branch of the left coronary artery not undergoingangioplasty. No patient had prior angioplasty, previous therapywith cholesterol-lowering medications, a recent myocardial infarction,or bypass surgery. No patient had insulin-dependent diabetesmellitus, hypertriglyceridemia, or valvular heart disease.
After the patients were determined to fulfill the above criteria,they gave informed consent for this study in accordance withthe guidelines established by the institutional review boardsof the participating centers. The patients were then randomlyassigned to receive dietary counseling (with the American HeartAssociation step 1 diet) and either lovastatin (40 mg orallytwice daily) or placebo. The following information was collectedfor all patients: age, sex, any history of cigarette smokingwithin the previous three months, any history of hypertension(previous diagnosis of hypertension), and any family historyof premature coronary atherosclerosis (myocardial infarctionin a first-degree relative before the age of 55 years). Serumlipid concentrations were evaluated with the patient fastingat randomization, at the time of angioplasty, and six monthsafter angioplasty.
Study Design
Treatment with vasoactive medications was discontinued 12 to24 hours before angioplasty. In the cardiac catheterizationlaboratory, immediately before coronary angioplasty, patientsunderwent the following procedure (previously described in detail13).After the administration of heparin, a 3-French coronary infusioncatheter (Cook, Bloomington, Ind.) was advanced through a guidingcatheter into a proximal segment of the coronary artery. Infusionsof acetylcholine chloride (Miochol, Iolab Pharmaceuticals, Claremont,Calif.) and nitroglycerin were administered through the infusioncatheter as previously described.13 Just before the end of eachinfusion, coronary arteriography was performed with non-ioniccontrast medium (Omnipaque, Sanofi–Winthrop, New York)and a power injector (Medrad, Pittsburgh). At the completionof the infusion, coronary angioplasty was performed, with subsequentclinical follow-up as outlined in the Lovastatin RestenosisTrial.12 An identical infusion was performed at the time ofthe 51/2-month follow-up catheterization, with the initial angiographicviews and the position of the infusion catheter reproduced exactly.
Quantitative Coronary Angiography
All films were analyzed at a central angiographic laboratory(Emory University) by investigators unaware of the study medicationand film sequence. Up to five segments of the study vessel wereselected for quantitative analysis on the basis of the availabilityof clearly definable segments. The study-vessel segments werechosen without the investigator's knowledge of the study medication,the film sequence, or the arterial responses to drug infusions.Available angiographic landmarks were used to ensure the measurementof identical segments at the initial and follow-up studies andwith all infusions. The guiding catheter was measured beforethe initial control angiogram and before the final nitroglycerinangiogram to ensure that there was no notable change in tubeheight, table height, or angiographic view during the studyand to allow calibration of the vessel dimensions.
Four end-diastolic cine frames from each infusion were chosenand marked for analysis by an experienced angiographer who wasunaware of the study medication and film sequence. Each framewas optically magnified two to three times and digitized ateight bits per pixel (with a 256-level gray scale). The vesseldimensions were analyzed with a previously validated automatededge-detection system (CAAS II software, PIE Medical, Maastricht,the Netherlands).14 Measurements from four frames were averagedto calculate a mean value for the diameter of each segment inthe study vessel.
For each patient, the arterial segment with the most constrictionin response to acetylcholine in the initial study was studiedat follow-up, and the two values were compared; in addition,the responses in all study-vessel segments were compared.
Statistical Analysis
The chi-square test or Fisher's exact test was used to determinethe level of significance of differences between treatment groupswith respect to categorical variables.15 Data are presentedas means ±SE. A t-test or Wilcoxon two-sample test wasused to determine the significance of differences between treatmentgroups with respect to continuous variables.15
Dose responses to acetylcholine were compared between treatmentgroups with the uniform-correlation model16 (intraclass correlationmatrix17), which accounts for the correlations in responsesto serial doses (in the analyses of the most constricting segments)and for both doses and segments (in the analyses of all segments)in individual patients. The effect of lovastatin was derivedby comparing a model containing the dose only with a model containingthe dose, the treatment, and the interaction of dose and treatment.The analysis was performed with the Proc Mixed program of SASsoftware.18
Probability values less than or equal to 0.05 were consideredto indicate statistical significance (by the two-tailed alternativehypothesis).
Results
The patients in the lovastatin and placebo groups underwentcoronary angioplasty 12±2 days after randomization, and23 patients (11 assigned to lovastatin and 12 assigned to placebo)were studied successfully. Follow-up catheterization was performed5.5±0.3 months after randomization in 19 of these patients.The four patients who were not studied at follow-up includedone patient assigned to placebo who had vessel closure within24 hours of angioplasty, one patient assigned to placebo whohad unstable angina requiring vasodilator therapy during follow-upcatheterization, one patient assigned to lovastatin who receivedvasodilator therapy immediately before the follow-up study,and one patient assigned to lovastatin whose infusion catheterwas mistakenly placed in a side branch at follow-up.
Clinical Data
The base-line clinical, hemodynamic, and angiographic characteristicsof the patients in the lovastatin and placebo groups were similar(Table 1). Lipid levels were similar in the patients in thetwo groups at the time of randomization. At 12 days, serum levelsof total and LDL cholesterol had decreased significantly inthe patients receiving lovastatin and remained significantlydiminished at 51/2 months. In the patients receiving placebo,lipid levels did not change significantly over the 51/2 monthsof the study. The data on lipid levels are shown in Table 1.
Table 1. Demographic, Clinical, and Laboratory Characteristics of the Study Patients.
Epicardial Coronary-Artery Responses to Acetylcholine
Responses to acetylcholine were studied in the left anteriordescending coronary artery in 5 patients (2 in the lovastatingroup and 3 in the placebo group) and in the circumflex coronaryartery in 18 patients (9 in each group). No study vessel hada stenosis obstructing more than 50 percent of the lumen.
Short-term lipid-lowering therapy did not significantly alterthe coronary-artery endothelial responses to acetylcholine (Table 2).In the analysis of mean changes in all segments in the placebogroup at 12 days (an analysis in which negative numbers indicateconstriction), the diameter of the epicardial coronary arterychanged by 2±1 percent, 1±1 percent, 0±2percent, and -7±2 percent in response to serial infusionsof acetylcholine (at concentrations of 10-9 M, 10-8 M, 10-7M, and 10-6 M, respectively). In the lovastatin group, the responseof the epicardial coronary artery was similar at 12 days (changes,0±1 percent, -2±1 percent, -5±2 percent,and -6±3 percent in response to the respective concentrationsof acetylcholine; P = 0.53). In the analysis of the most constrictingsegment in the placebo group, the most responsive epicardialcoronary-artery segment changed by 1±2 percent, 0±2percent, -2±4 percent, and -19±4 percent in responseto serial infusions of acetylcholine at the respective concentrations.In the lovastatin group, the most responsive epicardial coronary-arterysegment responded similarly to the respective concentrationsof acetylcholine (-2±2 percent, -4±4 percent,-12±5 percent, and -16±7 percent; P = 0.32). Sincethe predicted and observed means were similar, the uniform-correlationmodel provided a good fit for the observed data.
Table 2. Epicardial Coronary-Artery Responses to Acetylcholine, Expressed as the Percentage of Change in Luminal Diameter.
Longer-term lipid-lowering therapy significantly improved epicardialcoronary-artery responses to acetylcholine (Table 2 and Figure 1,2, 3, and 4). In the analysis of all segments in the placebogroup at 51/2 months, the epicardial coronary artery continuedto constrict in response to serial infusions of acetylcholineat concentrations of 10-9 M, 10-8 M, 10-7 M, and 10-6 M (changesin diameter, -1±1 percent, 1±1 percent, -2±2percent, and -9±3 percent, respectively). In the lovastatingroup, the response to acetylcholine at 51/2 months was significantlyimproved (3±1 percent, 2±2 percent, 0±2percent, and 2±3 percent) in response to the respectiveconcentrations of acetylcholine (P = 0.013) (Figure 1). In theanalysis of the most constricting segment in the placebo group,the most responsive epicardial coronary-artery segment (as determinedin the initial study) continued to constrict (by -3±3percent, -1±2 percent, -8±4 percent, and -18±5percent) in response to serial infusions of acetylcholine atthe respective concentrations. In the lovastatin group at 51/2months, the response to the respective concentrations of acetylcholinewas significantly improved (changes in diameter, 3±3percent, 3±3 percent, 0±2 percent, and 0±3percent; P = 0.004) (Figure 2). Again, because the predictedand observed means were similar, the uniform-correlation modelprovided a good fit for the observed data.
Figure 1. Mean (±SE) Responses in All Segments of the Epicardial Coronary Artery to Serial Infusions of Acetylcholine in the Two Groups at the Follow-up (51/2 Months) Study.
Responses are expressed as the percentage of change in diameter from the base-line value in all segments. The response to acetylcholine was significantly better in the lovastatin group than in the placebo group (P = 0.013). Negative numbers indicatevasoconstriction.
Figure 2. Mean (±SE) Responses in the Most Constricting Segment of the Epicardial Coronary Artery to Serial Infusions of Acetylcholine in the Two Groups at the Follow-up (51/2 Months) Study.
Responses are expressed as the percentage of change in diameter from the base-line value in the most constricting segment. The response to acetylcholine was significantly better in the lovastatin group than in the placebo group (P = 0.004). Negative numbers indicate vasoconstriction.
Representative coronary angiograms showing endothelial responsesin patients in the two groups are shown in Figure 3. The patientin the placebo group had similar and substantial vasoconstrictionin response to acetylcholine in both studies (Figure 3, left-handpanels), whereas the patient in the lovastatin group had substantialvasoconstriction in the initial study, with dramatic improvementat follow-up in the response to acetylcholine (a mild vasodilatorresponse) (Figure 3, right-hand panels). In the patients assignedto placebo, the mean change in response to the peak dose ofacetylcholine was +1 percent (from -19 percent constrictionin the initial study to -18 percent at follow-up). In the patientsassigned to lovastatin, the mean change in response to the peakdose of acetylcholine was +16 percent (from -16 percent constrictionin the initial study to 0 percent at follow-up) (Figure 4).
Figure 3. Representative Coronary Angiograms of Patients in the Placebo and Lovastatin Groups.
The left-hand panels show a segment of the circumflex marginal coronary artery at the initial (12 days) and follow-up (51/2 months) studies in a patient assigned to placebo. There is substantial and similar vasoconstriction in response to acetylcholine in both studies.
The right-hand panels show a segment of the circumflex coronary artery at the initial (12 days) and follow-up (51/2 months) studies in a patient assigned to lovastatin. There is substantial vasoconstriction in response to the peak infusion of acetylcholine in the initial study, with marked improvement (a mild vasodilator response) in the follow-up study.
Figure 4. Individual Responses to the Peak Dose of Acetylcholine among Those in the Placebo Group (10 Patients) and the Lovastatin Group (9 Patients) Who Were Studied both Initially and at Follow-up.
The most constricting segment in each patient was studied. Solid lines represent responses in individual patients, and dashed lines indicate the difference between the mean responses in the initial study (at 12 days) and the follow-up study (at 51/2 months). Negative numbers indicate vasoconstriction.
Epicardial Coronary-Artery Responses to Nitroglycerin
The patients in the two study groups had similar epicardialcoronary-artery responses to nitroglycerin (increase in diameterin the initial study, 13±3 percent in the placebo groupvs. 13±2 percent in the lovastatin group; at follow-up,16±4 percent in the placebo group vs. 16±2 percentin the lovastatin group; P not significant for any comparison).
Correlation between Lipid Levels and Endothelial Response
There was a significant inverse relation between the LDL cholesterollevel and the arterial response to acetylcholine at follow-upin the most constricting segment (r = -0.46, P<0.05). Decreasedlevels of LDL cholesterol at follow-up were associated withimproved responses to acetylcholine. No other significant relationsbetween changes in lipid levels and arterial responses to acetylcholinewere found.
Discussion
We have demonstrated that six months of lipid-lowering therapywith lovastatin can improve coronary endothelium-mediated vasodilatorresponses in patients with coronary atherosclerosis. AlthoughLDL cholesterol levels are reduced in a matter of days to weeks,improvement in the endothelial response lags behind, suggestingthat the reversal of coronary endothelial dysfunction requiresprolonged therapy. In this study, lipid-lowering therapy improvedbut did not completely normalize the endothelial response toacetylcholine, suggesting that the restoration of normal endothelium-mediatedvasodilatation may require even more extended therapy, as hasbeen noted in studies in animals.9 We have shown that lipid-loweringtherapy has an important beneficial effect on the regulationof coronary arterial tone in patients with symptomatic coronaryatherosclerosis.
The degradation of endothelial nitric oxide appears to be increasedin experimental models of atherosclerosis, leading to decreasedvasodilator activity.19,20 In animal models of atherosclerosis,scavenging of superoxide anions can restore endothelium-mediatedrelaxation to nearly normal.21 This observation is consistentwith the theory that byproducts of the oxidative environment(oxygen-derived free radicals) destroy nitric oxide, accountingfor the diminished endothelium-dependent vasodilatation andincreased vasoconstriction in atherosclerosis.
This theory is attractive in the context of the current understandingof atherogenesis. In atherosclerosis, the reduction–oxidationstate within the vessel wall is altered in a way that favorsoxidation. This oxidative state is essential for the propagationof the atherosclerotic process. Therefore, any byproducts ofoxidative metabolism may well be important contributors to themolecular pathobiology of atherosclerosis. A reduction in serumcholesterol is associated with the normalization of oxygen-derivedfree radical production22 and endothelium-mediated vasodilatationwithout normalization of the morphologic characteristics ofthe vessel.9 A similar mechanism could explain the observedimprovement in endothelium-mediated responses in our patients.
Previous trials of cholesterol-lowering therapy have demonstratedmoderate regression or lack of progression of coronary atherosclerosis2,3,4,5and in some cases substantial improvement in clinical outcome,3,4suggesting a beneficial effect of lipid lowering on vessel function.Leung et al.23 and Egashira et al.24 have demonstrated improvementin both epicardial23,24 and microvascular24 coronary endothelialresponses with lipid-lowering therapy. However, neither studywas randomized or placebo-controlled. The present trial showsthat lipid lowering has no effect in the short term but improvescoronary endothelial function in the longer term in patientswith symptomatic atherosclerotic coronary artery disease.
There is no consensus as yet that lowering lipid levels in patientswith coronary atherosclerosis reduces the rates of cardiac events.2,3,4,5It is clear, however, from previous trials of cholesterol loweringthat the effects on angiographically defined coronary diseaseare slight. If large clinical trials now under way25 confirmthat the treatment of elevated cholesterol levels in coronaryartery disease decreases the rates of events, the implicationwill be that in determining clinical outcome, changes in thefunctional status of the arterial wall may be more importantthan improvement in the degree of stenosis.
Previously, lipid-lowering therapy was not considered part ofthe pharmacologic armamentarium for the relief of angina. Thisstudy demonstrates that aggressive lipid lowering can have amarked effect on the regulation of coronary arterial tone, favoringdiminished vasoconstriction, improved vasodilatation, or both.These effects do not occur immediately, but are observed severalmonths after therapy is instituted. Using positron-emissiontomography to assess myocardial perfusion, Gould et al.26 havesuggested that lipid lowering may have beneficial effects onvessel function as early as three months after the start oftherapy. More extended periods of lipid-lowering therapy couldresult in further movement of the endothelium-dependent responsetoward normal levels. The time course of functional improvementand the usefulness of lipid lowering as antianginal therapywill need further definition.
The improvement in endothelium-mediated relaxation after 51/2months of lipid-lowering therapy may serve as a marker for amore generalized improvement in endothelial function. The abilityof the endothelium to regulate vascular growth, thrombus formation,and the inflammatory activity of the vessel wall may also improvewith lipid lowering. If this is true, strategies designed toalter the course of atherosclerotic vascular disease may focuson the ability of the endothelium to regulate vessel tone asa surrogate marker for vascular health.
This study evaluated endothelial function in minimally obstructedcoronary arteries in patients with substantial atheroscleroticobstruction at other sites in the coronary arterial tree. Lipidlowering appears to improve endothelial function in these minimallyobstructed vessels. This study did not address the ability oflipid lowering to improve endothelial function in severely stenoticcoronary arteries.
Since the initial evaluation was conducted after 12 days ofstudy medication, no true base-line study was performed. Bycomparing an approximation of a true base-line study (the initialstudy in the lovastatin group) with the 51/2-month follow-upstudy in the lovastatin group, we demonstrated a significantimprovement in endothelial function. Without a true base-linestudy, we cannot precisely assess the degree of improvementexpected with lipid lowering. However, we have answered theprincipal question — whether abnormal coronary endothelialresponses improve with this therapy. We believe that the actualdegree of improvement in endothelial responses would only havebeen more dramatic had a true base-line study been performed.
This study has demonstrated that aggressive lipid lowering withlovastatin can significantly improve endothelial regulationof coronary arterial tone in patients with coronary atherosclerosis.Aggressive lipid lowering may become part of our armamentariumfor the treatment of ischemic coronary syndromes. In addition,clinical assessment of the regulation of endothelial tone maybecome a starting point for directing preventive approachesand an end point for the evaluation of therapeutic efficacyin coronary atherosclerosis. An ability to improve vascularfunction and stabilize atherosclerotic plaques, combined witha reliable, inexpensive means of detecting this effect, couldpotentially avert the need for costly surgical or catheter-basedtherapies in many patients.
Supported in part by a grant-in-aid (89120113) from the AmericanHeart Association, Georgia Chapter, by a grant (HL48667) fromthe National Institutes of Health, and by Merck Research Laboratories,Rahway, N.J.
We are indebted to the staff members of the cardiac catheterizationlaboratories of Grady Memorial Hospital, Emory University Hospital,the University of Louisville Affiliated Hospitals, the MedicalCenter of Delaware, and the Carolinas Medical Center for theirassistance with this study.
Source Information
From the Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta (C.B.T., J.L.K., W.S.W., J.Z., R.W.A.); the Division of Cardiology, Department of Medicine, University of Louisville School of Medicine, Louisville, Ky. (J.D.T.); the Division of Cardiology, Medical Center of Delaware, Newark (M.E.S.); the Division of Biostatistics, School of Public Health, Emory University, Atlanta (A.S.K.); Merck Research Laboratories, Rahway, N.J. (S.J.B.); and the Division of Cardiology, Sanger Clinic, Charlotte, N.C. (J.C.C.).
Address reprint requests to Dr. Treasure at P.O. Drawer LL, Emory University, Atlanta, GA 30322.
References
Lipid Research Clinics Program. The Lipid Research Clinics Primary Trial results. I. Reduction in incidence of coronary heart disease. JAMA 1984;251:351-364. [Free Full Text]
Blankenhorn DH, Azen SP, Kramsch DM, et al. Coronary angiographic changes with lovastatin therapy: the Monitored Atherosclerosis Regression Study (MARS). Ann Intern Med 1993;119:969-976. [Free Full Text]
Watts GF, Lewis B, Brunt JNH, et al. Effects on coronary artery disease of lipid-lowering diet, or diet plus cholestyramine, in the St. Thomas' Atherosclerosis Regression Study (STARS). Lancet 1992;339:563-569. [CrossRef][Medline]
Brown G, Albers JJ, Fisher LD, et al. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med 1990;323:1289-1298. [Abstract]
MAAS Investigators. Effect of simvastatin on coronary atheroma: the Multicenter Anti-Atheroma Study (MAAS). Lancet 1994;344:633-638. [Erratum, Lancet 1994;344:762.] [CrossRef][Medline]
Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond cholesterol: modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med 1989;320:915-924. [Medline]
Steinbrecher UP, Parthasarathy S, Leake DS, Witzum JL, Steinberg D. Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids. Proc Natl Acad Sci U S A 1984;81:3883-3887. [Free Full Text]
Simon BC, Cunningham LD, Cohen RA. Oxidized low density lipoproteins cause contraction and inhibit endothelium-dependent relaxation in the pig coronary artery. J Clin Invest 1990;86:75-79.
Harrison DG, Armstrong ML, Freiman PC, Heistad DD. Restoration of endothelium-dependent relaxation by dietary treatment of atherosclerosis. J Clin Invest 1987;80:1808-1811.
Vita JA, Treasure CB, Nabel EG, et al. Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease. Circulation 1990;81:491-497. [Free Full Text]
Osborne JA, Lento PH, Siegfried MR, Stahl GL, Fusman B, Lefer AM. Cardiovascular effects of acute hypercholesterolemia in rabbits: reversal with lovastatin treatment. J Clin Invest 1989;83:465-473.
Weintraub WS, Boccuzzi SJ, Brown CL III, et al. Background and methods for the lovastatin restenosis trial after percutaneous transluminal coronary angioplasty. Am J Cardiol 1992;70:293-299. [Medline]
Ludmer PL, Selwyn AP, Shook TL, et al. Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N Engl J Med 1986;315:1046-1051. [Abstract]
Reiber JHC, Serruys PW, Kooijman CJ, et al. Assessment of short-, medium-, and long-term variations in arterial dimensions from computer-assisted quantitation of coronary cineangiograms. Circulation 1985;71:280-288. [Free Full Text]
Fisher LD, van Belle G. Biostatistics: a methodology for the health sciences. New York: John Wiley, 1993.
Diggle PJ, Liang K-Y, Zeger SL. Analysis of longitudinal data. Vol. 13 of Oxford statistical science series. Oxford, England: Oxford University Press, 1994.
Gibson CM, Sandor T, Stone PH, Pasternak RC, Rosner B, Sacks FM. Quantitative angiographic and statistical methods to assess serial changes in coronary luminal diameter and implications for atherosclerosis regression trials. Am J Cardiol 1992;69:1286-1290. [CrossRef][Medline]
SAS Institute, Inc. SAS technical report P-229: SAS/STAT software: changes and enhancements. Release 6.07. Cary, N.C.: SAS Institute, 1992:287-368.
Minor RL Jr, Myers PR, Guerra R Jr, Bates JN, Harrison DG. Diet-induced atherosclerosis increases the release of nitrogen oxides from rabbit aorta. J Clin Invest 1990;86:2109-2116.
Ohara Y, Peterson TE, Harrison DG. Hypercholesterolemia increases endothelial superoxide anion production. J Clin Invest 1993;91:2546-2551.
Mugge A, Elwell JH, Peterson TE, Hofmeyer TG, Heistad DD, Harrison DG. Chronic treatment with polyethylene-glycolated superoxide dismutase partially restores endothelium-dependent vascular relaxations in cholesterol-fed rabbits. Circ Res 1991;69:1293-1300. [Free Full Text]
Ohara Y, Peterson TE, Sayegh HS, Harrison DG. Dietary treatment of hypercholesterolemia normalizes endothelial superoxide anion production. Circulation 1993;88:I-467.abstract
Leung WH, Lau CP, Wong CK. Beneficial effect of cholesterol-lowering therapy on coronary endothelium-dependent relaxation in hypercholesterolaemic patients. Lancet 1993;341:1496-1500. [CrossRef][Medline]
Egashira K, Hirooka Y, Kai H, et al. Reduction in serum cholesterol with pravastatin improves endothelium-dependent coronary vasomotion in patients with hypercholesterolemia. Circulation 1994;89:2519-2524. [Free Full Text]
Design and baseline results of the Scandinavian simvastatin survival study of patients with stable angina and/or previous myocardial infarction. Am J Cardiol 1993;71:393-400. [CrossRef][Medline]
Gould KL, Martucci JP, Goldberg DI, et al. Short-term cholesterol lowering decreases size and severity of perfusion abnormalities by positron emission tomography after dipyridamole in patients with coronary artery disease: a potential noninvasive marker of healing coronary endothelium. Circulation 1994;89:1530-1538. [Free Full Text]
Eldor, R., Raz, I.
(2009). American Diabetes Association Indications for Statins in Diabetes: Is there evidence?. Diabetes Care
32: S384-S391
[Full Text]
Prinz, V., Endres, M.
(2009). The Acute (Cerebro)Vascular Effects of Statins. Anesth. Analg.
109: 572-584
[Abstract][Full Text]
Rodriguez, C., Alcudia, J. F., Martinez-Gonzalez, J., Guadall, A., Raposo, B., Sanchez-Gomez, S., Badimon, L.
(2009). Statins normalize vascular lysyl oxidase down-regulation induced by proatherogenic risk factors. Cardiovasc Res
83: 595-603
[Abstract][Full Text]
Stern, S., Bayes de Luna, A.
(2009). Coronary Artery Spasm: A 2009 Update. Circulation
119: 2531-2534
[Full Text]
Lavallee, P. C., Labreuche, J., Gongora-Rivera, F., Jaramillo, A., Brenner, D., Klein, I. F, Touboul, P.-J., Vicaut, E., Amarenco, P., on behalf of the Lacunar-B.I.C.H.A.T. Investigator,
(2009). Placebo-Controlled Trial of High-Dose Atorvastatin in Patients With Severe Cerebral Small Vessel Disease. Stroke
40: 1721-1728
[Abstract][Full Text]
Eikelboom, J. W., Hankey, G. J., Thom, J., Bhatt, D. L., Steg, P. G., Montalescot, G., Johnston, S. C., Steinhubl, S. R., Mak, K.-H., Easton, J. D., Hamm, C., Hu, T., Fox, K. A.A., Topol, E. J., on behalf of the Clopidogrel for High Atherothromb,
(2008). Incomplete Inhibition of Thromboxane Biosynthesis by Acetylsalicylic Acid: Determinants and Effect on Cardiovascular Risk. Circulation
118: 1705-1712
[Abstract][Full Text]
Zoghbi, G. J., Dorfman, T. A., Iskandrian, A. E.
(2008). The Effects of Medications on Myocardial Perfusion. J Am Coll Cardiol
52: 401-416
[Abstract][Full Text]
Yasue, H., Mizuno, Y., Harada, E., Itoh, T., Nakagawa, H., Nakayama, M., Ogawa, H., Tayama, S., Honda, T., Hokimoto, S., Ohshima, S., Hokamura, Y., Kugiyama, K., Horie, M., Yoshimura, M., Harada, M., Uemura, S., Saito, Y., for the SCAST (Statin and Coronary Artery Spasm Tr,
(2008). Effects of a 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor, Fluvastatin, on Coronary Spasm After Withdrawal of Calcium-Channel Blockers. J Am Coll Cardiol
51: 1742-1748
[Abstract][Full Text]
Maas, R., Schwedhelm, E., Kahl, L., Li, H., Benndorf, R., Luneburg, N., Forstermann, U., Boger, R. H.
(2008). Simultaneous Assessment of Endothelial Function, Nitric Oxide Synthase Activity, Nitric Oxide-Mediated Signaling, and Oxidative Stress in Individuals with and without Hypercholesterolemia. Clin. Chem.
54: 292-300
[Abstract][Full Text]
Yagi, S., Aihara, K.-i., Ikeda, Y., Sumitomo, Y., Yoshida, S., Ise, T., Iwase, T., Ishikawa, K., Azuma, H., Akaike, M., Matsumoto, T.
(2008). Pitavastatin, an HMG-CoA Reductase Inhibitor, Exerts eNOS-Independent Protective Actions Against Angiotensin II Induced Cardiovascular Remodeling and Renal Insufficiency. Circ. Res.
102: 68-76
[Abstract][Full Text]
Kosmidou, I., Moore, J. P., Weber, M., Searles, C. D.
(2007). Statin Treatment and 3' Polyadenylation of eNOS mRNA. Arterioscler. Thromb. Vasc. Bio.
27: 2642-2649
[Abstract][Full Text]
Mills, N. L., Tornqvist, H., Gonzalez, M. C., Vink, E., Robinson, S. D., Soderberg, S., Boon, N. A., Donaldson, K., Sandstrom, T., Blomberg, A., Newby, D. E.
(2007). Ischemic and Thrombotic Effects of Dilute Diesel-Exhaust Inhalation in Men with Coronary Heart Disease. NEJM
357: 1075-1082
[Abstract][Full Text]
Zaca, V., Rastogi, S., Imai, M., Wang, M., Sharov, V. G., Jiang, A., Goldstein, S., Sabbah, H. N.
(2007). Chronic Monotherapy With Rosuvastatin Prevents Progressive Left Ventricular Dysfunction and Remodeling in Dogs With Heart Failure. J Am Coll Cardiol
50: 551-557
[Abstract][Full Text]
Gao, P., Chen, Z.-q., Bao, Y.-h., Jiao, L.-q., Ling, F.
(2007). Correlation Between Carotid Intraplaque Hemorrhage and Clinical Symptoms: Systematic Review of Observational Studies. Stroke
38: 2382-2390
[Abstract][Full Text]
Boger, G. I., Rudolph, T. K., Maas, R., Schwedhelm, E., Dumbadze, E., Bierend, A., Benndorf, R. A., Boger, R. H.
(2007). Asymmetric Dimethylarginine Determines the Improvement of Endothelium-Dependent Vasodilation by Simvastatin: Effect of Combination With Oral L-Arginine. J Am Coll Cardiol
49: 2274-2282
[Abstract][Full Text]
Le Manach, Y., Godet, G., Coriat, P., Martinon, C., Bertrand, M., Fleron, M.-H., Riou, B.
(2007). The Impact of Postoperative Discontinuation or Continuation of Chronic Statin Therapy on Cardiac Outcome After Major Vascular Surgery. Anesth. Analg.
104: 1326-1333
[Abstract][Full Text]
Deanfield, J. E., Halcox, J. P., Rabelink, T. J.
(2007). Endothelial Function and Dysfunction: Testing and Clinical Relevance. Circulation
115: 1285-1295
[Full Text]
Khush, K. K., Waters, D. D., Bittner, V., Deedwania, P. C., Kastelein, J. J.P., Lewis, S. J., Wenger, N. K.
(2007). Effect of High-Dose Atorvastatin on Hospitalizations for Heart Failure: Subgroup Analysis of the Treating to New Targets (TNT) Study. Circulation
115: 576-583
[Abstract][Full Text]
Boodhwani, M., Mieno, S., Voisine, P., Feng, J., Sodha, N., Li, J., Sellke, F. W.
(2006). High-dose atorvastatin is associated with impaired myocardial angiogenesis in response to vascular endothelial growth factor in hypercholesterolemic swine. J. Thorac. Cardiovasc. Surg.
132: 1299-1306
[Abstract][Full Text]
Liao, J. K.
(2006). Rho-Kinase: A Potential Link Between Hypercholesterolemia and Abnormal Vascular Smooth Muscle Contraction. Circ. Res.
99: 238-239
[Full Text]
van der Harst, P., Voors, A. A., van Gilst, W. H., Bohm, M., van Veldhuisen, D. J.
(2006). Statins in the treatment of chronic heart failure: Biological and clinical considerations. Cardiovasc Res
71: 443-454
[Abstract][Full Text]
Douglas, K., O'Malley, P. G., Jackson, J. L.
(2006). Meta-Analysis: The Effect of Statins on Albuminuria. ANN INTERN MED
145: 117-124
[Abstract][Full Text]
Ohkita, M., Sugii, M., Ka, Y., Kitamura, A., Mori, T., Hayashi, T., Takaoka, M., Matsumura, Y.
(2006). Differential Effects of Different Statins on Endothelin-1 Gene Expression and Endothelial NOS Phosphorylation in Porcine Aortic Endothelial Cells.. Exp. Biol. Med.
231: 772-776
[Abstract][Full Text]
Fichtlscherer, S., Schmidt-Lucke, C., Bojunga, S., Rossig, L., Heeschen, C., Dimmeler, S., Zeiher, A. M.
(2006). Differential effects of short-term lipid lowering with ezetimibe and statins on endothelial function in patients with CAD: clinical evidence for 'pleiotropic' functions of statin therapy. Eur Heart J
27: 1182-1190
[Abstract][Full Text]
Nagaoka, T., Takahashi, A., Sato, E., Izumi, N., Hein, T. W., Kuo, L., Yoshida, A.
(2006). Effect of systemic administration of simvastatin on retinal circulation.. Arch Ophthalmol
124: 665-670
[Abstract][Full Text]
Heistad, D. D.
(2006). Oxidative Stress and Vascular Disease: 2005 Duff Lecture. Arterioscler. Thromb. Vasc. Bio.
26: 689-695
[Abstract][Full Text]
Giri, J., McDermott, M. M., Greenland, P., Guralnik, J. M., Criqui, M. H., Liu, K., Ferrucci, L., Green, D., Schneider, J. R., Tian, L.
(2006). Statin Use and Functional Decline in Patients With and Without Peripheral Arterial Disease. J Am Coll Cardiol
47: 998-1004
[Abstract][Full Text]
Zulli, A., Buxton, B. F., Black, M. J., Ming, Z., Cameron, A., Hare, D. L.
(2006). The Immunoquantification of Caveolin-1 and eNOS in Human and Rabbit Diseased Blood Vessels. J. Histochem. Cytochem.
54: 151-159
[Abstract][Full Text]
Hofma, S. H., van der Giessen, W. J., van Dalen, B. M., Lemos, P. A., McFadden, E. P., Sianos, G., Ligthart, J. M.R., van Essen, D., de Feyter, P. J., Serruys, P. W.
(2006). Indication of long-term endothelial dysfunction after sirolimus-eluting stent implantation. Eur Heart J
27: 166-170
[Abstract][Full Text]
Li, J.-J., Fang, C.-H., Qian, H.-Y., Hu, W.-L.
(2006). Time Course of Rapid C-Reactive Protein Reduction by Pravastatin in Patients with Stable Angina. ANGIOLOGY
57: 1-7
[Abstract]
Rikitake, Y., Liao, J. K.
(2005). Rho GTPases, Statins, and Nitric Oxide. Circ. Res.
97: 1232-1235
[Abstract][Full Text]
Tousoulis, D., Antoniades, C., Vassiliadou, C., Toutouza, M., Pitsavos, C., Tentolouris, C., Trikas, A., Stefanadis, C.
(2005). Effects of combined administration of low dose atorvastatin and vitamin E on inflammatory markers and endothelial function in patients with heart failure. Eur J Heart Fail
7: 1126-1132
[Abstract][Full Text]
Li, J.-J., Fang, C.-H.
(2005). Effects of 4 Weeks of Atorvastatin Administration on the Antiinflammatory Cytokine Interleukin-10 in Patients with Unstable Angina. Clin. Chem.
51: 1735-1738
[Full Text]
Di Napoli, P., Taccardi, A. A., Grilli, A., De Lutiis, M. A., Barsotti, A., Felaco, M., De Caterina, R.
(2005). Chronic treatment with rosuvastatin modulates nitric oxide synthase expression and reduces ischemia-reperfusion injury in rat hearts. Cardiovasc Res
66: 462-471
[Abstract][Full Text]
Stone, P. H., Lloyd-Jones, D. M., Kinlay, S., Frei, B., Carlson, W., Rubenstein, J., Andrews, T. C., Johnstone, M., Sopko, G., Cole, H., Orav, J., Selwyn, A. P., Creager, M. A., for the Vascular Basis Study Group,
(2005). Effect of Intensive Lipid Lowering, With or Without Antioxidant Vitamins, Compared With Moderate Lipid Lowering on Myocardial Ischemia in Patients With Stable Coronary Artery Disease: The Vascular Basis for the Treatment of Myocardial Ischemia Study. Circulation
111: 1747-1755
[Abstract][Full Text]
Kaufmann, P. A., Camici, P. G.
(2005). Myocardial Blood Flow Measurement by PET: Technical Aspects and Clinical Applications. JNM
46: 75-88
[Full Text]
Tousoulis, D, Antoniades, C, Bosinakou, E, Kotsopoulou, M, Tsioufis, C, Tentolouris, C, Trikas, A, Pitsavos, C, Stefanadis, C
(2005). Effects of atorvastatin on reactive hyperaemia and the thrombosis-fibrinolysis system in patients with heart failure. Heart
91: 27-31
[Abstract][Full Text]
Fazel, S., Weisel, R. D., Verma, S.
(2004). A novel technique to assess flow-mediated vasodilation. J Am Coll Cardiol
44: 1478-1480
[Full Text]
Bae, J.-H., Bassenge, E., Kim, K.-Y., Synn, Y.-C., Park, k.-R., Schwemmer, M.
(2004). Effects of Low-Dose Atorvastatin on Vascular Responses in Patients Undergoing Percutaneous Coronary Intervention With Stenting. J CARDIOVASC PHARMACOL THER
9: 185-192
[Abstract]
Waters, D.D., Khush, K.K.
(2004). Management of the acute coronary syndrome patient. Eur Heart J Suppl
6: C49-C57
[Abstract][Full Text]
Davignon, J., Ganz, P.
(2004). Role of Endothelial Dysfunction in Atherosclerosis. Circulation
109: III-27-III-32
[Abstract][Full Text]
Halcox, J. P.J., Deanfield, J. E.
(2004). Beyond the Laboratory: Clinical Implications for Statin Pleiotropy. Circulation
109: II-42-II-48
[Abstract][Full Text]
Kinlay, S., Behrendt, D., Fang, J. C., Delagrange, D., Morrow, J., Witztum, J. L., Rifai, N., Selwyn, A. P., Creager, M. A., Ganz, P.
(2004). long-term effect of combined vitamins e and c on coronary and peripheral endothelial function. J Am Coll Cardiol
43: 629-634
[Abstract][Full Text]
Economides, P. A., Caselli, A., Tiani, E., Khaodhiar, L., Horton, E. S., Veves, A.
(2004). The Effects of Atorvastatin on Endothelial Function in Diabetic Patients and Subjects at Risk for Type 2 Diabetes. J. Clin. Endocrinol. Metab.
89: 740-747
[Abstract][Full Text]
Trochu, J.-N., Mital, S., Zhang, X.-p., Xu, X., Ochoa, M., Liao, J. K, Recchia, F. A, Hintze, T. H
(2003). Preservation of NO production by statins in the treatment of heart failure. Cardiovasc Res
60: 250-258
[Abstract][Full Text]
Wassmann, S., Faul, A., Hennen, B., Scheller, B., Bohm, M., Nickenig, G.
(2003). Rapid Effect of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibition on Coronary Endothelial Function. Circ. Res.
93
: e98-e103
[Abstract][Full Text]
Widlansky, M. E., Gokce, N., Keaney, J. F. Jr, Vita, J. A.
(2003). The clinical implications of endothelial dysfunction. J Am Coll Cardiol
42: 1149-1160
[Abstract][Full Text]
Lowson, S. M.
(2003). Nitric Oxide Signaling and Clinical Alternatives to Nitric Oxide. SEMIN CARDIOTHORAC VASC ANESTH
7: 239-252
[Abstract]
Schwartz, R. G., Pearson, T. A., Kalaria, V. G., Mackin, M. L., Williford, D. J., Awasthi, A., Shah, A., Rains, A., Guido, J. J.
(2003). Prospective serial evaluation of myocardial perfusion and lipids during the first six months of pravastatin therapy: Coronary artery disease regression single photon emission computed tomography monitoring trial. J Am Coll Cardiol
42: 600-610
[Abstract][Full Text]
Blumenthal, R. S., Gluckman, T. J.
(2003). New insights into the relationship between myocardial perfusion and lipid-lowering. J Am Coll Cardiol
42: 611-613
[Full Text]
Griffiths, K. A., Sader, M. A., Skilton, M. R., Harmer, J. A., Celermajer, D. S.
(2003). Effects of raloxifene on endothelium-dependent dilation, lipoproteins, and markers of vascular function in postmenopausal women with coronary artery disease. J Am Coll Cardiol
42: 698-704
[Abstract][Full Text]
Node, K., Fujita, M., Kitakaze, M., Hori, M., Liao, J. K.
(2003). Short-Term Statin Therapy Improves Cardiac Function and Symptoms in Patients With Idiopathic Dilated Cardiomyopathy. Circulation
108: 839-843
[Abstract][Full Text]
Boger, R. H
(2003). Asymmetric dimethylarginine (ADMA) modulates endothelial function - therapeutic implications. Vasc Med
8: 149-151
Binggeli, C., Spieker, L. E., Corti, R., Sudano, I., Stojanovic, V., Hayoz, D., Luscher, T. F., Noll, G.
(2003). Statins enhance postischemic hyperemia in the skin circulation of hypercholesterolemic patients: A monitoring test of endothelial dysfunction for clinical practice?. J Am Coll Cardiol
42: 71-77
[Abstract][Full Text]
Hambrecht, R., Adams, V., Erbs, S., Linke, A., Krankel, N., Shu, Y., Baither, Y., Gielen, S., Thiele, H., Gummert, J.F., Mohr, F.W., Schuler, G.
(2003). Regular Physical Activity Improves Endothelial Function in Patients With Coronary Artery Disease by Increasing Phosphorylation of Endothelial Nitric Oxide Synthase. Circulation
107: 3152-3158
[Abstract][Full Text]
Fernandez-Varo, G., Ros, J., Morales-Ruiz, M., Cejudo-Martin, P., Arroyo, V., Sole, M., Rivera, F., Rodes, J., Jimenez, W.
(2003). Nitric Oxide Synthase 3-Dependent Vascular Remodeling and Circulatory Dysfunction in Cirrhosis. Am. J. Pathol.
162: 1985-1993
[Abstract][Full Text]
Wolfrum, S., Jensen, K. S., Liao, J. K.
(2003). Endothelium-Dependent Effects of Statins. Arterioscler. Thromb. Vasc. Bio.
23: 729-736
[Abstract][Full Text]
Sasaki, M., Bharwani, S., Jordan, P., Joh, T., Manas, K., Warren, A., Harada, H., Carter, P., Elrod, J. W., Wolcott, M., Grisham, M. B., Alexander, J. S.
(2003). The 3-Hydroxy-3-methylglutaryl-CoA Reductase Inhibitor Pravastatin Reduces Disease Activity and Inflammation in Dextran-Sulfate Induced Colitis. J. Pharmacol. Exp. Ther.
305: 78-85
[Abstract][Full Text]
Schindler, T. H., Hornig, B., Buser, P. T., Olschewski, M., Magosaki, N., Pfisterer, M., Nitzsche, E. U., Solzbach, U., Just, H.
(2003). Prognostic Value of Abnormal Vasoreactivity of Epicardial Coronary Arteries to Sympathetic Stimulation in Patients With Normal Coronary Angiograms. Arterioscler. Thromb. Vasc. Bio.
23: 495-501
[Abstract][Full Text]
Anderson, T. J., Hubacek, J., Wyse, D. G., Knudtson, M. L.
(2003). Effect of chelation therapy on endothelial function in patients with coronary artery disease: PATCH substudy. J Am Coll Cardiol
41: 420-425
[Abstract][Full Text]
Hattori, Y., Nakanishi, N., Akimoto, K., Yoshida, M., Kasai, K.
(2003). HMG-CoA Reductase Inhibitor Increases GTP Cyclohydrolase I mRNA and Tetrahydrobiopterin in Vascular Endothelial Cells. Arterioscler. Thromb. Vasc. Bio.
23: 176-182
[Abstract][Full Text]
Gervais, M., Pons, S., Nicoletti, A., Cosson, C., Giudicelli, J.-F., Richer, C.
(2003). Fluvastatin Prevents Renal Dysfunction and Vascular NO Deficit in Apolipoprotein E-Deficient Mice. Arterioscler. Thromb. Vasc. Bio.
23: 183-189
[Abstract][Full Text]
Staniloae, C., Schwab, A. J., Simard, A., Gallo, R., Dyrda, I., Gosselin, G., Lesperance, J., Ryan, J. W., Dupuis, J.
(2003). In vivo measurement of coronary circulation angiotensin-converting enzyme activity in humans. Am. J. Physiol. Heart Circ. Physiol.
284: H17-H22
[Abstract][Full Text]
de Jongh, S., Lilien, M. R., op't Roodt, J., Stroes, E. S. G., Bakker, H. D., Kastelein, J. J. P.
(2002). Early statin therapy restores endothelial function in children with familial hypercholesterolemia. J Am Coll Cardiol
40: 2117-2121
[Abstract][Full Text]
Fernandez-Real, J. M., Penarroja, G., Castro, A., Garcia-Bragado, F., Lopez-Bermejo, A., Ricart, W.
(2002). Blood Letting in High-Ferritin Type 2 Diabetes: Effects on vascular reactivity. Diabetes Care
25: 2249-2255
[Abstract][Full Text]
Honjo, M., Tanihara, H., Nishijima, K., Kiryu, J., Honda, Y., Yue, B. Y. J. T., Sawamura, T.
(2002). Statin Inhibits Leukocyte-Endothelial Interaction and Prevents Neuronal Death Induced by Ischemia-Reperfusion Injury in the Rat Retina. Arch Ophthalmol
120: 1707-1713
[Abstract][Full Text]
Lefer, D. J.
(2002). Statins as Potent Antiinflammatory Drugs. Circulation
106: 2041-2042
[Full Text]
Sanada, M., Higashi, Y., Nakagawa, K., Tsuda, M., Kodama, I., Kimura, M., Chayama, K., Ohama, K.
(2002). Hormone Replacement Effects on Endothelial Function Measured in the Forearm Resistance Artery in Normocholesterolemic and Hypercholesterolemic Postmenopausal Women. J. Clin. Endocrinol. Metab.
87: 4634-4641
[Abstract][Full Text]
Wright, R. S., Murphy, J. G., Bybee, K. A., Kopecky, S. L., LaBlanche, J.-M.
(2002). Statin Lipid-Lowering Therapy for Acute Myocardial Infarction and Unstable Angina: Efficacy and Mechanism of Benefit. Mayo Clin Proc.
77: 1085-1092
[Abstract]
Vecchione, C., Brandes, R. P.
(2002). Withdrawal of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Elicits Oxidative Stress and Induces Endothelial Dysfunction in Mice. Circ. Res.
91: 173-179
[Abstract][Full Text]
Iraculis, E., Cequier, A., Gomez-Hospital, J. A., Sabate, M., Mauri, J., Fernandez-Nofrerias, E., Garcia del Blanco, B., Jara, F., Esplugas, E.
(2002). Early dysfunction and long-term improvement in endothelium-dependent vasodilation in the infarct-related artery after thrombolysis. J Am Coll Cardiol
40: 257-265
[Abstract][Full Text]
Shiojima, I., Walsh, K.
(2002). Role of Akt Signaling in Vascular Homeostasis and Angiogenesis. Circ. Res.
90: 1243-1250
[Abstract][Full Text]
Sopko, G.
(2002). Preventing Cardiac Events and Restenosis After Percutaneous Coronary Intervention. JAMA
287: 3259-3261
[Full Text]
Yeung, A. C., Tsao, P.
(2002). Statin Therapy: Beyond Cholesterol Lowering and Antiinflammatory Effects. Circulation
105: 2937-2938
[Full Text]
Walter, D. H., Rittig, K., Bahlmann, F. H., Kirchmair, R., Silver, M., Murayama, T., Nishimura, H., Losordo, D. W., Asahara, T., Isner, J. M.
(2002). Statin Therapy Accelerates Reendothelialization: A Novel Effect Involving Mobilization and Incorporation of Bone Marrow-Derived Endothelial Progenitor Cells. Circulation
105: 3017-3024
[Abstract][Full Text]
van Etten, R. W., de Koning, E. J.P., Honing, M. L., Stroes, E. S., Gaillard, C. A., Rabelink, T. J.
(2002). Intensive Lipid Lowering by Statin Therapy Does Not Improve Vasoreactivity in Patients With Type 2 Diabetes. Arterioscler. Thromb. Vasc. Bio.
22: 799-804
[Abstract][Full Text]
Houghton, J. L., Philbin, E. F., Strogatz, D. S., Torosoff, M. T., Fein, S. A., Kuhner, P. A., Smith, V. E., Carr, A. A.
(2002). The presence of African American race predicts improvement in coronary endothelial function after supplementary L-arginine. J Am Coll Cardiol
39: 1314-1322
[Abstract][Full Text]
Kyriakides, Z. S., Psychari, S., Iliodromitis, E. K., Kolettis, T. M., Sbarouni, E., Kremastinos, D. T.
(2002). Hyperlipidemia Prevents the Expected Reduction of Myocardial Ischemia on Repeated Balloon Inflations During Angioplasty*. Chest
121: 1211-1215
[Abstract][Full Text]
Ferrier, K. E., Muhlmann, M. H., Baguet, J.-P., Cameron, J. D., Jennings, G. L., Dart, A. M., Kingwell, B. A.
(2002). Intensive cholesterol reduction lowers blood pressure and large artery stiffness in isolated systolic hypertension. J Am Coll Cardiol
39: 1020-1025
[Abstract][Full Text]
Ledoux, S., Laouari, D., Essig, M., Runembert, I., Trugnan, G., Michel, J.B., Friedlander, G.
(2002). Lovastatin Enhances Ecto-5'-Nucleotidase Activity and Cell Surface Expression in Endothelial Cells: Implication of Rho-Family GTPases. Circ. Res.
90: 420-427
[Abstract][Full Text]
Mannheimer, C., Camici, P., Chester, M.R., Collins, A., DeJongste, M., Eliasson, T., Follath, F., Hellemans, I., Herlitz, J., Luscher, T., Pasic, M., Thelle, D.
(2002). The problem of chronic refractory angina. Report from the ESC Joint Study Group on the Treatment of Refractory Angina. Eur Heart J
23: 355-370
[Full Text]
Sader, M. A., Celermajer, D. S.
(2002). Endothelial function, vascular reactivity and gender differences in the cardiovascular system. Cardiovasc Res
53: 597-604
[Full Text]
Kreisberg, R. A., Oberman, A.
(2002). Lipids and Atherosclerosis: Lessons Learned from Randomized Controlled Trials of Lipid Lowering and Other Relevant Studies. J. Clin. Endocrinol. Metab.
87: 423-437
[Full Text]
Tan, K. C. B., Chow, W. S., Tam, S. C. F., Ai, V. H. G., Lam, C. H. L., Lam, K. S. L.
(2002). Atorvastatin Lowers C-Reactive Protein and Improves Endothelium-Dependent Vasodilation in Type 2 Diabetes Mellitus. J. Clin. Endocrinol. Metab.
87: 563-568
[Abstract][Full Text]
Cobbe, S.M.
(2002). How best to combat the enemies? Lipid lowering. Eur Heart J Suppl
4: A48-A52
[Abstract]
Rockstroh, J., Brown, B. G.
(2002). Coronary Collateral Size, Flow Capacity, and Growth: Estimates From the Angiogram in Patients With Obstructive Coronary Disease. Circulation
105: 168-173
[Abstract][Full Text]
Kelm, M.
(2002). Flow-mediated dilatation in human circulation: diagnostic and therapeutic aspects. Am. J. Physiol. Heart Circ. Physiol.
282: H1-H5
[Full Text]
Stein, J. H., Carlsson, C. M., Papcke-Benson, K., Aeschlimann, S. E., Bodemer, A., Carnes, M., McBride, P. E.
(2001). The effects of lipid-lowering and antioxidant vitamin therapies on flow-mediated vasodilation of the brachial artery in older adults with hypercholesterolemia. J Am Coll Cardiol
38: 1806-1813
[Abstract][Full Text]
Ichiki, T., Takeda, K., Tokunou, T., Iino, N., Egashira, K., Shimokawa, H., Hirano, K., Kanaide, H., Takeshita, A.
(2001). Downregulation of Angiotensin II Type 1 Receptor by Hydrophobic 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors in Vascular Smooth Muscle Cells. Arterioscler. Thromb. Vasc. Bio.
21: 1896-1901
[Abstract][Full Text]
Sterzer, P., Meintzschel, F., Rosler, A., Lanfermann, H., Steinmetz, H., Sitzer, M.
(2001). Pravastatin Improves Cerebral Vasomotor Reactivity in Patients With Subcortical Small-Vessel Disease. Stroke
32: 2817-2820
[Abstract][Full Text]
Heitzer, T., Schlinzig, T., Krohn, K., Meinertz, T., Munzel, T.
(2001). Endothelial Dysfunction, Oxidative Stress, and Risk of Cardiovascular Events in Patients With Coronary Artery Disease. Circulation
104: 2673-2678
[Abstract][Full Text]
Mulder, H J G H, Schalij, M J, Kauer, B, Visser, R F, van Dijkman, P R M, Jukema, J W, Zwinderman, A H, Bruschke, A V G
(2001). Pravastatin and endothelium dependent vasomotion after coronary angioplasty: the PREFACE trial. Heart
86: 533-539
[Abstract][Full Text]
Takemoto, M., Liao, J. K.
(2001). Pleiotropic Effects of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors. Arterioscler. Thromb. Vasc. Bio.
21: 1712-1719
[Abstract][Full Text]
Kolyada, A. Y., Fedtsov, A., Madias, N. E.
(2001). 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Upregulate Inducible NO Synthase Expression and Activity in Vascular Smooth Muscle Cells. Hypertension
38: 1024-1029
[Abstract][Full Text]
Imamura, M., Biro, S., Kihara, T., Yoshifuku, S., Takasaki, K., Otsuji, Y., Minagoe, S., Toyama, Y., Tei, C.
(2001). Repeated thermal therapy improves impaired vascular endothelial function in patients with coronary risk factors. J Am Coll Cardiol
38: 1083-1088
[Abstract][Full Text]
