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The World Health Organization reports that the number of hypertensives, worldwide, is estimated to be 600 million people. In addition a considerable proportion ...
Journal of Human Hypertension (2002) 16, 517–524  2002 Nature Publishing Group All rights reserved 0950-9240/02 $25.00 www.nature.com/jhh

ORIGINAL ARTICLE

The effect of the combination of Mediterranean diet and leisure time physical activity on the risk of developing acute coronary syndromes, in hypertensive subjects C Pitsavos1, DB Panagiotakos1 C Chrysohoou1, PF Kokkinos2, J Skoumas1, I Papaioannou1, C Stefanadis1 and P Toutouzas1 1 Cardiology Department, School of Medicine, University of Athens, Greece; 2Veterans Affairs Medical Center and Cardiology Division, Georgetown University, Washington, DC, USA

The World Health Organization reports that the number of hypertensives, worldwide, is estimated to be 600 million people. In addition a considerable proportion of hypertensive subjects remains untreated or uncontrolled. In this work we investigated the combined effect of physical activity and Mediterranean diet on coronary risk, in hypertensives. Thus we randomly selected, from all Greek regions, 848 hospitalised patients (695 males, 58 ± 10 years old and 153 females, 65 ± 9 years old) with a first event of coronary heart disease (CHD) and 1078 paired, by sex, age, region controls, without any suspicions for CHD. Physically active were those who reported non-occupational physical activity more than once per week. Subjects ‘closer’ to the Mediterranean diet were assessed through a special nutrient questionnaire. A total of 418 (49%) of the patients and 303 (28%) of the controls were hypertensive. Of these, 115 (27%) patients and 70 (23%) controls were untreated, 148

(35%)–111 (36%) were uncontrolled and 155 (38%)–122 (41%) were controlled (P-value ⬍0.01). One hundred and sixty-two (19%) of the patients and 265 (25%) of the controls (P ⬍ 0.01) were ‘closer’ to the combination of Mediterranean type of diet and physical activity. The analysis showed that the previous combination is related to a 25% reduction of the coronary risk in controlled hypertensive subjects (OR = 0.75, P ⬍ 0.01), a 11% reduction in untreated (OR = 0.89, P ⬍ 0.05) and 17% reduction (OR = 0.83, P ⬍ 0.05) in uncontrolled, after adjusting for age, sex, educational and financial level and the conventional cardiovascular risk factors. Consequently, the adoption of Mediterranean diet by physically active subjects seems to reduce significantly the coronary risk and prevent, approximately, the one-third of acute CHD, in controlled hypertensive subjects. Journal of Human Hypertension (2002) 16, 517–524. doi: 10.1038/sj.jhh.1001445

Keywords: hypertension risk; coronary; Mediterranean diet; physical activity

Introduction Throughout the 20th century, many researchers have focused their interest on prevention and therapy of the cardiovascular diseases. The level of blood pressure has long been recognised as a major risk factor for several common cardiovascular diseases, including coronary heart disease, cerebrovascular disease and heart failure. The World Health Organization reports that the number of hypertensives, worldwide, is estimated to be 600 million people. Of them, 3 million will die, annually, as a Correspondence: DB Panagiotakos, 48–50 Chiou Str. Glyfada, Attica, 165 61, Hellas, Greece. E-mail: d.b.panagiotakos얀usa.net Received 5 December 2001, revised and accepted 22 April 2002

result of hypertension. It is also estimated that only 50% of the hypertensive patients are aware of their condition and one-half of these are treated. However, only the one-half of the treated hypertensives reaches the optimal blood pressure levels. Thus, at best 12.5% overall are adequately controlled.1,2 Moreover, based on the results of European survey (EUROASPIRE 1 study) approximately one-half of the investigated subjects had elevated blood pressure levels. Additionally, the one-half of the patients receiving blood pressure lowering drugs had a systolic blood pressure greater than 140 mm Hg and, almost, the one-fifth of them had systolic blood pressure greater than 160 mm Hg.3 Furthermore, elevated blood pressure levels constitutes a common problem in Greece where it is considered that almost

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one-fourth of the adults have hypertension, based on a recent report from CARDIO2000 study.4 There is evidence to support that several factors related with lifestyle habits, may influence blood pressure levels.5–7 Among them the beneficial effect of physical activity and healthy diet on human health, have been underlined in several studies. Reports from observational studies, especially the Seven Countries study and the Lyon Heart diet study, showed inverse associations between blood pressure levels and the consumption of a Mediterranean diet, as well as the intake as magnesium, potassium, calcium, fibre and protein.8–12 In addition, the DASH combination diet (rich in fruits, vegetables and low-fat dairy products and with reduced saturated and total fat) showed a significant reduction in the levels of systolic and diastolic blood pressure in hypertensive subjects.6 Regarding the effect of physical activity on human health it is generally accepted that moderate exercise can significantly reduce the levels of blood pressure in patients with mild to moderate essential hypertension.13–18 Also, in most studies regular physical activity was found to be associated with a reduced risk of coronary heart disease, even in middle-aged men.14 In this study, we aimed to evaluate the effect of the combination of Mediterranean type of diet and leisure time physical activity, on the risk of developing non-fatal acute coronary syndromes, in hypertensive subjects.

Materials and methods Study population The CARDIO2000 is a multicentre case-control study that investigates the association between several demographic, nutritional, lifestyle and medical risk factors with the risk of developing non-fatal acute coronary syndromes. From January 2000 to August 2001, 848 individuals who had just entered to the hospital for a first event of coronary heart disease (stable angina was excluded from the analysis) agreed to participate into the study (response rate 89%). Six hundred and fifty-eight (77%) of them were males (59.0 ± 10 years old) and 190 (23%) were females (65.3 ± 9 years old). The inclusion criteria for cardiac patients are: (1) First event of acute myocardial infarction diagnosed by two or more of the following features: typical electrocardiographic changes, compatible clinical symptoms, specific diagnostic enzyme elevations, or (2) First diagnosed unstable angina corresponding to class III of the Braunwald classification. Moreover, 1078 randomly selected cardiovascular disease-free subjects (controls), matched to the patients by age (±3 years), sex, and region agreed to participate (response rate 83%). Eight hundred and Journal of Human Hypertension

thirty (77%) of them were males (58.0 ± 10 years old) and 248 (23%) were females (64.8 ± 9 years old). Controls were, mainly, individuals who visited the out-patients departments of the same hospital and at the same period with the coronary patients, for routine examinations or minor surgical operations. Also, in country hospitals, where the available number of hospitalised controls was not sufficient for the matching procedure, we randomly enrolled into the study visitors of the same hospitals or population-based individuals. The controls were subjects without any clinical symptoms, signs or any suspicion of cardiovascular disease in their medical history, as a physician evaluated it. We used this type of control in order to have more accurate medical information, to eliminate the potential adverse effect of several, unknown, confounders and to increase the likelihood that cases and controls share the same study base.19 The number of the subjects was decided through power analysis, in order to evaluate differences in the coronary relative risk greater than 7% (statistical power ⬎0.80, significant level ⬍0.05). Stratification According to the population distribution provided by the National Statistical Services (census 2000), we stratified our sampling into all the Greek regions, in order to include various socio-economical levels and cultural particularities of the investigated population. The enrolled subjects are from, approximately, the one-half of the clinics, public or private, of the two biggest metropolitan cities (Athens and Thessalonica), and from, almost, all the major clinics of the other regions (three from Sterea Ellada, three from Thessalia, two from Hpeiros, five from Macedonia, two from Thrace, five from Peloponnese, two from Crete, five from Aegean and three from the Ionian islands). Randomised procedure In order to reduce the unbalanced distribution of several measured or unmeasured confounders, both patients and controls were randomly selected. Thus, a sequence of random numbers (1 . . . 0) was applied in the hospitals’ admission listings. The coronary patients who assigned to the number 1 were entered into the study and interviewed (ie, approximately the one-half of the cardiac patients that visited each cardiology clinic). The same procedure was applied for the controls, after taking into account the matching criteria. Investigated parameters A specialist achieved the information regarding the investigated medical factors from the subjects’ medical records, and the information regarding the lifestyle characteristics through a confidential question-

Mediterranean diet, exercise and hypertension C Pitsavos et al

naire during a specific interview after the 2nd day of the hospitalisation, for the cases and at entry for the controls. Physical activity was defined as any type of non-occupational physical exercise, at least once-a-week during the past year, and was gradated in qualitative terms such as light (expanded calories ⬍4 kcal/min, ie walking slowly, cycling stationary, light stretching etc), moderate (expanded calories 4 – 7 kcal/min, ie walking briskly, cycling outdoor, swimming moderate effort etc) and vigorous (expanded calories ⬎7 kcal/min, ie walking briskly uphill, long distance running, cycling fast or racing, swimming fast crawl etc).20 The rest of the subjects were defined as physically inactive. Also, the duration of physical exercise was taken into account. The presence of occupational exercise was recorded but it was not taken into account for the analysis due to difficulties in evaluation and standardisation. This exclusion may confound our findings, but the large sample size and the applied randomised procedure can spread the subjects who reported occupational exercise equally in both groups of the study. The evaluation of the nutritional habits was based on a nutrient questionnaire according to the guidelines from the Department of Nutrition of the National School of Public Health.21 The traditional Mediterranean type of diet is characterised by a pattern that is high in fruits, vegetables, bread, other cereals, potatoes, poultry, beans, nuts, fish, little red meat, dairy products, low alcohol consumption and olive oil as an important fat source.9–11,21,22 Thus we measured the consumption of these food items as an average per week, during the past year. Then, the frequency of consumption was quantified approximately in terms of the number of times a month the food was consumed. Thus, weekly consumption multiplied by 4 and a value of 0 was assigned to food items rarely or never consumed. In order to describe total diet we used composite scores, which are necessary for the evaluation of epidemiological associations.21 We defined subjects who are ‘closer’ to the Mediterranean type of diet using as cut-off points the median values of the monthly food consumption score as done by several investigators in the past.21 Finally, alcohol consumption was measured by daily ethanol intake, in wineglasses (100 cc– 12% ethanol). According to the collected medical information, the majority of the controls (86%) and of the patients (83%) had at least one-laboratory measurement during the past 12 months. In addition, we measured, both in patients and controls, arterial blood pressure levels (average of three measurements with subject sited and calm; using a standard sphygmomanometer; the systolic blood pressure level was determined by the first perception of sound (of tapping quality), while the diastolic blood pressure 1 (or phase IV) level was determined when the sounds cease to be tapping in quality and become fully muffed; the diastolic blood pressure II (or phase V)

level was determined by the perception of complete disappearance of sounds). Fast total cholesterol as well as fast blood glucose levels were measured in serum. For the cardiac patients the measurements were collected during the first 12 h of hospitalisation, and for the controls at the end of the interview. The previous information as well as the patients’ and controls’ reports assisted us to characterise the subjects as hypertensive, hypercholesterolaemic and diabetics. In particular, in keeping with the long-standing classification criteria used in several epidemiological studies,1,3,23,24 patients who reported never having been told of having hypertension and were not currently taking any antihypertensive medication and whose blood pressure was less than 140/90 mm Hg were classified as normotensives. Patients whose mean blood pressure levels were greater or equal to 140/90 mm Hg (phase V) or were under antihypertensive medication were classified as hypertensives. Hypertensive patients were then asked the following question: ‘Were you ever under any blood pressure lowering treatment, ie drugs or diet?’ Those who answered ‘no’ to the question were classified as ‘untreated hypertension’; those who answered ‘yes’ but their blood pressure, according to their medical records, was not controlled (⬎140/90 mm Hg) were classified ‘uncontrolled hypertension’, the rest of them were defined as ‘controlled hypertension’. Hypercholesterolaemia was defined as cholesterol levels greater than 220 mg/dl or greater than 200 mg/dl when two other risk factors for coronary heart disease or use of special hypo-lipidaemic treatment was present. Diabetics were those with fast blood glucose greater than 125 mg/dl or were under special diet or treatment. Finally, we measured the height and the weight both in patients and controls. In addition, we marked any significant changes in their body mass occurred during the past years. Thus, obesity was defined as body mass index (weight/{height}2) greater than 29.9 kg/m2. Current smokers were defined those who smoked at least one cigarette per day. Quantification of smoking status was based on the calculation of packyears adjusted for nicotine containment equal to 0.8mg per cigarette. Former smokers were defined as the subjects who stopped smoking for over 1 year. Subject’s educational level was classified into three groups: Group I, up to high school; Group II, high school but not academic and Group III, academic.25 Mean annual income, during the past 5 years, was defined as low (⬍4750 US$), moderated (4750– 8500 US$), good (8500–14 500 US$) and very good (⬎14 500 US$), according to the classification of the Ministry of Economics. Further details regarding the design and methodology of the CARDIO2000 study have been previously presented.4,22,25

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Statistical analysis Continuous variables are presented as mean ± one standard deviation while qualitative variables are Journal of Human Hypertension

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presented as absolute and relative frequencies. In order to fit multivariate risk models an exploratory analysis was initially applied. Contingency tables with calculation of ␹2 test, as well as the calculation of Student’s t-test were applied for the evaluation of the associations between the categorical and continuous variables with the outcome. Estimations of the relative risks of developing acute coronary syndromes, under several hypotheses, were performed by the calculation of the odds ratio (OR) and the corresponding confidence intervals through multiple logistic regression analysis, with stepwise elimination procedure.26 All reported P-values are based on two-sided tests and compared with a significant level of 5%. STATA 6 software was used for the calculations (STATA Corp. College Station, TX, USA).

Results Descriptive analysis Four hundred and eighteen (49%) of the 848 patients and 303 (28%) of the 1078 controls were defined as hypertensives. One hundred and fifteen (13%) of the hypertensive patients and 70 (6%) of the hypertensive controls were untreated, 148 (17%) of the patients and 111 (10%) were treated but uncontrolled and 155 (19%) of the patients and 122 (12%) of the controls were controlled. Two hundred and fifty-six (60%) of the coronary hypertensive patients and 224 (74%) of the hypertensive controls were defined as ‘closer’ to the Mediterranean-type of diet (P-value ⬍0.001). One hundred and thirty (31%) of the hypertensive patients and 121 (40%) of the hypertensive controls reported non-occupational physical activity (P-value ⬍0.001). The physically active patients and controls that reported consuming a diet ‘closer’ to the Mediterranean-type of diet were significantly younger than the subjects who reported sedentary life and did not adopt the Mediterranean diet (62.5 ± 9 vs 56.1 ± 10 years old, P-value = 0.023). Table 1 presents the prevalence of

hypertension, hypercholesterolaemia, diabetes mellitus, obesity and smoking habits, in patients and controls that adopted the Mediterranean diet and a physically active lifestyle compared with patients and controls that they did not adopt the afore-mentioned combination. As we can see both patients and controls that reported physical activity and were defined as ‘closer’ to the Mediterranean diet had lower prevalence of the conventional cardiovascular risk factors compared with the rest of the subjects (Table 1). No difference was observed regarding the presence of occupational exercise between patients and controls (172 (20%) vs 198 (18%), P-value = 0.2894). Also, no associations were found between the adoption of Mediterranean—type of diet or physical activity, compared with the income and the educational level of the subjects (P-value = NS). Investigating the potential confounding effect of groups of hypertension on the ‘link’ between the outcome and the combination of diet/physical activity (main factor of interest) as well as the other investigated demographic and cardiovascular factors, we performed stratified analysis. Table 2 presents the results of this analysis as well as the prevalence of several demographic and cardiovascular risk factors, both, in patients and controls group. As we can see, a significant association between groups of study (patients–controls) and smoking habits (positive), alcohol consumption (positive), educational and financial status (inverse), prevalence of hypercholesterolaemia (positive), sedentary life (positive) and obesity (positive), were observed adjusting for the hypertension groups. Multivariate analysis After taking into account the effect of the significant associations that arose from the previous analysis as well as the effect of several potential confounders like age and sex, by design, presence of hypercholesterolaemia, diabetes mellitus, smoking habits,

Table 1 Prevalence of the conventional cardiovascular risk factors in coronary hypertensive patients and controls, stratified by the main factor of interest, ie adoption of the Mediterranean diet and physically active lifestyle or not Mediterranean diet and physical activity Patients n (%) Hypertensives Untreated Treated-uncontrolled Treated-controlled Current smoking Hypercholesterolaemia Obesity Diabetes mellitus

71 15 19 37 42 39 27 17

(44) (9) (12) (23) (59) (55) (38) (24)

Controls n (%) 64 (24) 16 (6) 11 (4) 37 (14) 22 (34) 17 (27) 15 (24) 3 (4)

No Mediterranean diet and physically inactive Patients n (%)

Controls n (%)

347 123 117 107 222 212 142 101

239 (29) 81 (10) 89 (11) 69 (8) 67 (28) 84 (35) 67 (28) 22 (9)

(50) (18) (17) (15) (64) (61) (41) (29)

P-value

⬍0.01

⬍0.01 ⬍0.001 ⬍0.05 ⬍0.001

Last column represents the pooled probability value (P-value) that is derived from the cross-tabulated comparisons between group of the study (patients–controls) and the classical cardiovascular risk factors, stratified by the main factor of interest (ie, combination of Mediterranean diet and physical activity or not). Journal of Human Hypertension

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Table 2 Prevalence (%) of the cardiovascular risk factors and other socio-demographic variables, in patients and controls with hypertension Hypertensive patients Untreated

Smoking Hypercholesterolaemia Diabetes mellitus Obesity Sedentary life Mediterranean diet Alcohol consumption None Low (⭐200 cc/day) Moderate (300–500 cc/day) Heavy (⬎500 cc/day) Educational status None – Primary school Senior high or colleges University Financial status Low income Moderate income Good income Very good income

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Hypertensive controls Treated, controlled (n = 144) %

Untreated

(n = 138) %

Treated, uncontrolled (n = 136) %

(n = 97) %

Treated, uncontrolled (n = 100) %

Treated, controlled (n = 106) %

59 56 30 23 71 59

45 62 33 18 64 60

39 43 34 18 61 61

36 34 10 19 64 61

39 29 8 12 55 70

37** 22** 7** 10* 52** 79**

60 12 19 9

62 10 20 8

61 14 17 8

65 16 11 8

70 20 7 3

63* 27** 6** 4*

38 49 13

39 44 17

32 52 16

32 56 12

30 42 28

33* 42* 25

24 56 14 6

6 60 22 12

8 52 28 12

24 52 16 8

6 54 29 11

5 48** 33* 14*

Comparisons between patients and controls after taking into account the groups of hypertension they belong (stratified cross tabulation analysis). *P-value ⬍0.05; **P-value ⬍0.01.

premature history of coronary heart disease, and duration of exercise, we found that the effect of the combination of Mediterranean diet and physical activity on the coronary risk remains beneficial even in the case of untreated or uncontrolled hypertensive subjects (Table 3). Moreover, special attention was given to alcohol consumption. The analysis raises a J-curve association between alcohol intake and coronary risk

(Figure 1). Based on the developed dose-response risk model we observe that low alcohol consumption (100–200 cc wine glasses per day) by physically active individuals is associated with a 12% reduction of the risk of developing acute coronary syndromes compared with non-drinkers (OR = 0.88, P-value = 0.036), after taking into account the effect of the aforementioned confounders. On the contrary, moderate to high alcohol consumption (⬎300 cc per

Table 3 Results from the multivariate analysis that was developed to evaluate the coronary risk (OR; 95% confidence interval) in hypertensive subjects who are physically active and ‘close’ to the Mediterranean type of diet compared to the rest of them Hypertension Untreated

Mediterranean diet (yes vs no) Physical activity (light–moderate– vigorous vs no) Light Moderate Vigorous Interaction term (yes vs no)

Treated Controlled

Uncontrolled

0.92; (0.85–0.98)*

0.83; (0.79–0.86)*

0.93; (0.86–1.00)

0.95; (0.70–1.03) 0.87; (0.70–0.93)* 0.80; (0.71–0.86)** 0.79; (0.71–0.83)**

0.92; 0.86; 0.81; 0.75;

0.98; 0.93; 0.91; 0.83;

(0.70–0.99)* (0.71–0.92)* (0.71–0.85)** (0.72–0.78)**

(0.68–1.09) (0.70–1.01) (0.69–0.99)* (0.73–0.95)*

Estimates of the odds ratio after taking into account the effect of age and sex, by design, presence of hypercholesterolaemia, diabetes mellitus, family history of premature coronary disease, body mass index, smoking habits, alcohol consumption and social status. *Pvalue ⬍0.05; **P-value ⬍0.01. Journal of Human Hypertension

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Figure 1 Association between daily alcohol intake and odds (95% CI) of developing acute coronary syndromes, in hypertensive subjects who are physically active (continuous line) vs hypertensives that are physically inactive (dotted line). Curves were produced by the application of 2nd order polynomial interpolation.

day) by physically active individuals is associated with 31% increase of the risk of developing acute coronary syndromes, compared to non-drinkers (OR = 1.31, P-value = 0.002). No significant protective effects of alcohol consumption were observed in physically inactive individuals. Figure 1 shows the function that relates the estimated OR and the alcohol intake, by physical activity status. Finally, the calculated attributable risk by the formula: attributable risk = (odds ratio −1)/odds ratio,26 suggested that the one-third (33%) of the acute coronary events could be prevented by a combination of the adoption of the Mediterranean diet and physical exercise, in controlled hypertensive subjects. Also the previous combination can reduce the acute coronary events by 26% in untreated and by 20% in uncontrolled hypertensives.

Discussion In this study we evaluated the effect of the combination of Mediterranean diet and physical activity on the development of acute coronary syndromes, in hypertensive subjects. The exploratory analysis showed that the previous combination is associated with a healthier lifestyle, ie lower prevalence of hypercholesterolaemia, obesity and diabetes mellitus, as well as moderated smoking habits. Also, subjects with higher education and income achieved a better control of their blood pressure levels. However, the multivariate analysis, after controlling for the effect of the aforementioned confounders raise a significant and independent reduction of the coronary risk, due to the previous combination, not only in controlled hypertensive subjects, but in subjects who were untreated or uncontrolled, too. In particular, we estimated that the one-third of the nonJournal of Human Hypertension

fatal acute coronary events in controlled hypertensive subjects could be prevented through the adoption of a physically active lifestyle and the consumption of this traditional diet. Similar results were observed in uncontrolled or untreated hypertensives (20% and 26%, respectively). There is extensive scientific evidence on the relation between diet and incidence of coronary heart disease, and other disease.2,5,6–12 Dietary factors exert their influence largely through their effects on blood lipids and lipoproteins, as well as on the other established modifiable risk factors, with the exception of cigarette smoking. Our results support the hypothesis that the adoption of the Mediterranean diet by hypertensive subjects is associated with a significant reduction of the risk of developing acute coronary syndromes. The investigated type of diet is low in saturated fat, high in monounsaturated fat, mainly from olive oil, high in complex carbohydrates, from legumes, and high in fibre, mostly from vegetables and fruits.9–11 Based on the results from the Seven Countries study,8,9 the protective role of Mediterranean type of diet against atherosclerosis was explained, mainly, due to the reduction of cholesterol and blood pressure levels. Recently, the findings from the Lyon Diet Heart study illustrate the potential importance of the Mediterranean dietary pattern, especially when compared with other recommended diets, like Step-I diet.10,11 Results from a Spanish study indicate that the monounsaturated fatty acids diets lead to a significant reduction of both systolic and diastolic blood pressure.12 However it still remains a matter of debate if the protective influence is primarily caused by single nutrients, eg, dietary fatty acids, potassium or dietary fibre or if it can be attributed to the Mediterranean diet as a whole.10 According to several observational studies mortality or morbidity caused by coronary heart disease was found inversely related to the individuals’ physical activity status.13–18 In addition, some reports suggest that even a single session of moderate-to-long duration exercise can reduce blood pressure, glucose, and triglyceride levels and can increase high-density lipoprotein cholesterol levels. Therefore, the Centres for Disease Control and Prevention and the American College of Sports Medicine27 recommend at least 30 min of moderate-intensity physical activity on most, and preferably all, days of the week on the basis of documented improvements in fitness. According to the literature, even severe hypertension can be managed with a combination of drug therapy and physical exercise.28–30 However, the mechanisms responsible for the underlying exercise-induced reduction in blood pressure levels remain unclear.30 Based on the developed multifactorial risk model, our study showed that physical activity can reduce the risk of developing acute coronary syndromes by 16% in controlled hypertensive subjects (P-value ⬍0.01), by 16% in the untreated (P-value ⬍0.01) and by 6%

Mediterranean diet, exercise and hypertension C Pitsavos et al

in treated but uncontrolled hypertensives (P-value ⬍0.05), after controlling for the effect of several potential confounders, such as smoking habits, presence of hypercholesterolaemia, body mass index etc. Also, the effect of the intention of exercise seems to add benefits on the reduction of the coronary risk (Table 3). Alcohol consumption has received considerable attention in the past 10 to 20 years as a factor that has properties that tend to reduce the risk of developing coronary heart disease events. This protective effect has been illustrated in low quantities intake.5–7 In the present work we observed a Jshape association between alcohol consumption and coronary risk, in hypertensive subjects. Other investigators have, also, reported by the previous association between alcohol consumption and cardiovascular risk.33 Moreover, the presence of physical activity seems to offer further cardioprotective effects, compared to subjects that reported sedentary life (Figure 1). EUROASPIRE survey demonstrated a high prevalence of modifiable risk factors (including hypertension) in coronary heart disease patients.3,34 Also, the EUROASPIRE Study group investigators suggest to the cardiologists and other physicians to moderate the prevalence of the cardiovascular risk factors in order to further reduce coronary heart disease morbidity and mortality and improve patient’s chances of survival.3 Moreover several investigators, since the early 1990s, reported that non-pharmacological lifestyle interventions can be useful in the management of hypertensive subjects.34,35 Nowadays it is widely accepted from public health strategies that inappropriate diet and physical inactivity together with tobacco use have been recognised as the major risk factors for cardiovascular diseases.31,32 In this study we presented the effect of a non-pharmaceutical approach on the reduction of the burden of coronary disease in hypertensive subjects. Although the observed association is independent from the conventional risk factors it is hard to claim that our findings suggest causal evidence. In order to explain this ‘ecological’ effect much remains to be learned about the potential common biological mechanisms between diet and physical activity on the coronary risk, in hypertensives. Limitations of the study In retrospective case-control studies two, main, sources of systematic errors may exist, the selection and the recall bias. In order to eliminate selection bias we tried to set objective criteria, both, for patients and controls. However, insignificant misclassification may exist, since a small percentage of asymptomatic coronary patients may be wrongly assigned to controls, even they were evaluated by a cardiologist. Also, in case-control studies it is usually observed that patients who had a recent adverse event are more likely to place greater emphasis (overestimate) on several factors related to the dis-

ease than the control group (recall bias). In order to reduce this type of bias and analyse accurate information we made an effort to obtain accurate information from the patients as well as from their relatives or their accompanying persons. However, overestimation of the effect of the investigated combination may still exist. Concerning the medical information we tried to avoid recall bias obtaining accurate and detailed data from subjects’ medical records. However, over/under estimation may still exist, especially in the measurement of nutritional and smoking habits, and the onset of the investigated cardiovascular risk factors. Moreover, the coronary patients who died at entry or the day after were not included into the study. This bias could influence our results, but, since the proportion of deaths during the first 2 days was estimated between 2– 4% by the physicians of the study we believe that the inability to include the fatal events did not altere our findings significantly. Furthermore, regarding the potential effect of uncontrolled–unknown confounders, we tried to reduce it through multivariate analysis and by using the same study base both for patients and controls.26

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Acknowledgements This study was supported by research grants from the Hellenic Heart Foundation (11/1999–11/2002). The authors would like to thank the physicians and the specialists that coordinated this study: Dr K Tzioumis (Athens, Crete, Pelloponisos), Dr N Papaioannou (Athens, Thessalia), Dr P Starvopodis (Ionian Islands), Dr L Karra (Aegean Islands), Dr D Antoniades (Macedonia), Dr G Rembelos (Aegean Islands), Dr D Markou (Athens), A Moraiti, (Athens), D Evagelou (Crete), Dr S Vellas (Attica, Hpeirous), B Meidanis (Macedonia, Sterea Hellas, Thessalia), Dr S Loggos (Attica), Dr I Elefsiniotis (Athens), Dr N Marinakis (Aegean Islands), Dr G Koutsimbanis (Thrace), Dr G Sombolos (Pelloponisos) and Dr T Kyratzoglou (East Macedonia).

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