© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
High Levels of Nonesterified Fatty Acids Are Associated With Increased Familial Risk of Cardiovascular Disease
From the Department of Endocrinology (M.C., Y.W., P.A., L.G.), Malmö University Hospital, University of Lund, Lund, Sweden.
Correspondence to Professor Leif Groop, MD, PhD, Department of Endocrinology, University Hospital Malmö, S-205 02 Malmö, Sweden. E-mail Leif.Groop{at}endo.mas.lu.se
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Abstract |
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Abstract—To address the question of whether elevated concentrations of nonesterified fatty acids (NEFAs) are associated with an increased risk of cardiovascular disease, we measured NEFA concentrations in 140 diabetic and 343 nondiabetic unrelated Swedish subjects with a family history of type 2 diabetes and related the findings to history of cardiovascular disease in their parents. Parents of nondiabetic offspring belonging to the quartile of highest NEFA concentrations had a higher risk of myocardial infarction (35% versus 16%, P<0.01) and stroke (45% versus 16%, P<0.0005) than did parents of offspring from the lowest NEFA quartile. In a multiple logistic regression analysis, a high NEFA concentration in offspring was significantly associated with myocardial infarction and stroke in their parents. No such relationship was observed between diabetic offspring and their parents. Assuming that the same relationship between NEFA concentrations and cardiovascular disease is seen in the offspring and their parents, the findings suggest that elevated NEFA concentration is a risk factor for cardiovascular disease and could be pathogenically involved in the atherosclerotic process.
Key Words: fatty acids, nonesterified • cerebrovascular disorders • myocardial infarction • genetics • cardiovascular disease
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Introduction |
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Cardiovascular disease (CVD) and cerebrovascular disease strongly influence the outcome of patients with type 2 diabetes.1 Although hyperglycemia per se is associated with increased risk of CVD,2 3 4 its role in the pathogenesis of the atherosclerotic process has been debated.5 6 This uncertainty is partially attributed to the fact that no intervention studies aimed at lowering glycemia have been able to significantly reduce the incidence of CVD in patients with type 2 diabetes.7 8 Therefore, factors other than glucose may mediate the increased cardiovascular risk in type 2 diabetes. One putative candidate is an elevated concentration of nonesterified fatty acids (NEFAs). NEFA levels are elevated in type 2 diabetes9 10 and confer in nondiabetic individuals an increased risk of type 2 diabetes.11 12 In addition, elevated NEFA levels are associated with insulin resistance13 14 15 and hypertension,16 17 two conditions that have been ascribed an increased risk of CVD and cerebrovascular disease.18 19 20
To address this question, we measured NEFA concentrations in diabetic and nondiabetic individuals from families with clustering of type 2 diabetes and related the findings to history of CVD in their parents. This approach was chosen because there were too few cardiovascular events in the offspring. On the other hand, CVD shows strong familiality, and we have demonstrated a high concordance of NEFAs in siblings. In addition, there is a significant intraclass correlation of NEFA concentration between monozygotic twins (M. Lehtovirta, unpublished data, 2000). The data suggest that elevated NEFA concentrations in nondiabetic offspring are associated with an increased occurrence of CVD in their parents.
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Methods |
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All subjects participated in a family study in southern Sweden. The aim of the study was to identify genes increasing susceptibility to type 2 diabetes. Only 1 subject in each nuclear family was included. Of the participants, 140 subjects (80 men and 60 women) had type 2 diabetes and 343 subjects (150 men and 193 women) had normal or impaired glucose tolerance. Participants had a least 1 first-degree family member with type 2 diabetes. Subjects with 2 diabetic parents were excluded. All subjects underwent a 75-g oral glucose tolerance test (OGTT). The new World Health Organization criteria were used to diagnose diabetes; ie, patients were considered to have diabetes if their fasting blood glucose concentration was
6.1 mmol/L, if a
2-hour glucose concentration during an OGTT was >11.1 mmol/L, or
if they were taking antidiabetic medication.21 None of the
diabetic patients were being treated with insulin. Studies were performed in the morning at 8 AM after a 10-hour overnight fast. Subjects were asked not to smoke, not to take their morning medication, and not to perform any strenuous exercise the day before the tests. Height and weight were measured with subjects in light clothing but no shoes. Body mass index (BMI) was calculated and expressed in kilograms per meter squared. Hip circumference was measured at the level of the greater trochanter. Waist circumference was measured with a soft tape on standing subjects midway between the lowest rib and the iliac crest. Waist-to-hip ratio (WHR) was calculated as a measure of central adiposity. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured twice in the right arm with the subject in a supine position after a 15-minute rest, and the mean was calculated. Fat-free mass and percentage of body fat were estimated from total body resistivity with an impedance analyzer using the equations provided by the manufacturer (BIA 101, RJL Systems). During the OGTT, subjects ingested 75 g of glucose in a volume of 300 mL, and venous samples for measurement of blood glucose and serum insulin were drawn at -5, 0, 30, 60, and 120 minutes. For fasting glucose and insulin concentrations, the mean of the -5- and 0-minutes values were used. Venous fasting blood samples were drawn for measurement of serum concentrations of NEFAs, total cholesterol, HDL cholesterol, triglycerides, and serum aspartate aminotransferase (AST). A homeostasis model assessment (HOMA) index for ß-cell function22 was calculated as follows: ß-Cell Function=(20xFasting Insulin)/(Fasting Glucose-3.5).
Blood glucose was measured with use of a photometric method based on the glucose-dehydrogenase method using the HemoCue blood glucose analyzer. Serum was separated and kept at -20°C until analysis. NEFA concentration was measured by means of an enzymatic colorimetric method using a commercial kit (Wako Chemicals GmbH). Insulin concentrations were measured by specific radioimmunoassays (Dako Diagnostics Ltd). Total cholesterol, HDL cholesterol, triglyceride, and AST concentrations were analyzed with commercially available kits using Technicon DAX 48 (Bayer).
Questionnaire
Information about subjects’ personal and family histories of
diabetes, hypertension, stroke, and myocardial infarction (MI) was
obtained with use of a standardized, nurse-administered questionnaire.
MI was defined as either fatal or nonfatal MI. Stroke was defined as
cerebral thrombosis or hemorrhage diagnosed in the hospital or
a primary healthcare setting. Hypertension was defined as SBP
160 mm Hg, DBP 95 mm Hg, or use of antihypertensive
drugs. Before subjects were allowed to participate in the study, the
purpose, nature, and potential risks were explained; all subjects
provided written informed consent. The ethics committee of Lund
University approved the study protocol.
Statistical Methods
All data are mean±SD or median and 95% confidence
interval. Comparisons between groups were performed by using
2 analysis, Student’s t
test, or the Mann-Whitney U test where appropriate using a
BMDP statistical package (version 7, Biomedical Data Processing).
Log10-transformed means were used for skewed data
(2-hour glucose, fasting insulin, 2-hour insulin, HOMA ß-cell
function, triglycerides, AST, and NEFAs). NEFA
concentrations were adjusted for age by using the linear regression
equation and stratified according to quartiles. Variables in the
lowest quartile of NEFA concentrations were compared with variables
in the highest quartile of NEFA concentrations. To obtain insight into
which variables influenced NEFA concentration in the offspring,
Pearson univariate correlation and multiple regression
analysis were used. When comparing differences in NEFA between
men and women, NEFA concentration was adjusted for fat mass. To
identify factors associated with high NEFA concentrations, a multiple
regression analysis with NEFA as the dependent variable and
age, BMI, WHR, SBP, 2-hour glucose, 2-hour insulin,
cholesterol, HDL cholesterol,
triglycerides, and AST as independent variables was
performed. In addition, multiple logistic regression analyses
with stroke or MI as the dependent variable and BMI, WHR, SBP,
2-hour glucose, 2-hour insulin, cholesterol, HDL
cholesterol, triglycerides, and NEFA as
independent variables were also performed. For the regression
analyses, an NCSS statistical program (version 6.0.21,
Biomedical Data Processing) was used. A P value <0.05 was
considered statistically significant.
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Results |
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Baseline Characteristics
Table 1
shows baseline
characteristics of the subjects. Diabetic patients were older
(P<0.0001) and had a higher BMI (P<0.0001),
higher fat mass (P<0.005), higher blood pressure
(P<0.0001), higher fasting insulin (P<0.0001),
lower HOMA ß-cell function (P<0.0001), higher
triglycerides (P<0.0001), and lower HDL
cholesterol (P<0.0001) than nondiabetic
subjects. In addition, diabetic subjects had higher NEFA concentrations
than nondiabetic subjects (810±290 versus 720±310 µmol/L,
P<0.005), and women had higher NEFA concentrations than men
(810±300 versus 670±270 µmol/L, P<0.0001). These
differences disappeared when NEFA concentrations were expressed
relative to fat mass. NEFA concentrations showed a weak positive
correlation with age (r=0.16, P<0.01) and 2-hour
glucose (r=0.21, P<0.0001). Therefore, in the
subsequent analysis, diabetic and nondiabetic subjects were
considered separately and NEFA concentrations were adjusted for
age.
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Nondiabetic Subjects
Table 2 shows clinical
characteristics of nondiabetic subjects divided into quartiles of NEFA
concentrations. Data are presented separately for men and women
if differences were observed between the sexes (eg, fat mass and WHR).
The 2-hour glucose (P<0.001), 2-hour insulin
(P<0.001), cholesterol (P<0.05),
and AST (P<0.01) concentrations were higher in subjects
with the highest concentrations of NEFAs than in subjects with the
lowest NEFA concentrations. HOMA ß-cell function was impaired in
subjects with the highest NEFA concentrations compared with subjects
with the lowest NEFA concentrations (P<0.05). DBP was
higher in women from the highest NEFA quartile than in women from the
lowest NEFA quartile (78±8 versus 73±10 mm Hg,
P<0.05). In men, SBP was higher in those with the
highest NEFA concentrations compared with those with the lowest NEFA
concentrations (136±19 versus 128±18 mm Hg,
P<0.05). Also, cholesterol (5.8±1.2 versus
5.2±1.2 mmol/L, P<0.05) and triglyceride
(2.1 [1.6 to 2.6] versus 1.4 [1.2 to 1.7] mmol/L,
P<0.05) concentrations were higher in men from the highest
NEFA quartile than in men from the lowest NEFA quartile.
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Diabetic Subjects
Table 3 shows clinical
characteristics of diabetic patients divided into quartiles of NEFA
concentrations. Diabetic patients with the highest NEFA concentrations
had higher 2-hour glucose concentrations than diabetic patients with
the lowest NEFA concentrations (P<0.01).
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In the multiple regression analysis, SBP (P<0.0001) and AST (P<0.005) were positively associated with NEFA concentration in nondiabetic women. In nondiabetic men, 2-hour glucose (P<0.01) and AST (P<0.00001) values were associated with NEFA concentration. Age (P<0.0005) and cholesterol (P<0.05) were associated with NEFA concentrations in diabetic women. In diabetic men, there was a positive association with 2-hour glucose (P<0.01), HDL cholesterol (P<0.01), and AST (P<0.05) concentrations.
History of CVD
Of the nondiabetic subjects, 6 (2%, 4 men and 2 women) reported a
personal history of MI, 8 (2%, 4men and 4 women) reported a history of
stroke, and 45 (13%, 17 men and 28 women) had hypertension.
Of the diabetic patients, 15 (11%, 11 men and 4 women) reported a history of MI, 3 (2%, 1 man and 2 women) reported a history of stroke, and 58 (41%, 31 men and 27 women) had hypertension.
Parental History of CVD and Diabetes
Of the nondiabetic subjects, 105 (31%) reported a history of MI
and 76 (22%) a history of stroke in 1 or both parents, and 173 (50%)
reported hypertension in parents. Five subjects reported MI in both
parents, and 1 reported stroke in both parents. MI was more common in
fathers (22.5%) than in mothers (9.6%), as was stroke (12.9% versus
9.6%). Diabetes, however, was more prevalent in mothers (53%) than in
fathers (18%). Parental history of CVD in diabetic patients was
similar to that in nondiabetic subjects, with 53 (38%) reporting a
history of MI and 34 (24%) reporting a history of stroke. Hypertension
in parents was reported by 60 diabetic patients (43%). Nondiabetic
offspring from the highest NEFA quartile reported a higher prevalence
of stroke (35% versus 16%, P=0.006) and MI (45% versus
16%, P=0.0004) in their parents than did offspring from the
lowest NEFA quartile (Figure 1A).
Nondiabetic men from the highest NEFA quartile also reported a higher
prevalence of parental hypertension than men from the lowest NEFA
quartile (68% versus 42%, P=0.02). The relationship
between NEFA concentration in offspring and parental history of stroke
or MI was independent of a parental history of diabetes. The prevalence
of diabetes in parents was similar in the highest and lowest NEFA
quartiles and was seen in both diabetic and nondiabetic parents. Of
parents with MI from the highest NEFA quartile, 45% had diabetes,
compared with 36% of parents from the lowest NEFA quartile
(P=NS). Of parents with stroke, 47% from the highest NEFA
quartile had diabetes, compared with 29% from the lowest NEFA quartile
(P=NS). In diabetic patients, we did not observe any
relationship between NEFA concentration and prevalence of CVD in their
parents (Figure, B).
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) and MI (
) in
parents of nondiabetic (A) and diabetic (B) offspring belonging to
different quartiles of fasting NEFA concentrations.
*P<0.01 and **P<0.0005 compared with
subjects from the lowest NEFA quartile.
A multiple logistic regression model with forward selection was used to
identify variables that were independently associated with MI and
stroke in parents. High NEFA concentrations in nondiabetic offspring
were strongly associated with MI and stroke in parents (Table 4). In the analysis of
nondiabetic subjects, regardless of their sex, NEFA concentration was
the first variable to be added to the model for both stroke and MI.
No such relationship was seen between NEFA concentrations in diabetic
offspring and a history of CVD in parents.
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Discussion |
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The putative links between increased NEFA concentrations and coronary heart disease, insulin resistance, cancer, and other chronic diseases has been discussed by Frayn et al.23 The main finding of the present study was a strong association between fasting serum NEFA concentrations in nondiabetic offspring and a history of MI or stroke in their parents. This association was confirmed in a multiple logistic regression analysis in which NEFA concentration showed a strong independent association with parental history of CVD. The association becomes even stronger when one considers that subjects with high NEFA concentrations also had high insulin levels, which should have resulted in suppression of NEFAs.13 Several points of the study require comments. Although the cross-generation study design using CVD events in the parents as end points may seem strange, it has the advantage of including most of the cumulative end points in the aged parent generation. This approach has been successfully used for estimating risk associated with genetic markers.24 These CVD events are most likely underreported, because the research nurse based them on proband responses to the questionnaire and included only events requiring hospital care. There is, however, no reason to assume that reporting biases would have affected one NEFA quartile more than another.
How representative are fasting NEFA concentrations of diurnal NEFA excursions? During the day, NEFA concentrations are generally suppressed by meal-induced insulin secretion and reach peak concentration early in the morning.25 26 27 Previous studies have shown a strong correlation between fasting NEFA concentrations and NEFA concentrations measured during the day27 and between fasting NEFA concentrations and suppression of NEFA concentrations by low-dose insulin therapy.28
The study design also assumes that NEFA concentrations in offspring are reflected by similar NEFA concentrations in the parents or that the CVD event rate in parents will be reflected by a similar event rate in offspring. Although the latter assumption is supported by results of several studies,29 30 31 there are fewer data on heritability estimates of NEFAs. Given the large differences in age and BMI between parents and offspring, it may be impossible to demonstrate a parent-offspring correlation in levels of free fatty acids. Studies of families have, however, shown that genetic factors are major determinants of familial resemblance in plasma lipids and lipoproteins.32 In sex-matched sibling pairs, we observed a significant intraclass correlation for fasting NEFA concentrations (P=0.04), and a preliminary twin study showed stronger concordance for NEFAs in monozygotic than in dizygotic twins (M. Lehtovirta, unpublished data, 2000). In addition, using microdialysis and 133Xe clearance techniques, Eriksson et al33 showed that suppression of adipose tissue lipolysis was impaired by insulin in healthy relatives of patients with type 2 diabetes compared with healthy control subjects. Although these figures provide only moderate support for the familiality of NEFA, the findings that a high NEFA concentration in offspring is associated with high risk of MI and stroke in parents suggests that NEFAs or NEFA-related events at least partially increase susceptibility to CVD. An elevated NEFA concentration could also be the consequence of environmental factors, such as excessive alcohol consumption, smoking, or a diet rich in fat. Also, stressful events such as the venepuncture procedure could affect NEFA concentration. However, subjects were studied only once under standardized conditions. There was no evidence of differences in alcohol consumption or smoking habits between subjects from different NEFA quartiles. We have not observed any difference in free fatty acid levels between subgroups of smokers and nonsmokers, making it unlikely that the observed differences would be explained by different smoking habits. Finally, it was recently demonstrated that elevated NEFA levels predict CVD mortality in patients with type 2 diabetes.34
The question remains of how high NEFA concentrations could promote CVD. High levels of NEFA could lead to increased concentrations of VLDL, small, dense LDL particles, and elevated apoB concentrations in plasma, all of which are associated with an increased risk of coronary heart disease32 and stroke.35 Abdominal obesity, fasting hyperinsulinemia, and impaired NEFA suppression after OGTTs have been associated with premature MI.36 High levels of factor VII, type 1 plasminogen activator inhibitor, and tissue plasminogen activator antigen have been associated with CVD.37 38 39 Type 1 plasminogen activator inhibitor is increased in both obese nondiabetic subjects and in obese subjects with type 2 diabetes and is correlated with suppression of NEFA by insulin.40 In addition, fat intake influences NEFA concentrations and factor VII activity.41
Although NEFAs represent the main energy source for the resting heart, high NEFA concentrations also predispose to arrhythmia.42 43 Paolisso et al44 recently showed in patients with type 2 diabetes that a high basal plasma NEFA concentration was associated with a high frequency of ventricular premature complexes and that increased NEFA concentration (by intralipid infusion) increases ventricular premature complexes whereas decreased NEFA concentration (by acipimox administration) decreases them.
High concentrations of NEFAs are also linked to the acute phase of MI. NEFAs are elevated in plasma soon after the onset of MI and are associated with a significantly increased incidence of serious ventricular arrhythmias, heart block, and sudden death.45 Finally, recent data have shown that NEFAs of different chain lengths can alter expression of proteoglycan genes in arterial smooth muscle cells.46 The association between high NEFA concentration and stroke may be easier to explain. Hypertension is a strong predictor of stroke47 and has been associated with high NEFA concentrations and impaired action of insulin on NEFA metabolism.16 48 In support of this, in the multiple regression analysis SBP was independently associated with NEFA concentration in nondiabetic women. The association between NEFA levels and parental history of CVD was not observed in diabetic offspring. This is almost expected because NEFA concentrations are highly dependent on both insulin and glucose concentrations.15 26 49 50
We observed higher NEFA concentrations in diabetic than in nondiabetic subjects. Although the absolute insulin values during the OGTT were not lower in diabetic than in nondiabetic subjects, ß-cell function expressed with use of the HOMA model was significantly impaired in diabetic compared with nondiabetic subjects. Impaired suppression of NEFA turnover by insulin is a consistent finding in patients with type 2 diabetes.26 Therefore, in type 2 diabetes, NEFA levels reflect secondary changes rather than primary inherited traits.
There was also an unexpected association between high NEFA and high AST in most groups. AST concentration is considered to be a marker of hepatocellular damage. In patients with type 2 diabetes, abnormalities of liver enzymes may occur as a consequence of hepatocellular glycogen accumulation or steatosis of the liver.51
In conclusion, elevated fasting serum NEFA concentrations in offspring are associated with a history of CVD in parents. This association is not confounded by age and cannot be fully explained by conventional risk factors such as BMI, WHR, blood pressure, or 2-hour glucose, 2-hour insulin, or cholesterol levels. Assuming that this relationship between NEFA concentration and CVD is also observed in offspring, the findings suggest that elevated NEFA concentration is a risk factor for CVD and could also be pathogenically involved in the atherosclerotic process. Support for this view comes from a recent prospective study showing elevated NEFA concentrations 10 years earlier in patients with type 2 diabetes who died of CVD.34
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Acknowledgments |
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This work was supported by grants from the Swedish Medical Research Council, the Sigrid Juselius Foundation, the Swedish Diabetes Research Foundation, the Juvenile Diabetes Foundation (JDF-Wallenberg grant K 98-990-12812-01A), and a European Community paradigm BMH-4-CT95-0662 grant.
Received July 1, 1999; accepted January 13, 2000.
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