(Circulation. 1997;96:69-75.)
© 1997 American Heart Association, Inc.
Articles |
Diabetes Mellitus, Hypercholesterolemia, and Hypertension but Not Vascular Disease Per Se Are Associated With Persistent Platelet Activation In Vivo
Evidence Derived From the Study of Peripheral Arterial Disease
From the Departments of Medicine (G.D., C.G.) and Pharmacology (C.P.), University of Chieti "G. D'Annunzio"; the Institute of Internal and Vascular Medicine (P.G., R.V., G.G.N.), University of Perugia; Department of Medicine (F.V., S.B.), University of Rome; the Research Center of Vascular Diseases (M.C.), University of Milan; and Department of Pharmacology (G.C.), Catholic University of Rome, Italy.
Correspondence to Prof Carlo Patrono, Cattedra di Farmacologia I, Università degli Studi "G. D'Annunzio," Via dei Vestini, 31, 66013 Chieti, Italy. E-mail cpatrono{at}unich.it
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Abstract |
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Background Previous studies relating increased thromboxane (TX) biosynthesis to cardiovascular risk factors do not answer the question whether platelet activation is merely a consequence of more prevalent atherosclerotic lesions or reflects the influence of metabolic and hemodynamic disturbances on platelet biochemistry and function.
Methods and Results We examined 64 patients with large-vessel peripheral arterial disease and 64 age- and sex-matched control subjects. TXA2 biosynthesis was investigated in relation to cardiovascular risk factors by repeated measurements of the urinary excretion of its major enzymatic metabolite, 11-dehydro-TXB2, by radioimmunoassay. Urinary 11-dehydro-TXB2 was significantly (P=.0001) higher in patients with peripheral arterial disease (57±26 ng/h) than in control subjects (26±7 ng/h). Seventy percent of patients had metabolite excretion >2 SD above the normal mean. However, 11-dehydro-TXB2 excretion was enhanced only in association with cardiovascular risk factors. Multivariate analysis showed that diabetes, hypercholesterolemia, and hypertension were independently related to 11-dehydro-TXB2 excretion. During a median follow-up of 48 months, 8 patients experienced major vascular events. These patients had significantly (P=.001) higher 11-dehydro-TXB2 excretion at baseline than patients who remained event free.
Conclusions The occurrence of large-vessel peripheral arterial disease per se is not a trigger of platelet activation in vivo. Rather, the rate of TXA2 biosynthesis appears to reflect the influence of coexisting disorders such as diabetes mellitus, hypercholesterolemia, and hypertension on platelet biochemistry and function. Enhanced TXA2 biosynthesis may represent a common link between such diverse risk factors and the thrombotic complications of peripheral arterial disease.
Key Words: peripheral vascular disease • thromboxane • diabetes mellitus • hypercholesterolemia • hypertension
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Enhanced platelet biosynthesis of the proaggregative, vasoconstrictive substance thromboxane (TX) A2 has been associated with several cardiovascular risk factors. These include cigarette smoking,1 2 3 non–insulin-dependent diabetes mellitus,4 type IIa hypercholesterolemia,5 and homozygous homocystinuria.6 An unresolved question is whether persistent platelet activation in these settings is merely a consequence of more prevalent atherosclerotic lesions or reflects the influence of the accompanying metabolic and hemodynamic disturbances on platelet biochemistry and function.7
Arteriosclerosis obliterans of the lower limbs is an indicator of diffuse atherosclerotic disease and is associated with greatly increased cardiovascular and cerebrovascular morbidity and mortality.8 9 10 Moreover, a strong association of conventional risk factors with large-vessel peripheral arterial disease has been demonstrated.11 12 13
In the present study, we sought to determine whether the biosynthesis of TXA2 is altered in vivo through repeated measurements of the urinary excretion of its major enzymatic metabolites in patients with stable, large-vessel peripheral arterial disease. We compared a group of patients without any of the major cardiovascular risk factors (diabetes, hypertension, hypercholesterolemia, or smoking) to patients with these risk factors to evaluate the relative contribution of atherosclerosis per se versus the presence of these risk factors in affecting the rate of TXA2 biosynthesis in vivo. Furthermore, we examined in a preliminary fashion the hypothesis that enhanced TXA2 biosynthesis is associated with vascular complications during a 4-year follow-up period.
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Methods |
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Subjects
Sixty-four patients with large-vessel peripheral arterial disease (17 women and 47 men aged 62.5±8.9 years; range, 37 to 77 years) and 64 age- and sex-matched healthy subjects (17 women and 47 men aged 60.4±5.8 years; range, 35 to 75 years) were studied at four clinical centers on several occasions between March 1989 and December 1994 (Table 1
). Informed consent was
obtained from each participating subject. The study protocols were
approved by the internal medicine review boards of our
institutions.
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Patients with peripheral arterial disease were
selected for having at least one of the risk factors known to be
associated with enhanced TXA2 biosynthesis, ie, cigarette
smoking, diabetes mellitus, and type IIa
hypercholesterolemia, or none of the above. The
study aimed at recruiting at least 12 patients in each group, and the
length of the recruitment phase was related to the relatively rare
occurrence of patients without any such risk factors. Because of the
high prevalence of cigarette smoking (39%) and hypertension (25%) in
the entire study group (Table 1
), it was inevitable that such risk
factors were present in a variable proportion in addition to
diabetes mellitus, type IIa
hypercholesterolemia, or both. Sixty-four
healthy subjects were recruited by the same participating clinical
centers and matched by age and sex to the study patients. Although they
were selected for not having any cardiovascular risk
factors, 2 were later found to be cigarette smokers and 1 to be
hypertensive.
Peripheral arterial disease was defined both by
a history of intermittent claudication localized to the calf with no
resting pain and relieved within 10 minutes by rest14 and
by an ankle-arm index 
0.85 at rest.
The ankle-arm index, the ratio of ankle to arm systolic blood
pressure, usually 
1.0 in normal adults,14 15 16 17 18 was
measured according to a standard protocol by trained
technicians.15
The patients had unilateral (n=12) or bilateral (n=52) disease. In none
of the patients had arterial disease undergone detectable
progression during the previous 6 months as judged by clinical
evaluation during outpatient visits. Moreover, all had mild-to-moderate
symptoms. Approximately one third of patients had one or more
additional signs of atherosclerotic arterial disease, such
as stable angina pectoris, previous myocardial infarction, or a history
of transient cerebral ischemia (Table 1).
Non–insulin-dependent diabetes mellitus was defined in accordance with
the criteria of the American Diabetes Association.19 Type
IIa hypercholesterolemia was defined in
accordance with WHO criteria20 on the basis of the
determination of total plasma cholesterol and
triglyceride levels after a 12-hour fast. Hypertension was
defined as current systolic or diastolic blood
pressure >140/90 mm Hg.21 Blood pressure was
measured both in the supine and standing positions. Smokers were
currently smoking 5 to 30 cigarettes per day. The smoking habit was
confirmed by careful history documenting regular smoking for 1 year.
No participant smoked pipes or cigars. All measurements that led to
categorization into the different subgroups were performed repeatedly
(at least twice) during a 6-month period.
All patients were asked to abstain from taking any nonsteroidal anti-inflammatory or antiplatelet drug for at least 15 days before the study. Peripheral arterial disease patients who also had non–insulin-dependent diabetes mellitus followed an isocaloric diet and at the time of study were being treated with oral hypoglycemic drugs or insulin (intermediate-acting and regular insulin) for several months. Peripheral arterial disease patients with hypercholesterolemia followed a hypocholesterolemic diet at the time of study.
Patients with liver failure or renal disease (creatinine clearance <80 mL/min, serum creatinine level >2 mg/dL, urinary albumin excretion >0.3 g/d) as well as patients with body-mass index >28 were excluded from the study.
Design of the Studies
In the first study, a cross-sectional comparison of
11-dehydro-TXB2 excretion was performed between patients
and control subjects. Urine was collected from each subject during the
12-hour period preceding blood sampling; the samples were frozen
immediately and kept at -20°C until extraction. The reproducibility
of TXA2 biosynthesis was assessed by obtaining an
additional urine sample a week later from all patients. In 14 patients,
a third urine sample was obtained after a 2-year follow-up.
In a second study, we examined whether the metabolic disposition of TXB2 is altered in peripheral arterial disease in association with cigarette smoking3 by measuring the urinary excretion of its major enzymatic metabolites, ie, 11-dehydro-TXB2 and 2,3-dinor-TXB2.22 For this study, urine samples were obtained from six smokers with peripheral arterial disease (four men, two women; age range, 46 to 62 years) and six healthy nonsmokers (four men, two women; age range, 43 to 60 years).
A third study was designed to examine the relative contribution of platelet cyclooxygenase activity to the enhanced excretion of 11-dehydro-TXB2 associated with cardiovascular risk factors. Four patients (two with diabetes mellitus and two with hypercholesterolemia; age range, 39 to 69 years) were given aspirin (50 mg/d for 7 days), and 12-hour urine samples were obtained before and at the end of aspirin administration and on the 3rd, 5th, 7th, and 10th day after aspirin was withdrawn.
Follow-up
The vital status of the study patients was reviewed annually for
4 years to ascertain the occurrence of fatal and nonfatal vascular
events. One patient died of stomach cancer and five patients were lost
to follow-up because they refused to undergo the scheduled visits.
These five patients were excluded from the analysis of
TXA2 biosynthesis in relation to vascular complications.
For this analysis, stroke, myocardial infarction, and cardiac
death were considered major vascular events. Stroke was defined as
rapid onset of a neurological deficit that persisted for 24 hours
unless death supervened and included specific localizing findings
confirmed by neurological examination or brain scan, with no evidence
of an underlying nonvascular cause. Determination of fatal stroke was
based on death certificate data plus data on preterminal
hospitalization with a definite diagnosis of stroke. Nonfatal
myocardial infarction was defined as typical symptoms plus either
typical ECG changes (including new Q waves) or significant enzyme
elevation. Determination of fatal myocardial infarction was based on
death within 4 weeks after myocardial infarction. Cardiac death was
defined as death within 24 hours of the onset of severe cardiac
symptoms, unrelated to other known causes.
Analyses
Immunoreactive 11-dehydro-TXB2 and
2,3-dinor-TXB2 were extracted from 20-mL urine aliquots and
analyzed by previously validated radioimmunoassay
techniques.23 24
All blood samples for lipid, lipoprotein, and apolipoprotein analyses were drawn into sodium and potassium EDTA (1 mg/mL). Cholesterol and triglycerides were determined enzymatically. HDL cholesterol was determined by the phosphotungstic acid/MgCl2 precipitation method. LDL cholesterol was calculated by Friedewald's formula.25 These procedures have been described in detail elsewhere.26
Statistical Analysis
Statistical analysis was performed by use of
2 statistics or Fisher's exact test (if n5)
for independence and by unpaired t test. The linear
regression test was used to assess the correlation between continuous
variables. When necessary, log transformation was used to normalize
the data or appropriate nonparametric tests were
used.27 The aspirin study was analyzed with the
Kruskal-Wallis method and Mann-Whitney U test adjusted for
multiple comparisons. Moreover, the association of
11-dehydro-TXB2 excretion with the different
cardiovascular risk factors was assessed by multiple
regression analysis.
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Results |
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The rate of TXA2 biosynthesis, as reflected by the excretion of its major enzymatic metabolite, 11-dehydro-TXB2, was significantly (P=.0001) higher in patients with peripheral arterial disease (57±26 and 60±32 ng/h, as assessed on two different occasions) than in age- and sex-matched control subjects (26±7 ng/h). In 45 (70%) of the 64 patients, metabolite excretion was >2 SD above the control mean (Fig 1
).
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Influence of Risk Factors
We analyzed 11-dehydro-TXB2 excretion in
prospectively selected subgroups of patients with
peripheral arterial disease based on the
presence of cardiovascular risk factors previously
associated with enhanced TXA2 biosynthesis.1 2 3 4 5 6
As detailed in Table 2, 11-dehydro-TXB2
excretion was significantly higher in patients with
peripheral arterial disease in association with
cigarette smoking, non–insulin-dependent diabetes mellitus,
hypercholesterolemia, or both diabetes mellitus
and hypercholesterolemia than in control
subjects adequately matched for age and sex. Despite comparable
arterial disease (Table 3), patients who had
none of the above risk factors excreted 11-dehydro-TXB2 at
a rate indistinguishable from that of control subjects. Moreover, there
was no statistically significant correlation between metabolite
excretion and the ankle-arm index (r=.09;
P=.4742).
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As shown in Fig 2, only 1 (7%) of the 14 patients with
peripheral arterial disease but without risk
factors had 11-dehydro-TXB2 excretion above the normal
range, in contrast to 67% to 83% of the other subgroups. Hypertensive
patients excreted 11-dehydro-TXB2 at a nonsignificantly
(P=.1267) higher rate than normotensive patients: 75
(median; range 23 to 123 ng/h) versus 50 ng/h (range, 20 to 111 ng/h).
Because of the high prevalence of cigarette smoking (30% to 42%) and
hypertension (25% to 38%) in the subgroups of patients with other
risk factors, we performed a multiple regression analysis of
11-dehydro-TXB2 excretion rates. Such analysis
revealed that only diabetes mellitus (regression coefficient of 14.0;
standard error of 6.1; P<.03),
hypercholesterolemia (regression coefficient of
22.4; standard error of 6.3; P<.001), and hypertension
(regression coefficient of 14.1; standard error of 7.1;
P<.05) were independently related to
11-dehydro-TXB2 excretion.
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Reproducibility of TX Biosynthesis
In 14 nonselected patients, including patients with (n=11) and
without (n=3) cardiovascular risk factors, urinary
11-dehydro-TXB2 excretion was measured again after a 2-year
follow-up. Metabolite excretion at 2 years averaged 52±21 versus
52±20 and 59±29 ng/h in the two samples obtained at baseline. The
intrasubject coefficient of variation of 11-dehydro-TXB2
excretion averaged 23±7% on the basis of three metabolite
measurements in each patient. The 3 patients without risk factors, who
had perfectly normal metabolite excretion rates at baseline (28±8
ng/h), continued to have normal values at 2 years (28±2 ng/h) with an
intrasubject coefficient of variation (22±4%) indistinguishable from
that of patients with risk factors (23±8%).
Does Cigarette Smoking Alter TX Metabolism?
Cigarette smoking has been reported to alter TXB2
metabolism in humans.3 Thus, we performed
paired measurements of 11-dehydro-TXB2 and
2,3-dinor-TXB2, the major enzymatic metabolites of
TXB2 originating via the 11-hydroxy-dehydrogenase and
ß-oxidation pathways, respectively, in six patients with
peripheral arterial disease who were current
cigarette smokers and in six age- and sex-matched healthy nonsmokers.
The urinary excretion of 11-dehydro-TXB2 was enhanced in
patients versus control subjects (59±19 versus 28±6 ng/h;
P=.0037) to the same extent as that of
2,3-dinor-TXB2 (39±17 versus 17±6 ng/h;
P=.0262), thus resulting in a comparable ratio between the
two metabolites of 1.5 versus 1.6 in patients and control subjects,
respectively. A highly significant linear correlation was found between
individual excretion rates of the two TXB2 metabolites (Fig 3).
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) and in six age- and sex-matched control subjects (
) who
were nonsmokers. Linear regression analysis yielded a
statistically significant correlation (r=.934;
P=.0001) between the two metabolites.
Effects of Low-Dose Aspirin on TX Biosynthesis
To characterize the platelet dependence of enhanced
TXA2 biosynthesis in patients with peripheral
arterial disease and cardiovascular risk
factors, we assessed the extent of suppression and pattern of recovery
of 11-dehydro-TXB2 excretion in response to low-dose
aspirin (50 mg/d for 7 days). We studied four patients with
non–insulin-dependent diabetes mellitus or
hypercholesterolemia. The basal rate of
11-dehydro-TXB2 excretion averaged 47±9 ng/h and was
significantly (P=.0011) reduced by 
75%, well into the
normal range, at the end of 1 week of aspirin administration. As shown
in Fig 4, the pattern of recovery of
11-dehydro-TXB2 excretion after aspirin withdrawal was
linear over the next 10 days, a finding consistent with the
slow pattern of recovery of platelet
cyclooxygenase activity after
acetylation by aspirin.28
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TX Biosynthesis in Relation to Vascular Complications
During a median follow-up of 48 months, eight patients experienced
major vascular events. There were four acute myocardial infarctions
(three nonfatal and one fatal), three acute ischemic strokes
(one nonfatal and two fatal), and one cardiac death. Patients who
experienced these events during follow-up had significantly
(P=.001) higher 11-dehydro-TXB2 excretion at
baseline than patients who remained event free: 91 (range, 67 to 127
ng/h) versus 50 ng/h (range, 16 to 124 ng/h). Eight (100%) of eight
and 21 (41%) of 51, respectively, had metabolite excretion in excess
of the median value (56 ng/h).
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Discussion |
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We have previously reported4 5 6 that the rate of TXA2 biosynthesis is persistently increased in patients with metabolic disorders associated with enhanced risk of thrombotic complications. These include non–insulin-dependent diabetes mellitus,4 type IIa hypercholesterolemia,5 and homozygous homocystinuria.6 Abnormally high 11-dehydro-TXB2 excretion could be largely suppressed by low-dose aspirin in these studies, thus suggesting that it reflected a platelet source of TXA2 biosynthesis. Moreover, pharmacological intervention with intensive insulin treatment,4 simvastatin,26 or probucol6 allowed us to demonstrate a role for glycemic control, blood cholesterol levels, and oxidative mechanisms, respectively, as determinants of platelet activation in these clinical settings. However, because these complex metabolic disorders are also accompanied by accelerated atherosclerosis and more prevalent vascular lesions, it was not possible in these studies to assess the contribution of vascular disease vis-à-vis the underlying metabolic disorder in determining a state of persistent platelet activation.
The present study was designed to investigate the relative importance of diffuse atherosclerotic lesions and cardiovascular risk factors in affecting the determinants of platelet activation. Therefore, we investigated the rate of TXA2 biosynthesis29 30 in a relatively large group of patients with peripheral arterial disease, carefully characterized in terms of the extent of vascular involvement and presence of cardiovascular risk factors previously associated with enhanced TXA2 biosynthesis.
The main finding of the present study is that large-vessel peripheral arterial disease per se is not a trigger of platelet activation in vivo. Rather, the rate of TXA2 biosynthesis appears to reflect the influence of diabetes mellitus, hypercholesterolemia, and hypertension on platelet biochemistry and function. We used the ankle-arm blood pressure index as a measure of the extent of vascular involvement11 16 17 and compared subgroups of patients with presumably comparable severity of atherosclerotic disease.
In a prospective population study in Sweden,31 an
ankle-arm index <0.9 was found to be a more powerful marker of
generalized arteriosclerotic disease than an
ultrasonographically detected carotid stenosis of 30%. All
of our patients had an ankle-arm index <0.85, with mean values ranging
between 0.60 and 0.63 in the five different subgroups examined (Table 3). In the subgroup of patients without major
cardiovascular risk factors, mean
11-dehydro-TXB2 excretion was within 1 SD of the control
mean value in age- and sex-matched healthy subjects (Table 2).
Moreover, in the entire study population, there was no relationship
between the ankle-arm index and the rate of 11-dehydro-TXB2
excretion, thus suggesting that the presence of diffuse vascular
lesions in patients with large-vessel peripheral
arterial disease does not provide a stronger stimulus to
platelet activation than that provided by a lesser degree of
vascular involvement in healthy control subjects of comparable age.
Similarly, TXA2 biosynthesis was normal in the patients
with stable coronary disease studied by Fitzgerald et
al.32
In contrast, the vast majority (ie, 70% to 80%) of patients with
coexisting risk factors had abnormally high TXA2
biosynthesis that was reproducible over an extended period of
observation. On the basis of multiple regression analysis,
diabetes mellitus, hypercholesterolemia, and
high blood pressure were independently related to
11-dehydro-TXB2 excretion. Cigarette smoking, though
associated with enhanced TXA2 biosynthesis as reported
previously in subjects without peripheral vascular
disease,1 2 3 was not independently correlated with
metabolite excretion. We examined the possibility of underestimating
the actual rate of TXA2 biosynthesis in cigarette smokers
because of reduced conversion of TXB2 to
11-dehydro-TXB2, as described in healthy cigarette
smokers.3 However, paired measurements of
11-dehydro-TXB2 and of 2,3-dinor-TXB2, a major
product of ß-oxidation,18 revealed a remarkably
similar ratio between the two in patients and control subjects (Fig 3).
These results tend to exclude altered metabolic disposition
of TXB2 as a result of cigarette smoking,
consistent with data of Rangemark et al.33
The independent contribution of high blood pressure in affecting the rate of TXA2 biosynthesis is an unexpected finding of the present study in light of the negative findings in a previous study of patients with mild essential hypertension.34 In contrast, the independent role of diabetes mellitus and hypercholesterolemia as major determinants of enhanced TXA2 biosynthesis in the setting of peripheral arterial disease confirms earlier findings in patients with non–insulin-dependent diabetes mellitus4 and type IIa hypercholesterolemia.5
Enhanced TXA2 biosynthesis detected in association with
diabetes mellitus and hypercholesterolemia was
largely suppressed by a daily regimen of low-dose aspirin, and recovery
of 11-dehydro-TXB2 excretion showed a time course that
reflected the rate of platelet turnover (Fig 4). Although
extraplatelet sources might contribute to total body synthesis of
TXA2, such contribution appears to be small in patients
with peripheral arterial disease and comparable
to that previously established in healthy subjects.35
Previous studies36 37 38 39 40 41 42 43 44 45 46 47 examined various aspects of platelet function, including TXA2 biosynthesis, in patients with peripheral arterial disease. A large proportion of these studies reported abnormal platelet function, as measured ex vivo by various techniques,40 41 42 or detected high circulating levels of platelet products.43 44 45 46 47 The limitations of these capacity indexes as well as the pitfalls of plasma measurements of platelet products have been discussed previously.7 30
The noninvasive measurement of 11-dehydro-TXB2 excretion, a widely accepted method of assessing platelet function in vivo,7 30 has been used in very few studies of patients with peripheral arterial disease.36 37 38 39 However, these studies were both too small and possibly confounded by the uncharacterized presence of cardiovascular risk factors to provide a reliable assessment of the contribution of the latter vis-à-vis the underlying vascular disease in determining the rate of TXA2 biosynthesis.
The limited follow-up data from the present study suggest that enhanced TXA2 biosynthesis and TXA2-mediated amplification of platelet activation in response to plaque fissuring may represent a common link between different risk factors (namely, diabetes mellitus, hypercholesterolemia, and hypertension) and the occurrence of thrombotic complications in patients with peripheral arterial disease.
Despite an obvious rationale, there is still substantial uncertainty as to the clinical indication for antiplatelet therapy in patients with peripheral arterial disease because of inadequate trials in this setting.48 The Antiplatelet Trialists' Collaboration identified more than 20 randomized trials of antiplatelet drugs in more than 3000 patients with intermittent claudication and described a 20% odds reduction of major vascular events, which failed to reach statistical significance.48 Additional trials49 have not resolved such statistical uncertainty about the efficacy of antiplatelet drugs in these patients. It is interesting to note that aspirin was used in only 5 of 27 antiplatelet trials, at doses ranging between 975 and 1500 mg/d.48 Thus, it might be argued that the proper antiplatelet regimen, ie, aspirin 75 to 100 mg/d,50 has not been tested in patients with peripheral arterial disease. Clearly, a trial of adequate size is needed to assess the efficacy and safety of low-dose aspirin in this setting. The results of the present study may help to identify a group of patients ideally suited for such a trial, ie, those with enhanced 11-dehydro-TXB2 excretion. Moreover, this approach may help define guidelines for antiplatelet therapy in patients with peripheral arterial disease.
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Acknowledgments |
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This study was supported by grants from Consiglio Nazionale delle Ricerche (CNR), Progetto Finalizzato Prevenzione e Controllo dei Fattori di Malattia (SP8: 94.00560.PF41, 94.00627.PF41, 95.00882.PF41, and 95.00807.PF41). We are indebted to Dr Rino Migliacci for patient referral and helpful criticism and to Rossella Tonelli, Alessandra Migliavacca, and Andre Harris for expert editorial assistance.
Received November 18, 1996; revision received January 7, 1997; accepted January 17, 1997.
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