To what extent are the effects of diet on coronary heart disease lipid-mediated?

International Journal of Cardiology 95 (2004) 35 – 38 www.elsevier.com/locate/ijcard

To what extent are the effects of diet on coronary heart disease lipid-mediated? M. Serrano-Martinez a,b,*, E. Martinez-Losa a,b, M. Prado-Santamaria a,b, C. Brugarolas-Brufau a,b, E. Fernandez-Jarne a,c, M.A. Martinez-Gonzalez a a

Department of Epidemiology and Public Health, Irunlarrea s/n, Facultad de Medicina, University of Navarre, 31080 Pamplona, Spain b Primary Care, Navarre Regional Health Service, Pamplona, Spain c Department of Cardiology, University Clinic of Navarre, Pamplona, Spain Received 25 February 2003; accepted 11 March 2003

Abstract Background: Cohort and case-control studies support the effect of diet on coronary heart disease. The objective of this study was to analyze the strength of the influence of dietary fat subtypes and other nutrients on serum lipids levels in patients with a first acute myocardial infarction. Methods: We studied 139 patients with a first myocardial infarction and no previous history of vascular disease. Serum lipids were determined, and nutrient intake was analyzed using a validated 118-food item questionnaire. Results: Multiple regression models found weak but significant associations between the intake of different fatty acids and total to HDL cholesterol ratio (atherogenic index) when we adjusted for age, gender and body mass index (BMI). Positive associations with serum HDL cholesterol concentration were observed for energy-adjusted intake of red wine, alcohol intake, and omega-3 fatty acids intake. However, these nutrients explained less than 12% of the variability in the atherogenic index, and less than 17% in the variability of HDL. Conclusions: Our results suggest only a modest contribution of the investigated nutrients on serum lipids (atherogenic index and HDL cholesterol) in coronary patients. Alternative mechanisms of dietary factors not directly related with serum lipids or, more likely, a global effect of diet on inflammatory and antioxidant parameters should be studied in order to better understand the nature of dietary habits’ influence on cardiovascular disease. D 2003 Elsevier Ireland Ltd. All rights reserved. Keywords: Diet; Atherogenic index; HDL cholesterol; Coronary heart disease; Myocardial infarction

1. Introduction The association between serum lipids and myocardial infarction has been extensively reported. Particularly, cholesterol fractions have been related with coronary atherosclerosis and cardiovascular events [1]. The pathway towards vascular injury has been explained by means of a cholesterol deposition on the vascular wall, and in recent years, inflammatory mechanisms have been reported to be involved in the process of cardiovascular diseases [2]. Dietary intake of some nutrients or food items, mainly fatty acids and carbohydrates, has been found to be directly related to lipid risk factors in healthy persons and also those with cardiovascular disease risk [3– 8]. Serum levels of * Corresponding author. Department of Epidemiology and Public Health, Irunlarrea s/n, Facultad de Medicina, University of Navarre, 31080 Pamplona, Spain. Tel.: +34-948-425600; fax: +34-948-425649. E-mail address: [email protected] (M. Serrano-Martinez). 0167-5273/$ - see front matter D 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2003.03.001

HDL cholesterol can be raised by some dietary components such as omega-3 fatty acids, alcohol and reduced with higher carbohydrate intake [3,8,9]. These associations have promoted the hypothesis that most of the effect of diet on coronary heart disease is mediated through changes in serum lipids. This is the traditional belief, which is currently challenged. Thus, some reports have described an inverse association of vascular disease with other dietary elements, such as vitamins and natural antioxidants present in some foods and in wine [10,11]. In fact, a randomized trial of dietary intervention found a substantial reduction in coronary heart disease events without changing serum cholesterol levels in coronary patients [12]. Moreover, the beneficial effects of statins on the prevention of cardiovascular events are only partially mediated by cholesterol reduction, since they have some other well-known protective effects on vascular wall [13]. Most studies designed to assess the association between diet and serum lipids have been conducted in healthy

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Table 1 Mean, standard deviation and range of clinical and dietary variables in 139 patients with recent myocardial infarction

Age (years) HDL cholesterol (mmol/l) Atherogenic index (total cholesterol/HDL units) BMI (kg/m2) Total energy intake (kcal/day) Dietary intake of carbohydrates (g/day) Dietary carbohydrates/total energy intake (%) Dietary intake of n 3 fatty acids (g/day) Dietary n 3 fatty acids/ total energy intake (%) Dietary intake of total fat (g/day) Dietary intake of saturated fat (g/day) Dietary intake of monounsaturated fat (g/day) Dietary intake of polyunsaturated fat (g/day) Dietary intake of trans fatty acids (g/day) Red wine consumption (g/day) Total alcohol consumption (g/day) Alcohol from wine/total alcohol (%)

Mean

S.D.

61.9 1.08 5.23

11.1 0.30 1.83

Range 34 – 79 0.57 – 2.17 2.38 – 16.76

27.7 4.3 18.6 – 54.7 2601.1 773.2 1243.8 – 6691.9 306.49 103.22 137.82 – 701.49 47.06

7.13

1.03

0.64

0 – 5.62

0.38

0.22

0 – 1.50

90.89 30.52

32.03 11.93

35.80 – 216.61 11.24 – 85.02

44.57

16.51

16.27 – 100.26

15.79

7.19

5.31 – 38.04

0.49

0.59

136.60 174.71 17.33 21.92 92.98 46.63

33.10 – 64.31

0 – 3.67 0 – 700.00 0 – 119.86 0 – 100

individuals. Evidence is scarce regarding these diet-lipid associations among patients with coronary heart disease [6]. The main goal of this research was to study evidences of the effect of diet on serum lipids in coronary patients. This report describes the quantitative relationships of the major dietary fatty acids, alcohol and carbohydrates with serum HDL cholesterol and the atherogenic index, in patients who have recently suffered a first myocardial infarction.

Emphasis was paid to ensure that the answers were related to long-term dietary exposures and not to recent changes in diet. Nine options for frequency of consumption were possible. The nine response categories ranged from ‘‘never/almost never’’ to ‘‘six or more times per day’’. The type of fat used in frying was specifically assessed. A dietitian updated the nutrient data bank using the latest available information included in the food composition tables for Spain. Total energy-adjusted intakes were computed using the residuals method [16]. Coronary risk factors (smoking, diabetes, high blood pressure, high blood cholesterol) and family history of cardiovascular disease were registered. Systolic and fifthphase diastolic blood pressure readings were recorded for each participant. Weight and height were directly measured according to a standardized protocol, with the subject barefooted and dressed in light clothing. For each participant, we calculated the body mass index (BMI) as the weight in kilograms divided by the squared height in meters (kg/m2). Serum lipid profile was determined in the first 24 h after the coronary event by standard laboratory methods. Multivariate linear regression models were firstly fitted using the atherogenic index (ratio total cholesterol/HDL) as the dependent variable and mean absolute daily intake of total, saturated, monounsaturated, polyunsaturated, trans, and omega-3 fat, separately in each multivariate model as the independent variables. Alternatively, HDL cholesterol serum concentration was used as the dependent variable and percentage of daily total energy intake from omega-3 fatty acids, from carbohydrates, from total alcohol, and energy-adjusted red wine intake were used in separate multivariate models as the independent variables. Covariates in the models were age, gender and BMI. Further adjustments for smoking habit and systolic or diastolic arterial pressure were also done.

3. Results 2. Patients and methods One hundred and thirty nine patients aged under 80, 83.5% men, with a first myocardial infarction and no previous history of vascular disease were consecutively assessed. These subjects had to meet the criteria of the MONICA project [14]. Any clinical suspicion or definite diagnosis of previous vascular disease was a criterion for excluding them from the study. Informed consent was obtained from the patients, and the project was approved by the Institutional Review Board of the University of Navarre Medical School. Four trained physicians conducted face-to-face interviews with patients in a standard way and using the same semi-quantitative food-frequency questionnaire. This was a questionnaire (118 food items) previously validated in Spain [15]. For each food item, a commonly used portion size was specified, and participants were asked how often they had consumed that unit on average over the previous year.

Descriptive data for clinical and dietary variables of the patients included in this study are shown in Table 1.

Table 2 Type of fat and atherogenic index in 139 patients with recent myocardial infarction Independent variables Total fat (g/day) Saturated fat (g/day) Monounsaturated fat (g/day) Polyunsaturated fat (g/day) n 3 fatty acids (g/day) Trans fat (g/day)

R2 0.105 0.115 0.098 0.078 0.080 0.095

Beta 0.011 0.034 0.020 0.025 0.296 0.498

95%IC 0.002 – 0.021 0.009 – 0.060 0.001 – 0.039 0.018 – 0.068 0.768 – 0.176 0.002 – 0.998

p 0.02 0.01 0.04 0.27 0.23 0.05

Multiple regression models using atherogenic index (total cholesterol/HDL) as the dependent variable. Different models were fitted for each nutrient. Models include age, sex, body mass index and the absolute value of daily intake of each specific nutrient (type of fat).

M. Serrano-Martinez et al. / International Journal of Cardiology 95 (2004) 35–38

In separate multiple regression models (one for each type of fat), we found that absolute values of total fat, saturated fat, and monounsaturated fat intake were significantly associated with the atherogenic index, when age, gender and BMI were controlled for (see Table 2). However, these nutrients explained less than 12% (R2 values between 0.078 and 0.115) of the variability of the atherogenic index. However, prediction was somewhat stronger for serum HDL cholesterol, although lower than 17% (R2 values between 0.137 and 0.164), when the percentage of total energy from dietary carbohydrates, omega-3 fatty acids, total alcohol, and energy-adjusted red wine were separately considered in different multiple regression models adjusted for age, gender and BMI (see Table 3). The multiple regression analysis also showed that an 1-g/day increase in some of the studied dietary fat components induced a small but significant variation in the atherogenic index (introducing age, sex and BMI as independent terms). This change was 0.011 units in the atherogenic index (95% confidence intervals, CI: 0.002 to 0.021) for total fat, 0.034 units (95%CI: 0.009 to 0.060) for saturated fatty acids and 0.020 units (95%CI: 0.001 to 0.039) for monounsaturated fatty acids. A change of 0.498 units (95%IC: –0.002 to 0.998) by each gram of daily intake of trans fatty acids was marginally significant ( p = 0.05) (see Table 2). HDL cholesterol increased 11.13 mg/dl (95%CI: 2.84 to 19.42) for a 1% increase in energy intake from omega3 fatty acids, 0.572 mg/dl (95%CI: 0.158 to 0.987) for a 1% increase in energy intake from alcohol, and 0.017 mg/dl (95%CI: 0.005 to 0.028) for each g/day of increment in energy-adjusted red wine intake. A negative effect of 0.259 near to statistical significance on HDL concentration (95%IC: 0.524 to 0.006, p = 0.06) was observed for each 1% increment in energy from carbohydrates (see Table 3). Further adjustment of the multiple regression models for diabetes, smoking habit and systolic or diastolic arterial pressure did not materially change the above-mentioned estimates.

Table 3 Diet and serum HDL cholesterol in 139 patients with recent myocardial infarction Independent variables

R2

Carbohydrates (%E) n 3 fatty acids (%E) Alcohol (%E) Energy-adjusted red wine (g/day)

0.137 0.157 0.160 0.164

Beta 0.259 11.13 0.572 0.017

95%IC 0.524 – 0.006 2.84 – 19.42 0.158 – 0.987 0.005 – 0.028

p 0.06 0.01 0.01 0.01

Multiple regression for serum HDL cholesterol as the dependent variable. Different models were fitted for each nutrient. Models include age, sex, body mass index and the daily intake of each specific nutrient as a percentage of total daily energy (%E).

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4. Discussion Saturated and trans fats lead to higher plasma total and LDL cholesterol, and higher plasma lipids may lead to a higher coronary risk [1,17,18]. However, dietary habits and diet changes usually follow established patterns [19]. Hence, a single nutrient effect may show associations that could be confounded by some other diet component. It was hypothesized that vascular injury is mainly due to elevated serum lipids concentrations, and that these elevations are secondary to dietary habits. However, evidences from recent research indicate that other relevant pathogenic mechanisms have a determinant role in the atherosclerotic vascular damage, as the inflammatory cascade and the oxidative stress of the vascular wall [2,20]. If the old hypothesis were true, most of the variability in serum lipids observed in coronary patients would be explained by differences in nutrient intake. In our study, most of fatty acids had a limited influence on the values of atherogenic index. This was true for total fat and saturated, monounsaturated and trans fatty acids after adjustments by age, gender and BMI. Apparent and continuous positive associations were also found in our patients between HDL cholesterol and the following nutrients: omega-3 fatty acids, total alcohol and red wine. Negative marginal associations were present for carbohydrates also after controlling for age, sex and BMI in the statistical models. An increase of 11,13 mg/dl was induced by 1% increase in energy intake from n 3 fats. This figure is not actually very high, since mean daily intake of energy from these fats was of 0.38% of total energy. Previous reports in healthy people have shown an increased cardiovascular risk linked to the dietary variables studied in this paper [4,21 – 23]. All subjects included in our analysis recently had an acute myocardial infarction. It would be expected in these patients a strong association between dietary habits and the lipid risk profile. Contrarily to this view, our results suggest only a modest contribution of dietary factors on serum lipids (atherogenic index and HDL cholesterol values). Therefore, our findings support a limited influence of diet on the serum lipids of coronary patients. On the other hand, the finding of the weak relations between dietary fats and serum lipids in coronary patients, as could be also expected in healthy people, might lead us to suspect that perhaps the diet-lipid theory is not the main way to vascular damage. This support the idea that other dietary influences, less apparent and accessible to clinical investigation and management, may participate in the mechanisms causing the vascular injury. Several limitations of our study must be acknowledged. Our sample size was not large and our design is susceptible to be affected by recall bias. However, recall bias can be easily found when differential over-reporting exists in some cases but not in others, but this is unlikely in our study, since patients were all interviewed in the same manner and care was paid to the accuracy of the answers to the questionnaire. Samples were managed in the same way for lipid quantifi-

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cation in the laboratory, and analysis was performed as routine determinations. What this article adds in our opinion is some strength to the hypothesis of a global diet effect on the vascular tree, not only mediated by certain nutrients conditioning plasma lipids concentrations. Further studies would be necessary to ascertain the role of alternative dietary components which could be important mediators of the effect of diet on CHD risk, such as the total antioxidant dietary load, which might determine a protective action from inflammatory mechanisms leading to coronary atherosclerosis. This will further reinforce the convenience of positive counseling on olive oil, vegetables, fruits, fiber and fish in daily diet whose protective effect against cardiovascular disease has already been pointed out [24 – 28].

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