Serum
lipids as risk factors for patients with peripheral arterial disease
(Portuguese
PDF version) Winston
Bonetti Yoshida1, Fabiana Aparecida Bosco2, Flavia
A.T.M. Medeiros2, Hamilton Almeida Rollo3, Ivete
N. Dalben4 1.
Associate Professor, Department of Surgery and Orthopedics, UNESP, Botucatu.
2. Undergraduate Student, Faculdade de Medicina de Botucatu, UNESP.
3. Assistant Professor, Department of Surgery and Orthopedics, UNESP, Botucatu.
4. Assistant Professor, Department of Public Health, UNESP, Botucatu. Supported
by PIBIC/CNPq/UNESP. Correspondence:
Winston Bonetti Yoshida
Departamento de Cirurgia e Ortopedia
Faculdade
de Medicina de Botucatu - UNESP
CEP18618-970 - Botucatu - SP
Fax: +55
(14) 6821-7428
E-mail: winston@fmb.unesp.br
ABSTRACT Objectives:
Some studies suggest that there is no clear relationship between peripheral arterial
disease and hyperlipidemia. The aim of the present study was to correlate the
lipid profile of 77 patients with peripheral arterial disease, admitted to our
Vascular Surgery Service between August 1997 and July 1998, with the results of
physical examination, ankle brachial pressure index and arteriography.
Methods: The data were analyzed through SPSS-v8 software.
Results:
Among the patients studied, 69.7% were men and 30.3% were women; 17.8% of the
patients showed total lipids > 800 mg/dl; 33.3% of them, total cholesterol
> 200 mg/dl; 38.9%, LDL > 130 mg/dl; 84.9%, HDL < 35 mg/dl; 17.8%, triglycerides
> 200mg/dl; 63.6%, apo AI < 115mg/dl; and 12.9%, apo B > 150 mg/dl. There
was no correlation between lipid levels and the intensity of atherosclerotic lesions.
Conclusions: We concluded that the frequency of dyslipidemia was important
in this preliminary group of patients. These findings show the necessity for new
studies, with a larger patient population and with matched control cases, so that
more conclusive data on this controversial issue can be obtained.
Key-words:
atherosclerosis, dyslipidemia, cholesterol, apo AI, apo B.
Palavras-chave: aterosclerose, colesterol, dislipidemia,
apo-A-I, apo-B.
J
Vasc Br 2003;2(1):05-12
INTRODUCTION
The etiopathogenic
importance of serum cholesterol levels in coronary atherosclerosis is
widely known. The risk factors for coronary artery disease (CAD) include
age > 45 years for men and >55 years for women (or before, in
case of early menopause); family history of CAD; smoking; hypertension
(> 140 x 90 mmHg); and low levels of high-density lipoprotein (HDL)-cholesterol
(< 35 mg/dl).1 The relationship between
serum cholesterol and coronary disease is based on the low-density lipoprotein
(LDL) levels which, when elevated, often are concurrent with prominent
lesions to the walls of these arteries.
The recommended levels of lipoprotein fractions have varied over time
and, currently, the recommended levels of LDL-cholesterol are the following:
< 100 mg/dl for patients with CAD or at risk for CAD, < 130 mg/dl
for patients with more than two risk factors and < 160 mg/dl for
patients with 0-1 risk factor.1 Recent studies
have shown that triglyceride (TG) levels seem to be a strong and independent
predisposing factor for acute myocardial infarction (AMI), especially
when cholesterol levels are also elevated.1
If high cholesterol levels are followed by hypertriglyceridemia >
200 mg/dl, the non-HDL-cholesterol levels (total cholesterol - HDL cholesterol)
have to be calculated. The non-HDL-cholesterol levels are concerned
with lipoproteins related to apolipoprotein B (apo B): LDL, remnants,
intermediate-density lipoproteins (IDL) and very low-density lipoproteins
(VLDL). In addition, the non-HDL-cholesterol levels seem to be more
efficient in predicting risk than LDL levels alone.2
With regard to HDL-cholesterol,
the risk of CAD increases as its values decrease (the ideal values are those 35
mg/dl.3 Every 1 mg/dl of increase in HDL-cholesterol
corresponds to approximately > 3% of reduction in vascular events.4
Quite recently, an extensive study has shown that high levels of apo B are
better predictors of vascular events than LDL and apolipoprotein A1 (apo A1);
on the other hand, low levels of apo B are better predictors than HDL.5
On top of that, in the 4S6 study, the levels of apo
B were reduced by simvastatin, and a linear correlation was observed between apo
B levels and mortality, thus showing that apo B levels are better markers of simvastatin
therapy.
As far as peripheral arterial disease (PAD) is concerned, some
studies associate it with high levels of TG and/or total cholesterol (TC),3,7,8
of apo B and VLDL.9 Low levels of HDL and apo A1 were
also more frequent in this type of patient than in controls.10,11
Other studies showed a relationship between PAD and high levels of TG (separately);
of TC and TG bound to VLDL; of TC and TG bound to IDL; and low HDL levels.12
High TG levels and low HDL levels were observed by other authors.7,13,14
The prevalence of abdominal aortic aneurysm was higher in patients with increased
serum cholesterol. Multicenter studies, conducted by the Pathobiological Determinants
of Atherosclerosis in Youth (PDAY)15 group, with
patients who died violently between the ages of 15 and 34, revealed an association
between aortic atherosclerosis and atherosclerosis of the right coronary artery
and high levels of VLDL and LDL and low HDL levels.
Another study16
correlated the extent of coronary stenosis with the extent of atherosclerosis
of the proximal part of the femoral artery in 290 patients submitted to angiography.
No narrow relationship was observed as to the extent of atherosclerosis in these
segments. On the other hand, it was observed that both male and female individuals,
smokers, sedentary persons, hypertensive, hyperuricemic and hyperglycemic individuals
were at high risk for PAD. Especially in women, high TG levels were found to be
an important risk factor for PAD.
Due to such variation in the lipid
profile of patients with PAD and since no studies have been performed with patients
of similar socioeconomic and nutritional levels to the ones observed in our setting,
we carried out the present study with the aim of prospectively and consecutively
assessing patients with PAD admitted to the Vascular Surgery Service of Hospital
das Clínicas of UNESP, and correlating the atherosclerotic lesions detected
on angiographic examination with serum lipid levels. PATIENTS
AND METHODS
Seventy-seven consecutive patients with clinical history of PAD were prospectively
studied between August 1997 and July 1998. These patients were admitted to the
Vascular Surgery Service with indication of contrast angiography for diagnosis
and planning of surgical treatment of their arteriopathy. All the exams described
further below belonged to the preoperative routine evaluation of these patients.
The exclusion criteria were patients with TG > 400 mg %, due to inaccurate
Friedewald equation, and patients whose angiography did not allow conclusive codification
and/or those who had aneurysms or fistulas. In the case of patients with several
hospital admissions, we considered only the first one.Clinical
assessment
First of all, based on the anamnestic interview, the patients were categorized
as to gender, color, age and origin. We also tried to identify previous history
of diabetes mellitus, arterial hypertension, smoking, alcoholism, obesity, ischemic
heart disease, hypothyroidism, menopause, chronic renal insufficiency and sedentary
lifestyle.
After that, the patients were submitted to general physical
examination so that we could verify whether they had some detectable systemic
disease on clinical examination and could assess their general health status.
Vascular examination aimed at detecting symptomatologic characteristics of
patients with PAD. Based on this examination, the patients were classified as
carriers or non-carriers of (1) trophic disorders (muscle atrophy, reduced hair
growth, pigmentation or fingernail disorders or, ulcers or gangrenes); (2) skin
color disorders (cyanosis, erythrocyanosis, pallor); (3) temperature-related disorders
(increase or reduction in temperature); (4) sensory or motor disorders; and (5)
previous amputations.
Peripheral perfusion was symptomatologically quantified
by way of pulse palpation. The pulses of each peripheral artery scored between
0 and 4, directly proportional to the amplitude. The common femoral, popliteal,
pedal, and posterior tibial arteries, on both sides, were examined.
The scores of each hemibody were added and divided by the number of examined arteries,
and a mean was obtained for each one of them. Likewise, the mean for the femoropopliteal
and distal segments of each side was calculated. The examined segments were classified
as normal, reduced pulse or total occlusion, based on the score.
Ankle brachial pressure index
The systolic arterial pressure
was checked by Doppler ultrasound at the pedal, posterior tibial and humeral arteries.
The ankle brachial pressure index (ABPI) was calculated, and the highest value
was recorded on the protocol.
Cardiological assessment
Due to the frequent association
with coronary atherosclerosis, the patients were assessed clinically and by electrocardiogram,
and chest x-ray (PA and lateral). According to the results of these exams, the
patients were classified as free of cardiopathies, having ischemic heart disease
or having any other cardiopathies.
Laboratory assessment
The biochemical exams described in the
present study were carried out at the Laboratory of Clinical Analysis and at the
Blood Center of the School of Medicine of UNESP.
Lipid profile
The lipid profile was determined after a 12-hour fasting
period.
o Total lipids (TL), TC and TG were calculated by total enzymatic
colorimetry using glucose oxidase-peroxidase (GOD - PAP).
o The fraction of
HDL-cholesterol was calculated manually by sodium phosphotungstate.
o The
fraction of LDL-cholesterol was calculated by Friedewald formula, only valid with
TG <400 mg %. LDL = TC - (VLDL+HDL). The reference values in adults older than
20 years, according to the Brazilian Consensus on Dyslipidemias, in 19943,
are shown in Table 1.
o The apo A1 and apo B doses were determined by immunoturbimetry
and spectrophotometric reading. The reference values are shown in Table 2.  Table
1 -Reference
values of serum lipids in adults, according to the Brazilian Consensus on Dyslipidemias3
 |
| Desirable
(mg/dl) | Borderline
high (mg/dl) | High
(mg/dl) | |
| Total
lipids | 400
- 800 | | |
| Total
cholesterol | <
200 | 200
- 239 | >
240 | | LDL-cholesterol | <
130 | 130
- 159 | >
160 | | HDL-cholesterol | >
35 | | |
| Triglycerides | <
200 | | >
200 | |
Table
2 - Reference values of apolipoproteins determined by immunoturbimetry
|
| Proteins | Men
(mg/dl) | Women
(mg/dl) | |
| Apo-A1 | 115-190 | 115-220 |
| Apo-B | 70-160 | 60-150 |
|
Other exams
With the aim of confirming the risk factors mentioned
during anamnestic interview and detecting unmentioned factors, we performed the
following exams to quantify:
o Fasting glucose, GOD-PAP method. Plasma
and serum reference levels: 70-110mg/dl.
o Uric acid, by enzymatic colorimetry.
Patients with >7 mg/dl were considered hyperuricemic.
o Urea and
creatinine, by modified Jaffe method. Reference values: urea 15-40 mg/dl and creatinine
0.6-1.4 mg/dl.
o Blood typing (direct and reverse) by means of antisera and
a well-known red cell panel.
Angiographic exam
Each peripheral artery of the lower limbs
was evaluated by angiography, and scores were kept according to the severity of
the lesion to the affected segment: (01) normal; (02) stenosis of 30%; (03) stenosis
between 30 and 60%; (04) stenosis greater than 60%; (05) total occlusion.
Visceral branches were not assessed, as this would require selective visceral
catheterization.
We also determined an index that would favor the necessary
correlations. The assessed arteries were grouped as follows: iliac (common, internal
and external); femoropopliteal (common, deep and superficial femoral, and suprapatellar
and infrapatellar popliteal) and distal (anterior and posterior tibial, fibular,
pedal and plantar arch). As with pulse palpation, the scores of the examined side
were added and divided by the number of assessed arteries, and a mean for each
hemibody was obtained. The mean was also calculated per segment and, finally,
a general index was obtained (mean involvement of all arteries assessed.) The
segments were classified as normal, stenosis < 60%, stenosis > 60% or total
occlusion.
Statistical analysis
For quantitative variables:
a)
Determination of central trend values (mean and dispersion median, standard deviation,
and variation coefficient) and position values (percentiles);
b) Calculation
of correlation coefficient between variable pairs.
For qualitative analysis:
a) Elaboration of tables containing the frequency of occurrence of each class;
b) Calculation of association coefficients between variable pairs. The
descriptive, comparative and correlation analysis was made by means of the SPSS
v.8.0 program. RESULTS
Seventy-seven patients
were studied, of whom 71.1% belonged to DIR XI administrative region of Botucatu.
The mean age of the group was 65.6 years, but 69-year-olds were more frequent.
Men accounted for 69.7% of the sample and there was no significant age difference
between males and females. Whites totaled 85.5% of the sample.
In the
studied group, 98.7% had a previous history of intermittent claudication, 36.4%
had ulcers and gangrenes, 13% were amputees and 35.8% of the men were sexually
impotent. With regard to the risk factors for PAD, the following prevalence, in
order of frequency, was obtained: current and/or previous smoking (88.2%), of
which 78.6% had been smoking for over 15 years and 17.9% for over 50 years; sedentary
lifestyle (86.8%); systemic arterial hypertension (58.7%); frequent consumption
of alcoholic beverages (58.7%), of which 97.8% had been consuming alcohol for
more than 20 years; blood type A (40.27%); diabetes mellitus (37.3%); chronic
renal insufficiency (22.7%); ischemic heart disease separately or associated with
other heart disease (22.4%); hyperuricemia (20.77%); family history of PAD (15.5%),
deep vein thrombosis (3.9%), and hypothyroidism (2.6%). The frequency of dyslipidemia
is shown in Table 3. Table
3 - Frequency of dyslipidemia in 77 patients with CAD
|
| Fraction | Male
(n = 54) | Female
(n = 23) | Total
(n = 77) | |
| Total
lipids > 800 mg/dl | 4
(7.5%) | 6
(25.0%)* | 17.8% |
| TC
> 200 mg/dl | 12
(22.6%) | 14
(58.3%)* | 33.3% |
| LDL-cholesterol
> 130 mg/dl | 16
(30.1%) | 13
(54.1%) | 38.9% |
| HDL-cholesterol
< 35 mg/dl | 41
(77.3%) | 21(87.5%) | 84.9% |
| Triglycerides
> 200 mg/dl | 8
(14.8%) | 5
(20.8%) | 17.8% |
| Apo
- A1 < 115 mg/dl | 33
(69.3%) | 16
(30.6%) | 63.6% |
| Apo
- B > 150 mg/dl | 1
(10%) | 9
(90%)* | 12.9% |
|
There was statistically significant difference between males and females and TL
levels (chi-squared test = 4.07; P = 0.04), TC (chi-squared test = 7.94;
P = 0.004) and apo B (Fisher's test with P = 0.0001), with a higher
frequency among females (Table 3). Of all patients, 17.8% had TL >800 mg/dl;
33.3%, TC >200 mg/dl; 38.9% LDL >130 mg/dl; 84.9% HDL <35 mg/dl; 17.8%
TG >200 mg/dl; 63.6% apo Al < 115 mg/dl; and 12.9% apo B >150 mg/dl.
Regarding the special vascular physical examination, 80.5% of the patients
showed skin color disorders; 77.9%, ulcers or gangrenes; 72.7%, sensory disorders;
44.1%, reduced motor function; 71.4%, temperature disorders (increase or reduction);
and 12.9%, amputations. The frequencies of disorders according to pulse palpation
are shown in Table 4. Table
4 - Frequency of clinical disorders according to pulse palpation
|
| Indexes | Normal | Reduced
pulse | Total
occlusion | Losses |
|
| General | 3
(3.89%) | 47
(61.03%) | 26
(33.76%) | 1
(1.73%) | | Femoropopliteal | 8
(10.38%) | 64
(83.11%) | 3
(3.89%) | 2
(2.59%) | | Distal | 3
(3.89%) | 22
(28.57%) | 51
(66.23%) | 2
(2.59%) | |
When Doppler ultrasound was used to assess the same patients, only 12.9% of them
showed one of ABPI >1.0.
The results of arteriography are shown in Table
5. Table
5 - Frequency of arteriographic alterations according to the suggested indexes
|
| Indexes | Normal | Stenosis
< 60% | Stenosis
> 60% | Total
occlusion | Losses |
|
| General | 3
(3.80%) | 46
(59.7%) | 6
(7.7%) | 1
(1.2%) | 21
(27.2%) | | Iliac | 21
(27.27%) | 19
(24.6%) | 2
(2.5%) | 4
(5.1%) | 27
(35.0%) | | Femoropopliteal | 10
(12.9%) | 35
(45.4%) | 5
(6.4%) | 4
(5.1%) | 19
(24.6%) | | Distal | 5
(6.4%) | 21
(27.2%) | 6
(7.7%) | 9
(11.6%) | 30
(38.9%) | |
Figures 1 and 2 respectively present the results of the symptomatologic and arteriographic
assessment as against the mean results of the lipid profile. The statistical analysis
of the means did not reveal any association between lipid levels and the progression
of vascular disorders in the current sample. Figure
1 - Mean values of lipid fractions in relation to the clinical alsessment by way
of pulse palpation. 
Figure
2 - Mean values of lipid fractions in ralation to the arteriographic findings. 
DISCUSSION
PAD is a chronic disorder
that affects the aorta and its branches, in addition to the lower and upper limb
arteries. Its incidence is not clearly established in our setting, due to the
paucity of epidemiological data. In the USA, PAD affects approximately 8 to 12
million people and is associated with high morbidity and mortality.17,18
In Partners' study,19 the prevalence of PAD in primary
care was high (29%), although physicians were not attentive to its diagnosis;
the simple measurement of ABPI showed a large number of patients with PAD who
had not been clinically detected. Furthermore, the patients did not receive the
same care during the treatment of dyslipidemias and arterial hypertension given
to patients with coronary disorders.
In the study conducted by Caprie,20
with 19,185 patients with PAD, CAD or cerebrovascular disease (CVD), nearly one
third (n = 6,482) of the patients presented clinical evidence of PAD. The analyses
of this subgroup showed that PAD was an important marker of AMI or stroke, especially
in previous cases of diabetes, advanced age, transient ischemic attack (TIA),
stroke or angina. In this study, 73% of the patients with PAD were males and the
age averaged 64 years.
PAD is predominant in individuals aged between
50 and 70 years, preferably men, whose characteristic symptom of arterial occlusive
disease21 is intermittent claudication. Of the 77
studied patients, male individuals, all symptomatic and within the age range described
above, prevailed. One third of the male population complained of sexual impotence.
As far as risk factors are concerned, several studies,11,22
showed a strong association between smoking habit and PAD, of which smoking was
one of the most prevalent risk factors. In the studied sample, 88.2% of the patients
were smokers or former smokers. In the study carried out by Caprie,20
38% were current smokers and 53% were former smokers.
Diabetes mellitus
(DM), in its turn, has been shown to increase the incidence and worsen the prognosis
of patients with PAD.21 The present study revealed
a DM prevalence of 37.3%, which should be carefully considered in the prognosis
of these patients. In the study conducted by Caprie,20
this prevalence was 21%.
Some literature data22
associate hyperuricemia with higher incidence of PAD in supraaortic branches,
which amounted to 20.7% in this study. The change in the metabolism of uric acid
is likely to be part of a generalized metabolic disorder, which includes dyslipoproteinemia,
hyperglycemia, hyperinsulinemia and hypertension.22
According to other literature data,9 patients
with blood type A are more liable to the development of PAD, despite the fact
that the etiopathogenic mechanism is not known. By analyzing the distribution
of blood types in our sample, we observed that type A is the most prevalent.
Other risk factors mentioned in the literature22
were also found in our sample: sedentary lifestyle, systemic arterial hypertension,
alcoholism, chronic renal insufficiency, hypothyroidism, and family history of
PAD.
With regard to hyperlipidemia, some studies have shown that hypertriglyceridemia
is strongly associated with PAD.11,23
These studies also associated PAD with low HDL levels, which was clearly observed
in male patients. Still, other studies,13,16 suggested
that low HDL levels could be an independent risk factor for PAD, although they
have little relevance to individual prognosis and no relation to the severity
of the disease.
Some studies relate PAD to high TC levels.3,7,8
Conversely, a study that correlated familial hypercholesterolemia and PAD did
not yield satisfactory results, perhaps due to the sample size.24
High LDL levels were found by other authors in patients with PAD.7,8
Some studies13,16 suggested that the lipid profile
of patients with PAD should be complemented with the quantitation of apolipoproteins
(apo A1 and apo B). Apo A1 is directly related to HDL levels and is often reduced
in patients with PAD. In the present study, 84.9% of the patients showed HDL levels
below the desirable values, and apo A1 followed this trend as well. Curiously
enough, most of the sample showed low LDL levels (61.1 %), which is consistent
with the results of apo B.
Clinical studies showed beneficial effects
of cholesterol reduction in coronary artery disease.25
In PAD, especially, a meta-analysis of 698 patients treated with different lipid-lowering
drugs revealed a total mortality of 0.7% in treated patients as against 2.9 %
among those who received placebo, a difference that was not statistically significant.26
However, this study demonstrated that lipid-lowering treatments reduced the development
of atherosclerotic disease, assessed by angiography, and the severity of claudication.
Several other studies also showed the benefits of cholesterol reduction in
the stabilization or regression of femoral atherosclerosis.27-29
In brief, the reduction of lipids is usually beneficial to patients with PAD,
which is often associated with CAD and/or CVD. Currently, LDL < 100mg/dl and
TG < 150 mg/dl are recommended to these patients.30
By analyzing the special vascular physical examination, all findings regarding
inspection were compatible with those described in the literature.21
Pulse palpation, according to the literature,22 shows
reduction or absence of peripheral pulses, especially of anterior tibial pulse,
in approximately 10 to 30% of the symptomatic cases. The data obtained through
the present study show that 28.5% of the studied patients had reduced pulse in
this segment, whereas pulse was totally absent in 66.2%.
In this study,
it was not possible to establish a statistical correlation between lipid profile
of the patients and the extent of vascular involvement assessed by clinical examination,
Doppler ultrasound and arteriography.
In conclusion, the present study
showed a relevant frequency of dyslipidemia among PAD patients. These findings
indicate the need for further studies, with a larger study sample and paired controls,
so that the relationship between PAD and the lipid profile of patients can be
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