Volume 2, Number
12: December 1999
Endothelium-dependent flow-mediated vasodilation in
the postprandial state in type 2 diabetes mellitus
Naturoceutical agents and cardiovascular medicine:
the hope, the hype and the harm
Impact of cilostazol on clinical and angiographic
outcome after primary stenting for acute myocardial infarction
Effect
of long-term cilostazol administration on coronary flow velocity and coronary
flow reserve
Endothelium-dependent flow-mediated vasodilation in
the postprandial state in type 2 diabetes mellitus
Reference: Am J Cardiology 1999;84(10):1272-1274.
Cardiovascular disease is the major cause of mortality in patients with diabetes
mellitus (DM). There is substantial evidence that endothelium-dependent vasodilation is impaired in patients with DM.
The mechanisms of endothelial dysfunction in DM are not clear, but systemic hypertension and hyperlipidemia are 2 factors affecting endothelial function
adversely. Both blood glucose and plasma lipids generally increase in the postprandial state. In patients with DM, this is often exaggerated, the magnitude
of postprandial glycemia and hypertriglyceridemia being greater than in healthy subjects. Recently, endothelium-dependent vasodilation was reportedly
impaired by elevating blood glucose in healthy humans in vivo. Williams et al
reported that acute hyperglycemia induced by intraarterial infusion of 50% dextrose impaired endothelium-dependent vasodilation in healthy subjects,
implicating elevated glucose as a cause of the endothelial dysfunction in DM. Furthermore, endothelium-dependent vasodilation was also reportedly impaired
by postprandial acute hypertriglyceridemia in healthy subjects. Therefore, endothelium-dependent vasodilation in DM could be affected in the
postprandial state by acute hyperglycemia or acute hypertriglyceridemia, or by both. The combined effects of postprandial hyperglycemia and
hypertriglyceridemia on endothelial function in DM have not yet been investigated. This study investigates whether endothelium-dependent
vasodilation in DM was affected by a fat- and sucrose-rich meal.
Seven subjects with well-controlled non–insulin-dependent DM, defined according to the World Health Organization criteria using the oral glucose
tolerance test, were recruited into this study. The average duration of DM was 19.7 ± 14.1 months (range 3 to 36). Patients with fasting blood glucose >150
mg/dl, taking lipid-lowering or antihypertensive drugs, or oral sulfonylurea, were
excluded. All patients had satisfactory glucose control, and no apparent micro- or
macroangiopathy.
Studies were begun at 8 A.M. after a 12-hour fasting period. All patients were
admitted to the ward on the day before the study. Written informed consent was obtained from all patients and protocol was approved by the institutional
ethics committee. Fasting blood was obtained for measuring serum lipids, glucose, and insulin, after which subjects had a high-fat, high-sucrose meal
containing 40 g/m2 body surface area of bovine milk fat (Fresh Cream, Meiji Milk Co., Tokyo, Japan) with 75 g of sucrose. Blood collections were repeated
1.5, 3, 6, and 9 hours after the meal. Flow-mediated vasodilation of the brachial
artery was measured before and 3 hours after the experimental meal.
Plasma lipids, high-density lipoprotein (HDL) cholesterol, glucose, insulin, and
hemoglobin A1c were measured in the central laboratory of the Medical College Hospital. Low-density lipoprotein cholesterol was calculated. Remnant-like
particles were isolated and cholesterol measured by a method reported previously using immunoaffinity mixed gel containing antiapolipoprotein B100
and antiapolipoprotein A-I (Jimro, Takasaki, Japan). Flow-mediated vasodilation of the brachial artery was measured by a method
reported previously. After a 10-minute equilibration period, images of the brachial arteries of subjects were obtained by using a 7.5-MHz ultrasound
transducer (Hewlett-Packard, Tokyo, Japan). In each study, we confirmed the clear visualization of the 3 layers of the vessel wall, including the ''m'' line in
both walls. A cuff placed on the forearm was inflated to 200 mm Hg for 5 minutes. Imaging of the artery was performed before cuff inflation (baseline),
and for 1.5 minutes after cuff deflation. Fifteen minutes after acquisition of the
postocclusion image, the baseline image was regained, after which nitroglycerin was given sublingually; 5 minutes later another image was
acquired. The brachial artery diameter was defined as the distance from the anterior to the posterior m line. The mean diameter was calculated from 4
cardiac cycles synchronized with the R wave on the electrocardiogram. Measurements were obtained within 1 minute before cuff inflation and 1 to 1.5
minutes after deflation using a Kontron Cardio 500 (Kontron, Tokyo, Japan). Flow-mediated vasodilation was determined by calculating the change in the
brachial artery diameter (percent increase for the baseline diameters), and endothelium-independent, nitroglycerin-induced vasodilation was also
calculated.
The present study demonstrates that endothelium-dependent vasodilation in the
preprandial state correlated inversely with the levels of fasting blood glucose and hemoglobin A1c in type 2 DM patients. Furthermore,
endothelium-dependent vasodilation was attenuated by the fat- and sucrose-rich meal in these subjects. Because endothelium-independent
vasodilation was not affected by the experimental meal, the diminished response in the postprandial state would be mediated by endothelium-derived
nitric oxide.
Nitric oxide-mediated vasomotor dysfunction has been demonstrated in patients
with DM. In this study, preprandial flow-mediated vasodilation showed a significant negative correlation with the levels of fasting
blood glucose and hemoglobin A1c in patients with type 2 DM. Mean flow-mediated vasodilation in this study was 8.1± 2.6% in the preprandial state,
less than that in healthy Japanese subjects described previously. These
data suggest that patients with better diabetic control had better endothelial function.
Endothelium-dependent vasodilation worsened during the postprandial state after the fat- and sucrose-rich meal in diabetic patients, but we cannot
differentiate whether glucose or lipid was primarily responsible for this effect.
Both postprandial flow-mediated vasodilation and change in flow-mediated vasodilation correlated significantly with postprandial changes in blood glucose,
establishing hyperglycemia as 1 determinant of reduced flow-mediated
vasodilation. There was no correlation between changes in flow-mediated vasodilation and changes in insulin levels, which may be due to the variance of
the insulin response or the difference in the duration of DM.
Postprandial hypertriglyceridemia has also been reported to impair endothelial function. Further, remnant-like particles isolated from postprandial
plasma in hypertriglyceridemic patients have been reported to impair endothelium function in vitro.
In this study, however, postprandial flow-mediated vasodilation and change in flow-mediated vasodilation were not
correlated with any changes in plasma lipids and lipoproteins, although triglycerides and remnant-like particles (cholesterol) increased significantly
3 hours after the meal. Therefore, it cannot be ruled out that triglyceride-rich
lipoproteins, which appeared in the postprandial state, might contribute to the decrease in endothelium-dependent vasodilation. However, the absence of a
statistically significant correlation between plasma triglycerides and the response in flow-mediated dilatation make it likely that hyperglycemia exerted
the predominant effect in this experimental condition.
In conclusion, we found that a fat- and sucrose-rich meal attenuated flow-mediated vasodilation in patients with type 2 DM. Preprandial vasodilation
correlated inversely with levels of fasting blood glucose and hemoglobin A1c, and postprandial changes in flow-mediated vasodilation and blood glucose
correlated significantly as well. These data reinforce the benefit of strict glycemic control in preventing the development of vascular complication in
patients with DM.
Naturoceutical agents and cardiovascular medicine:
the hope, the hype and the harm
Reference: ACC Current Journal Review 1999;8(5):53-57.
A naturoceutical agent is defined as a megavitamin, herbal or other dietary
supplement that is consumed in order to prevent or provide relief from disease or subjective physical or psychological complaints. The term naturoceutical
reflects two common observations regarding their contemporary use. First, prevailing consumer perception of these over-the-counter compounds is that
their ''natural'' origin implies inherent safety and the absence of side effects.
The second observation is that naturoceutical agents are being recommended or self-prescribed with clear prophylactic or therapeutic ''pharmaceutical''
intention. This practice has become increasingly prevalent in Western society and mandates physician attention and concern.
As determined by Eisenberg et al. and Astin et al., sociodemographic stratification demonstrates
that the utilization of unconventional therapy is not a phenomenon confined to unique societal subsets. However, individuals with chronic disease or illness
clearly represent a group more likely to seek health improvement specifically through naturoceutical use. Nearly one in five people taking prescription
medication also uses naturoceutical agents. This extrapolates to more than 15 million adults and includes approximately 3 million patients over the age of
65. Given the relative paucity of data regarding the efficacy, safety, mode of action and pharmacokinetics of naturoceutical agents, this represents an
exceedingly large population exposure.
Observational surveys in specific patient populations confirm that naturoceutical
use is even higher among patients with chronic debilitating or life-threatening disorders. Surveys of patients with cancer, inflammatory bowel disease,
arthritis, fibromyalgia and psoriasis have generally shown a much higher prevalence of alternative medicine use than that found in the general United
States population. In the author's experience, naturoceutical consumption was determined to be exceedingly common among patients with moderate-to-severe
chronic heart failure. This predominantly older, white male population demonstrated a remarkable 44% prevalence of naturoceutical use. No other
published data are available on the relative frequency of naturoceutical use by patients with other cardiovascular disorders. Factors contributing to the
excessive prevalence of naturoceutical use in individuals with chronic heart
failure are numerous but related to the high morbidity and mortality risk associated with this syndrome. Patients with chronic heart failure have common
comorbid conditions, including coronary, cerebral and peripheral atherosclerosis, hypertension, diabetes, hyperlipidemia and arrhythmia.
Disease-related factors that serve to diminish perceived health status include stress/anxiety, fatigue, exercise intolerance, memory impairment, depression,
sleep disturbances and sexual dysfunction. For this characteristically elderly
population, conditions such as prostatism and arthritis are also common. A plethora of naturoceutical agents with the promise of helping to alleviate or
prevent these disease, conditions or their symptoms are widely available without prescription in the United States today. This abundance of
choice was reflected in the survey of heart failure patients, with over 90% of
naturoceutical consumers using multiple products.
The astronomical rise in the use of complementary and alternative medical therapies does not reflect patient dissatisfaction with traditional or conventional
medical care. In the Stanford study, perceived efficacy was deemed to be the most important influential factor in the decision to use alternative health
care practices.. Advertisements and paid celebrity endorsements serve to reinforce public expectation of efficacy and safety. Kaptchuk and Eisenberg
detailed the influence of four cultural assumptions and shared beliefs that help explain the persuasive appeal of alternative or complementary medicine in
our society. These premises include nature, vitalism, science and spirituality.
Specifically applicable to botanical naturoceutical agents, derivation from a natural source imparts a metaphorical ''veneer of purity and safety for health
and healing.'' Although many cardiovascular and related pharmaceutical agents
were originally derived from natural sources, these authors point out that the romantic concept of ''beneficent nature'' allows one to overlook negative
examples, such as hemlock, oleander glycosides, pennyroyal and amanita mushrooms. The premise of vitalism is illustrated in the sense of control and
empowerment gained over illness with self-actuated therapy. Science is not disregarded but evoked using concepts of tradition (ancient Chinese medicine)
and authority (German E Commission monographs) rather than through rigorous scientific method. Spiritual overtones deriving from the stress or fear
of illness can create a ''form of religiosity'' expressed as a zealous commitment
to naturoceutical use in the affirmation of ''a quest for health, perhaps with less
self-awareness''.
The Nutrition Labeling and Education Act of 1990 mandated labeling of food and nutritional supplements as a guide for consumers. In 1994, the Dietary
Supplement and Education Act exempted dietary supplements from Food and
Drug Administration (FDA) regulation and allowed statements describing the role of a nutrient or ingredient in altering body structure or function. Without
proactive regulatory enforcement, naturoceutical products subsequently flooded store shelves in the spirit of free enterprise. FDA intervention remains
limited to removing specific products from the market only after significant harm is demonstrated. The FDA Modernization Act of 1997, however, required
that marketed products claiming to affect body structure or function inform the FDA and include on the disclaimer ''This statement has not been evaluated by
the FDA. This product is not intended to diagnose, treat, cure or prevent any
disease.'' Thus, a supplement label can state that the product helps to promote or maintain a healthy cholesterol level but may not claim to lower cholesterol
and the risk of heart disease. Last summer, the FDA issued rulings prohibiting food label claims relating the antioxidant vitamins C, E, A and -carotene
specifically to risk reduction of atherosclerosis, coronary heart disease and certain cancers. In the spirit of the FDA Modernization Act, there must be
an attributed ''authoritative statement'' from a recognized scientific body supporting such claims.
There remains appropriate and significant concern over inadequate regulation
of product quality assurance other than by the manufacturer. Quality-control issues exist regarding contaminants, substituted ingredients, such as caffeine,
and variation in the content/activity of the key ingredient (when known). Reports
of undeclared pharmaceuticals, digitalis or cardiac glycoside and heavy metal adulteration of herbal products raise serious safety issues
.
The potential harm of physician ennui or silent approval of uninformed naturoceutical use by patients is substantial. First, ineffectual therapies may
delay or confound evaluation, diagnosis and the institution of standard treatment. Secondly, either the patient or the physician may mistakenly
attribute adverse effects to underlying illness or to concomitant prescription
medications. For example, although physicians should recognize signs and symptoms of toxicity from excessive doses of vitamins, they may fail to
determine the total daily dose their patients ingest. Undisclosed or unrecognized naturoceutical use clearly contributes to physician
underreporting of possible adverse events. For example, supplements containing ma huang (ephedra) have been associated with serious and fatal
cardiovascular events, and reports suggest that this risk is greater in women than men
. Finally, the possibility for toxicity related to altered naturoceutical metabolism due to age, gender or abnormal physiology is
infrequently considered. Physicians routinely monitor and adjust the dose of prescription drugs according to body size, age, gender, presence of renal or
hepatic dysfunction or when used in combination with other medications. Little data is available detailing which naturoceutical agents should require similar
precautions, although combination products are increasingly common. Naturoceutical toxicity and naturoceutical-pharmaceutical interactions are
being reported with increasing frequency in relation to patients with cardiovascular disorders. The Offices of Dietary Supplements and
Special Nutritionals within the United States FDA have established the Special
Nutritionals/Adverse Event Monitoring System whose information lies in the public domain. The Special Nutritionals/Adverse Event Monitoring System
report contains all naturoceutical-related adverse events reported to the FDA by
professionals or consumers and is accessible on the internet (http://www.fda.gov/medwatch). When last updated 10/20/98, the report
contained a total of 2,621 reports about 3,451 products. The relative risk for side effects or medication interactions cannot be estimated from
available data.
In summary, the prevalence of naturoceutical consumption by the American
public is high and may approach 50% in individuals at risk for or suffering from
chronic cardiovascular disorders, such as heart failure. Definitive and objective
research delineating the efficacy, safety and mechanism of action of naturoceutical agents is clearly needed to safeguard public well being.
Physicians must learn more about these popular agents and should routinely document naturoceutical use by their patients. Practitioners should be
prepared to discuss with patients the relative risk/benefit ratio of this alternative
medical practice in reference to the quality and quantity of information available. Potential adverse interactions of naturoceutical agents with
prescribed medications or toxicity due to aged or abnormal physiology should
be considered and reported when suspected.
Impact of cilostazol on clinical and angiographic
outcome after primary stenting for acute myocardial infarction
Reference: American Journal of Cardiology 1999;84(9):1074-76.
Primary stenting is a recent major breakthrough in the treatment of acute
myocardial infarction (AMI) that has been shown to improve clinical outcome compared with conventional primary balloon angioplasty.
Antiplatelet therapy with aspirin plus ticlopidine are widely used to reduce risk
of thrombotic occlusion of the stent. However, angiographic restenosis was still
allowed in 15% to 20% of patients enrolled in early trials and ticlopidine is not associated with significant reduction in angiographic
restenosis or need for repeat interventions. Thus, drugs more effective than ticlopidine in reducing restenosis are needed. Cilostazol, or
6-[4-(1-cyclohexyl-1H-tetrazol-5-yl) butoxy]-3, 4-dihydro-2 (1H)-quinolinone, is
a novel and potent inhibitor of phosphodiesterase in platelets and vascular smooth muscle cells.
This agent has an antiplatelet effect similar to
ticlopidine and is effective in preventing subacute stent thrombosis. Moreover,
cilostazol appears to have an inhibitory effect on intimal proliferation, and may
reduce the occurrence of restenosis after directional coronary atherectomy or elective stent implantation.
The objective of this study was to compare 6-month clinical and angiographic outcomes in patients randomized to receive
either cilostazol or a brief course of ticlopidine after primary stenting for AMI.
Primary stenting was defined as intentional implantation of a coronary stent in
the culprit lesion of AMI. Successful primary stenting was defined angiographically as visually estimated residual stenosis 5% associated with
grade 3 flow according to the criteria of the Thrombolysis In Myocardial Infarction
(TIMI) trial. Major cardiac events were defined as cardiac death,
reinfarction, or need for emergent revascularization procedure to the stent occlusion. Vascular complications were defined as occurrence of bleeding or
hematoma at the puncture site requiring transfusion or vascular repair.
Between September 1995 and May 1997, 54 patients who presented within 12 hours of an AMI with total occlusion (TIMI grade 0 or 1 flow) of the
infarct-related artery underwent primary stenting using a Palmaz-Schatz stent. AMI was defined as ischemic chest pain lasting >30 minutes, accompanied by
ST-segment elevation 0.1 mV in 2 contiguous electrocardiographic leads. Patients with cardiogenic shock were included. Primary stenting was attempted
if the infarct-related artery did not show evidence of severe calcification on fluoroscopy or excessive angulation proximal to the lesion likely to increase the
risk of stent dislodgment, and if the arterial diameter was 2.5 mm. We excluded a total of 3 patients from the study because of a culprit lesion located
in a saphenous vein graft (n = 1), or true ostial lesions of the left anterior descending (n = 1) or left circumflex (n = 1) artery. 2 Therefore, 51 patients
who underwent primary stenting were enrolled. Written informed consent was obtained before study enrollment.
After the patients received 3 chewable 81-mg baby aspirin tablets and an intravenous bolus infusion of 150 U/kg of heparin, primary stenting was
performed via a femoral approach. After predilation at a pressure of 10 atm for 30 seconds, an articulated 15-mm Palmaz-Schatz stent (Johnson and
Johnson Interventional Systems, Warren, New Jersey) was either mounted manually on a low-profile balloon catheter or implanted using a delivery system.
The balloon size was chosen carefully with respect to the diameter of the adjacent nondiseased coronary artery (balloon-to-artery ratio, 1:1 to 1:1.2).
Stenting throughout the length of the lesion was considered essential. After the
stent was deployed, high-pressure poststenting dilation (15 to 18 atm) was performed. To reduce the residual stenosis to <5%, additional poststenting
dilation using either higher inflation pressures (up to 20 atm) or a larger balloon
was required in some cases. Continuous intravenous infusion of 150 U/kg/day of heparin was continued for 72 hours. As antiplatelet treatment, all patients
received aspirin (81 mg 3 times a day for 6 months); in addition, patients were randomized by means of sealed envelopes to receive cilostazol (100 mg twice a
day for 6 months) or control medication. The control medication, given to prevent subacute stent thrombosis, was ticlopidine 100 mg twice a day for 1
month.
Clinical and angiographic outcomes at 6 months were analyzed. All randomized
patients were encouraged to undergo follow-up coronary arteriography 6 months after the procedure (or earlier in the event of recurrent symptoms or
clinical evidence of ischemia). Quantitative angiographic parameters (minimal lumen diameter, reference diameter, and percent stenosis) were measured by
using a digital edge-detection algorithm (Cardio 500; Kontron Electronik, Eching, Germany). The measurements were obtained during diastole using the
single matched images demonstrating the greatest degree of stenosis. Restenosis was defined as diameter stenosis >50% at the 6-month follow-up
angiography. Acute gain was defined as poststenting minimal lumen diameter, because the culprit lesion had shown total occlusion before
predilation. Late loss was calculated as the difference between the acute gain and the minimal
lumen diameter measured at follow-up angiography. Loss index was calculated as the ratio of late loss to acute gain.
Detailed case report forms were completed for all patients, and the information
was entered into a computer database. Data are expressed as mean ± SD. Comparisons between the study groups were made using the Mann-Whitney U
test for continuous variables and chi-square test for categorical variables. A p
value <0.05 was considered statistically significant.
Of the 51 patients in whom primary stenting was attempted, a successful result
was obtained in 50 (98%). In the failed procedure, a stent mounted on a low-profile balloon could not be crossed through the target lesion. This patient
was treated with conventional balloon angioplasty. The 50 patients with successful primary stenting were randomized to the cilostazol (n = 25) or the
control group (n = 25). Particulars for the 50 patients and procedures included no significant differences between the
2 groups. There were 4 major cardiac events; during the first month, 4 patients
(2 in the cilostazol group and 2 in the control group), all with cardiogenic shock
on admission, died of refractory cardiogenic shock with no clinical or electrocardiographic evidence of stent occlusion. No adverse effects of
antiplatelet agents such as neutropenia, liver dysfunction, or bleeding were observed during the follow-up period. Two asymptomatic patients in the control
group declined follow-up coronary angiography. Therefore, angiographic outcomes at 6 months were assessed in 44 patients (cilostazol group [n = 23]
and control group [n = 21]). The rate of restenosis was lower in the cilostazol group than in the control group. Although the quantitative angiographic
parameters immediately after the procedure did not differ between groups, late
loss and loss index were significantly less in the cilostazol group than in the
control group. All target lesion revascularization procedures in 4 control group patients were repeat balloon angioplasties. Although 2 control
patients had no angina 4 months after the procedure, they had ST-segment depression during stress electrocardiography, and underwent early follow-up
coronary arteriography and target lesion revascularization. With regard to the
angina status, only 2 control group patients, who developed restenosis at 6-month follow-up angiography, had mild effort angina and required target
lesion revascularization. This study demonstrated that administration of cilostazol after primary stenting
with the Palmaz-Schatz stent was associated with decreased angiographic late loss and loss index, resulting in better overall clinical and angiographic
outcomes.
Significant residual stenosis after primary balloon angioplasty in patients with
AMI, in concert with intimal hyperplasia, unopposed vessel recoil, and late remodeling, results in angiographic restenosis in >40% of infarct-associated
arteries within 6 months. Although the process of neointimal formation is not fully understood, adherent platelets and the resulting
mural thrombus may be important in promoting the migration and proliferation of smooth muscle cells.
However, most clinical trials designed to assess the effects of antithrombotic agents on restenosis have been disappointing.
Because stenting produces much greater initial gain, it is associated with lower
restenosis rate than balloon angioplasty, but stenting induces more late loss of
luminal diameters. Because this late effect is caused predominantly by neointimal formation,
antiproliferative therapies may have greater importance than after balloon angioplasty, when both early elastic recoil and
late arterial remodeling contribute to luminal narrowing.
Cilostazol is a novel inhibitor of type III phosphodiesterase in both platelets and
vascular smooth muscle cells that increases intracellular levels of cyclic adenosine monophosphate.
The antiplatelet effects of cilostazol are 10 to 30 times more potent than those of aspirin in inhibiting aggregation
induced by adenosine diphosphate, collagen, epinephrine, or arachidonic acid.
Notably, cilostazol also inhibits proliferation of rat vascular smooth muscle cells in tissue culture.
This effect also may be mediated by increased intracellular levels of cyclic adenosine monophosphate. Recent molecular
biologic studies indicate that cilostazol increases expression of the p53 gene, which inhibits the proliferation cycle of vascular smooth muscle cells and
suppresses expression of heparin-binding epidermal growth factor–like growth
factor. This drug also opposes endothelial cell death by increasing local concentrations of hepatocyte growth factor.
In a controlled study in dogs, oral administration of cilostazol prevented intimal hyperplasia after
placement of Gianturco Z stents. Accordingly, cilostazol appears to show
potential for reducing restenosis after coronary interventions, such as directional coronary atherectomy
or elective stent implantation. These trials depict a significantly smaller late loss and/or loss index in patients treated
with cilostazol than in those treated with aspirin or ticlopidine, as did the present study. However, the present study involved relatively few
patients for randomization, and the interpretation of the data should be rather
cautiously done.
Cilostazol, an antiplatelet drug that also may inhibit smooth muscle proliferation,
was given together with aspirin after primary stenting to treat patients with AMI.
In a randomized controlled trials of 50 patients, clinical and angiographic
outcome at 6 months was significantly improved by cilostazol.
Effect
of long-term cilostazol administration on coronary flow velocity and coronary
flow reserve
Reference: J Cardiology 1999
Oct;34(4):183-8.
Cilostazol, a novel potent inhibitor of phosphodiesterase, increases coronary flow. The effects of cilostazol on coronary flow velocity and coronary flow reserve were studied in 103 patients with coronary artery disease who underwent coronary angiography. Cilostazol 200 mg/day was administered for 3 months (31 patients) or 6 months (37 patients), and coronary flow reserve were measured before and after the cilostazol administration. Coronary flow reserve were measured twice at an interval of 6 months in the control group (35 patients). The Doppler guide wire was advanced into the coronary artery with no significant vessel stenosis. After obtaining continuous baseline coronary flow velocity, an intracoronary infusion of papaverine (10 mg) was performed to measure coronary flow reserve. There were no significant differences in coronary flow velocity just before intracoronary papaverine infusion between the initial and follow-up studies in any of the 3 groups. Coronary flow reserve increased significantly after cilostazol administration in the 3 months and 6 months groups compared with before administration (3 months group: 2.8 +/- 0.8 vs 2.4 +/- 0.9, p < 0.05; 6 months group: 2.8 +/- 1.0 vs 2.4 +/- 0.7, p < 0.01). However, there was no significant difference in coronary flow reserve in the control group between follow-up and initial studies (2.7 +/- 0.8 vs 2.5 +/- 0.8, NS). In conclusion, the long-term oral administration of cilostazol for 3 or 6 months improves coronary flow reserve.
