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Evaluation of lipid profile in the peripheral arterial disease
(Portuguese PDF version)

Antônio Carlos Brandão,¹ Daniel Maranho Trindade,² Marcela Augusta Pinhel,³ Alexandre Maiera Anacleto,⁴ José Maria Pereira de Godoy,⁵ José Ernesto dos Santos,⁶ Dorotéia Rossi Silva Souza¹

1. Ph.D. Adjunct professor, Department of Molecular Biology, Faculdade de Medicina de São José do Rio Preto (FAMERP), São José do Rio Preto, SP, Brazil.
2. Ph.D. Professor, Department of Molecular Genetics, Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil.
3. Intern biologist, Department of Molecular Biology, FAMERP, São José do Rio Preto, SP, Brazil.
4. Physician, Instituto de Moléstias Cardiovascular, São José do Rio Preto, SP, Brazil.
5. Ph.D. Adjunct professor, Department of Cardiology and Cardiovascular Surgery, FAMERP, São José do Rio Preto, SP, Brazil.
6. Ph.D. Professor, Department of Medical Clinic, Faculdade de Medicina de Ribeirão Preto, USP, Ribeirão Preto, SP, Brazil.

Correspondence:
José Maria Pereira de Godoy
Rua Floriano Peixoto, 2950
CEP 15020-010 - São José do Rio Preto, SP, Brazil
E-mail: godoyjmp@riopreto.com.br

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ABSTRACT

Objective: The aims of this study were to analyze the lipid profile in peripheral arterial disease and to evaluate its influence, as well as the age factor in the obstructive and aneurysmal peripheral arterial disease.

Method: A total of 124 individuals were studied, 62 patients with peripheral arterial disease confirmed by angiography, divided into patients with obstructive peripheral arterial disease and patients with aneurysmal peripheral arterial disease, and 62 control individuals. The serum levels of lipoprotein (a), triglycerides, total cholesterol, and low-density (LDLc), high-density (HDLc) and very low-density (VLDLc) lipoprotein cholesterol fractions were measured.

Results: Desirable levels of total cholesterol, LDLc, VLDLc, and triglycerides were detected in both groups. However, patients with obstructive peripheral arterial disease and the control group showed mean levels of triglycerides (175.8 ± 36.1 mg/dl and 169.7 ± 41.5 mg/dl, respectively) significantly higher when compared to the aneurysmal peripheral arterial disease group (138.4 ± 28.9 mg/dl; P = 0.001). The mean levels of HDLc were significantly lower in patients with obstructive peripheral arterial disease (35.2 ± 15.3 mg/dl) and aneurysmal peripheral arterial disease (33.1 ± 10.7 mg/dl) when compared to the control individuals (41.5 ± 11.8 mg/dl; P = 0.010). The levels of lipoprotein (a) were high in all three groups. There was an association of obstructive peripheral arterial disease and increased levels of LDLc, triglycerides and lipoprotein (a) and decreased levels of HDLc and age. On the other hand, increased levels of triglycerides, lipoprotein (a), and age and decreased levels of HDLc and LDLc were associated to aneurysmal peripheral arterial disease.

Conclusion: In conclusion, reduced levels of HDLc only in patients with peripheral arterial disease confirm its effect in protecting against the disease. High levels of LDLc and low age are associated with obstructive peripheral arterial disease, while increased age seems to be related with aneurysmal peripheral arterial disease.

Key-words: lipoprotein (a), aneurysm, atherosclerosis.

J Vasc Br 2005;4(2):129-36

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The atherosclerotic peripheral arterial disease (PAD) affects 11 to 15% of the population with more than 60 years old.¹ Epidemiologic studies show that around 5% of men and 2.5% of women over 60 years old present symptoms of intermittent claudication, due to the obstruction of arteries by atherosclerotic plaques.^2-4 The prevalence of the disease increases with specific examinations performed on symptomatic or asymptomatic patients.¹ The correlations between the incidence of coronary artery disease (CAD) and high plasmatic levels of total cholesterol (TC), and between the action of the low-density lipoprotein cholesterol (LDLc) and the reduction of high-density lipoproteins (HDLc) are demonstrated by several epidemiologic studies.^5-8

Lipoprotein (a) [Lp (a)], described in the early 1960's as a variant of the LDL and having, as LDL, apoB-100, besides the apo (a), is also associated to the cardiovascular disease.^9,10 The molecular homology between glycoprotein apo (a) and the plasminogen,^11,12 both with genic loci in the human chromosome^6,13 has encouraged investigations as an attempt to clear the Lp(a) atherogenicity, due to its interference in the fibrinolysis. Several studies using qualitative and quantitative techniques demonstrate the increase in the level of Lp(a) as a risk factor for atherosclerosis, both of peripheral and coronary arteries.^14-20 Increased plasmatic levels of Lp(a) were also found in patients with aortic aneurysm when compared with a control group.^21-23

The aim of the present study was to analyze the lipid profile in patients with PAD, as well as to evaluate its association and age to the obstructive peripheral arterial disease (OPAD) or to the aneurysmal peripheral arterial disease (APAD).

PATIENTS AND METHOD

We studied 124 individuals, Caucasians and males, with ages varying from 38 to 80 years, distributed into two groups. Group 1 was composed of 62 patients with clinical symptoms and PAD confirmed by angiography, with ages varying from 38 and 79 years (mean and standard deviation = 62 ± 8.6 years). Of these patients, 40 presented atherosclerotic obstruction of the iliac, femoral and/or carotid arteries, and 22 had thoracic, abdominal or thoracoabdominal aortic aneurysm. All patients with obstructive disease and aneurysm were submitted to surgery. Group 2 was composed of 62 individuals with no clinical history or alterations at clinical examination, with ages varying from 43 to 80 years (mean and standard deviation = 59 ± 9.2 years). Individuals with renal disease, hepatic disease or diabetes mellitus were excluded. All individuals agreed to participate in the study by signing a consent form.

Table 1 shows the characteristics of the assessed individuals concerning the type of artery lesion, presence of hypertension, smoking, and types of medication used. Those who had quit smoking for at least 2 years were included among the non-smoking individuals.

Table 1 - Distribution of individuals according to symptoms of vascular insufficiency, systemic arterial hypertension (SAH), smoking, and medication

	SAH		Smoking		Medication
Patients (n = 62)					ACE inhibitor		Diuretics
	n	%	n	%	n	%	n	%
With obstruction (n = 40)
Carotid (n = 3)	2	5	1	2.5	2	5	1	2.5
Femoral (n = 22)	10	25	14	35	9	22.5	4	10
Others (n = 15)	4	10	3	7.5	4	10	1	2.5
Total	16	40	18	45	15	37.5	6	15
Aneurysm (n = 22)
AA (n = 13)	5	22.7	5	22.5	2	9.1	2	9.1
TAA (n = 9)	7	32	3	13.6	2	9.1	2	9.1
Total	12	54.7	8	36.1	4	18.2	4	18.2
Total	28	45	26	42	19	30.6	10	16.1
Controls (n = 62)	5	8.1	23	37.1	2	3.2	2	3.2

ACE = angiotensin converting enzyme; AA = abdominal aorta; TAA = thoracoabdominal aorta.

 

Venous blood samples were collected from individuals, after fasting for at least 12 hours, in order to measure the serum levels of triglycerides (TG), TC, and fractions of cholesterol (VLDLc, LDLc, and HDLc). Serum concentrations of TG and TC were determined by chromatographic enzymatic methods. HDLc levels were obtained by direct measurement, using the commercial kit produced by LabTeste Brasil, with measurements performed at the biochemical system COBAS MIRA "S" (Roche). LDLc and VLDLc levels were calculated by the Friedewald formula, used for TG levels lower than 400 mg/dl. Lp(a) levels were measured by turbidimetry, using the commercial kit produced by APE (Belgium). The reference values for lipid profile variables were according to the Brazilian Society of Cardiology.²¹ Desirable levels for Lp(a) were equal or lower than 30 mg/dl. For evaluating lipid profile, the total number of patients with PAD and isolated values for patients with OPAD and APAD were considered.

Statistical analysis

For the comparative study of the lipid profile between patients and control group, as well as in the subgroups with OPAD and aortic aneurysm, the Student's t test with the Welch correction was used. For variables without Gaussian distribution the non-parametric Kruskal-Wallis test was used. For multivariate test analysis, the analysis of main components was applied to determine association factors among variables HDL, LDL, TG, Lp(a), and age. The Tukey test was used for multiple comparisons for the lipid profile in patients and control group separately. An a error equal to %5 was admitted, with significance level for P ≤ 0.05.

RESULTS

Figure 1 shows mean values and standard deviations of variables pertaining to the lipid profile in patients and control group. Values within desirable limits for plasmatic levels of TC, LDLc, VLDLc, and TG can be observed in both groups. On the other hand, mean values for plasmatic Lp(a) are increased in patients (45.4 ± 26.3 mg/dl) and controls (47.1 ± 25.2 mg/dl), with no significant difference between them (P = 0.71). The mean levels of HDLc were significantly lower in patients (34.4 ± 13.9 mg/dl) in relation to controls (41.5 ± 11.8 mg/dl; P = 0.0028).

Figure 1 - Mean values and standard deviation (SD) of total cholesterol, fractions of low-density lipoprotein cholesterol (LDLc), high-density (HDLc), and very-low-density (VLDLc), triglycerides (TG), and lipoprotein (a) [Lp(a)] in patients with obstructive peripheral arterial disease and controls.

M = mean value in mg/dl; SD = standard deviation.

Table 2 shows mean values and standard deviations of variables pertaining to the lipid profile in patients with OPAD or APAD and controls. Values within desirable limits for plasmatic levels of TC, LDLc, VLDLc, and TG can be observed in all groups. However, in patients with APOD (175.8 ± 36.1 mg/dl) and controls (169.7 ± 41.5 mg/dl), the mean levels of TC proved to be significantly increased in relation to the APAD (138.4 ± 28.9 mg/dl; P = 0.001). For LDLc, although with desirable mean values in all groups, patient with OPAD presented significantly higher values (108.9 ± 30.5 mg/dl) in relation to the APAD (82.7 ± 24.0 mg/dl; P = 0.011). Mean values of HDLc were significantly reduced in patients with OPAD (35.2 ± 15.5 mg/dl) and APAD (33.1 ± 10.7 mg/dl) in relation to controls (41.5 ± 11.8 mg/dl; P = 0.010). Mean values for plasmatic Lp(a) were increased in patients and controls.

Table 2 - Mean values and standard deviation (SD) of total cholesterol, fractions of low-density lipoprotein cholesterol (LDLc), high-density (HDLc), and very-low-density (VLDLc), triglycerides (TG), and lipoprotein (a) [Lp(a)] in patients with obstructive peripheral arterial disease or with aortic aneurysm and controls

Lipid profile	Peripheral arterial disease				Controls		P
(mg/dl)	Obstructive (n = 40)		Aneurysm (n = 22)		(n = 62)
	Mean	SD	Mean	SD	Mean	SD
Total cholesterol	175.8	36.1	138.4	28.9	169.7	41.5	0.001
LDLc	108.9	30.5	82.7	24.0	98.3	35.6	0.011
HDLc	35.2	15.5	33.1	10.7	41.5	11.8	0.010
VLDLc	32.4	22.4	22.6	11.7	29.9	14.5	0.063
TG	158.9	114.4	110.8	61.1	149.5	72.7	0.059
Lp(a)	46.0	26.5	44.1	26.5	47.1	25.2	0.897

 

The distribution of plasmatic levels for the lipid profile of patients with PAD and controls is shown in Figure 2. The variation from 78 to 267 mg/dl for patients and 95 to 338 mg/dl for controls can be observed in the TC levels. For LDLc, minimum values were 28 and 35 mg/dl for patients and controls, respectively, and maximum levels were 196 and 232 mg/dl. For HDLc, there was an increased distribution of values in the range below 35 mg/dl for patients, with a minimum level of 16 mg/dl. The values above this interval were rare, with a maximum of 80 mg/dl. On the other hand, values varied from 16 to 77 mg/dl for controls, mainly distributed in the range above 35 mg/dl. VLDLc levels varied from 8 to 125 mg/dl for patients, and from 8 to 80 mg/dl for controls, with a prevalence of individuals from both groups in the normality range. The TG plasmatic levels were concentrated within the desirable range of values in both groups, although maximum values of 624 and 402 mg/dl were recorded in patients and controls, with minimum values of 11 and 42 mg/dl, respectively. The Lp (a) presented a marked variation, occupying a wide distribution range above 30 mg/dl, within a desirable limit in patients and controls, whose values varied from 5 to 106 mg/dl and 11 to 103 mg/dl, respectively.

Figure 2 - Distribution of individual values for the lipid profile of patients with peripheral arterial disease and controls. (A) total cholesterol; (B) fraction of low-density lipoprotein cholesterol; (C) fraction of high-density lipoprotein cholesterol; (D) fraction of very-low-density lipoprotein cholesterol; (E) triglycerides; (F) lipoprotein.

The multivariate analysis of main components determined four association factors (F1, F2, F3, and F4) among variables HDLc, LDLc, TG, Lp(a), and age for controls, patients, and subgroups with obstruction or aneurysm. Factor 1, which included individuals with high levels of LDLc, TG and Lp(a), reduced levels of HDLc and low age (age below the group's mean age), explained 33.3% of the total variation. Factor 3, which identified individuals with low levels of LDLc and HDLc, high levels of TG e Lp(a) and advanced age (above the group's mean age), explained 18.9% of the total variation. Factor 2 associated high levels of TG and low levels of HDLc, LDLc, Lp(a), and age. Factor 4 related an increase in the levels of HDLc, TG, Lp(a) to a reduction in the values of LDLc and age. These factors explained 21.2 and 16.7% of the total variation, respectively, and did not present significance between patients and controls (P > 0.05).

Figure 3 shows the distribution of patients with OPAD or APAD and controls. Its division into quadrants sets a region to the left and another to the right related to Factor 1, while upper and lower quadrants refer to Factor 3. These quadrants are marked by a horizontal and a vertical line at the position corresponding to the value zero. Value zero indicates the centered average of the factors, and the negative and positive values identify controls and patients with OPAD and APAD, below or above mean values, respectively.

Figure 3 - Dispersion diagram of Factors 1 and 3, responsible for 33.3% and 18.9%, respectively, of the total variation observed in patients with obstructive peripheral arterial disease and aortic aneurysm and controls. The vertical line, which separates quadrants to the right and left, indicates Factor 1, and the horizontal line that defines upper and lower regions indicates Factor 3. The symbols indicate each individual and the group to which they belong.

The distribution of individuals in relation to Factor 1 shows a high frequency of cases with OPAD to the right (60%; n = 24), while most patients with APAD (82%; n = 18) are represented to the left, with values below average. For the controls, the distribution of values is homogeneous in relation to the regions to the left (53%; n = 33) and right (47%; n = 29). In this case, Factor 1 separates patients with OPAD from those with APAD (P = 0.028). It shows an association between OPAD and an increase in the plasmatic levels of LDLc, TG, and Lp(a) and a reduction in HDLc and age.

It can be seen, regarding Factor 3, a marked distribution (95%; n = 19) of patients with APAD in the upper quadrant related to values above average, which indicates a less satisfactory profile for this disease, concerning higher values of TG, Lp(a), and age, and reduced levels of LDLc and HDLc. Only 5% (n = 3) presented values below average. On the other hand, patients with OPAD and controls show most values distributed in the lower region (55%, n = 34 and 58%, n = 56, respectively). In this case, Factor 3 separates patients with APAD from controls and OPAD (P < 0.001), revealing an association of increased values of TG, Lp(a), and age, and reduction in the levels of HDLc and LDLc with aortic aneurysm.

DISCUSSION

In this study, the mean level of TC in patients with PAD and controls is within the desirable limit (162.5 ± 38.0 and 169.7 ± 41.5 mg/dl, respectively). However, the type of peripheral arterial disease determines the difference in the level of TC among patients with OPAD (175.8 ± 36.1 mg/dl), compared to the aortic aneurysm (138.4 ± 28.9 mg/dl; P = 0.001). Although both mean values of TC remain within desirable limits, an increase of 27% (37.4 mg/dl) can be observed in patients with OPAD.

Epidemiologic studies on secondary prevention have mentioned the benefits of the reduction in plasmatic cholesterol levels.²⁴ A meta-analysis study points out to the fact that, in every reduction of 10% in cholesterol, there is a reduction of 15% in the mortality risk for cardiovascular diseases and of 11% in the total risk of mortality.²⁵ It serves as a confirmation that increased levels of cholesterol have an influence on the formation of the atherosclerotic plaque, leading to the artery obstruction, although not so markedly in case of aneurysm. On the other hand, the mean level of HDLc remained low, independently from the type of lesion, and proved to be significantly lower in patients (34.4 ± 13.9 mg/dl) in relation to controls (41.5 ± 11.8 mg/dl), confirming its protective effect against the disease.

The correlation between the incidence of CAD and increased plasmatic levels of TC, LDLc, and VLDLc and reduced levels of HDLc is demonstrated in several studies.^5,8,26 Increased levels of LDLc and lower levels of HDLc, as well as increased levels of TG and Lp(a) have been related to OPAD²⁷ and aortic aneurysm.²⁰ Although the OPAD can be related to an increase in the levels of TG (228 mg/dl) and LDLc (150 mg/dl) and reduction in HDLc (36.9 mg/dl), there is no evidence of a significant increase in TC (216 mg/dl) in relation to controls (203.8 mg/dl).²⁸

On the other hand, a study with 140 male patients with PAD and ages varying from 40 to 80 years showed a significant increase in the levels of TC (221 mg/dl), LDLc (137 mg/dl) and TG (141 mg/dl), and reduced levels of HDLc (43,2 mg/dl) in relation to controls.²⁹ Nevertheless, the analysis of 98 patients with abdominal aortic aneurysm and 102 controls suggests that risk factors for the disease are not associated to the lipid profile, different from risk factors for atherosclerosis.³⁰

In the present study, the mean level of LDLc, although within desirable levels, was also significantly higher among patients with OPAD (108.9 ± 30.5 mg/dl) in relation to patients with aortic aneurysm (82.7 ± 24.0 mg/dl). It reinforces the effect of LDLc as a risk factor for OPAD, although not so markedly for the aortic aneurysm, confirming the diversity in the etiopathogeny, development and evolution of the arterial lesion.

On the other hand, there were no significant differences between patients and controls for TG, VLDLc and Lp(a) in this study, even considering the obstructive or aneurysmal lesions. It suggests an absence of relationship between plasmatic levels and PAD, although the mean levels of Lp(a) had values above desirable in all groups. These results are in accordance to another study on patients with PAD, in which the mean value of Lp(a) (88.5 mg/dl) was similar to controls (75.1 mg/dl).³¹ On the other hand, there is a report of increase in the level of Lp(a) in patients with aortic aneurysm when compared to controls, occurring 8 weeks after the surgery, although all levels have remained within the desirable limit.²⁰

In this study, the analysis of variance (ANOVA) correlated the variables LDLc, HDLc, TG, Lp(a), and age with PAD. Among the four association factors identified, Factors 1 and 3, which explained 33.3% and 18.9%, respectively, of the total variation of the number of patients with PAD proved to be significant. Factor 1 showed a reduction in the plasmatic levels of TG, Lp(a) and LDLc, and an increase in HDLc and age in the presence of aortic aneurysm, opposed to OPAD and controls, which showed an increase in the plasmatic levels of LDLc, TG, and Lp(a), and reduction in HDLc and age. Therefore, this factor characterized patients with aneurysm, distinguishing them from the control group and from patients with OPAD, confirming the importance of HDLc as a protective factor in the evolution of the obstructive arterial disease and of LDLc, Lp(a) and TG as aggravating factors. Among analyzed parameters, age might be a major and independent factor for the disease in patients with aneurysm.

Factor 3 associated patients with aortic aneurysm to the increase in the plasmatic levels of TG, Lp(a) and age, and to a reduction in the levels of HDLc and LDLc. This profile separated this group of patients with OPAD, which, along with the controls, proved to have an association with the increase in concentrations of HDLc and LDLc and the reduction in values for TG and age. However, this factor represented a less significant influence (18.9%) on the total variation, compared to Factor 1 (33.3%).

Levels of LDLc, which presented a relationship of increase in Factor 1 and Factor 3, are an effective parameter in the evolution of the obstructive disease. HDLc seems to be a major protective factor for OPAD or aortic aneurysm in all patients, while age plays an important role in the development of the disease, mainly in the aortic aneurysm.

Other non-lipid factors, such as smoking and hypertension, are important and independent for the disease.³¹ Nevertheless, in this study, smoking had a similar prevalence in patients and controls (42 and 37.1%, respectively). However, some authors report a more marked relation between smoking and PAD than between smoking and CAD.^32-36 Smoking has also been related to the abdominal aortic aneurysm.^37,38 Results confirm the high prevalence of arterial hypertension in patients with PAD (45%), compared to controls (8.1%). There is a reference of hypertension associated to the increase in the risk of abdominal aortic aneurysm in around 30% to 40%, but the use of anti-hypertensive drugs reduces the risk in around 70% to 80%.³⁹ There is also an association between diabetes and PAD related to lower limbs,^40-43 not reported in this study since it was an exclusion criterion in the group of patients.

CONCLUSION

Reduced levels of HDLc only in patients confirm its effect in protecting against PAD. On the other hand, increased levels of TC and LDLc characterize the patients, although remaining within desirable limits in all groups. However, high levels of LDLc and low age are associated with OPAD, while increased age seems to be related with APAD.

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