Featured Commentary

Issue No. 2: March, 2011

Mediterranean diet for combating the metabolic syndrome

The second in a series of regular Commentaries highlighting topical issues relevant to EAS activities.

The increasing prevalence of the metabolic syndrome poses a major public health issue for the 21st century. By far the most significant impact the metabolic syndrome has on health is the increased incidence of atheromatous vascular disease.

Lifestyle interventions represent an attractive means of addressing this challenge. The Mediterranean diet is characterised by high consumption of monounsaturated fats; daily consumption of vegetables, fruits, whole cereal grains and low-fat dairy products; weekly consumption of fish, poultry, nuts and legumes; moderate alcohol intake and limited consumption of red meat. This dietary pattern has previously been shown to have cardioprotective effects,[1] as well as beneficial effects in obesity and type 2 diabetes.[2-4]

A recent systematic review and meta-analysis of 50 research studies (both observational studies and randomised controlled trials) evaluated the effect of the Mediterranean diet on the metabolic syndrome and its individual components.[5] The analysis included data from over half a million subjects. Adherence with a Mediterranean diet reduced the risk of developing the metabolic syndrome by 31%, and had beneficial effects on its individual components (see Box).

The authors did acknowledge a number of limitations in their analysis. The dietary pattern was not consistent across studies; in some clinical trials the Mediterranean diet was a component of a lifestyle intervention plan; and there was evidence of significant heterogeneity in the analysis with regard to the effect of the diet on the components of the metabolic syndrome (i.e., location, sample size, duration of intervention and level of encouragement of adherence).

However, even with these caveats, the results of this analysis have important implications from the public heath perspective. The Mediterranean diet has practical advantages as it can be easily adopted across different age groups and cultures. As such it may offer a cost-effective approach to prevention of the metabolic syndrome. As a consequence, adherence to the Mediterranean diet, in conjunction with other lifestyle and pharmacotherapeutic approaches, may offer the opportunity to impact the substantial morbidity and mortality conferred by cardiometabolic disease.

Interaction between exercise and HDL-modifying genes

Genetic influences over HDL cholesterol plasma levels are multifactorial, which is not surprising given the complexity of HDL metabolism. Previous genome-wide association studies have identified a number of single nucleotide polymorphisms (SNPs) in key lipid genes that influence HDL cholesterol concentration. However, lifestyle factors also have an effect. In particular, regular aerobic exercise is known to raise HDL cholesterol levels. However, the combined effects of exercise and these SNPs on HDL cholesterol concentration, especially in women, are not clear. This was key aim of this prospective cohort study involving nearly 23,000 apparently healthy women who were participants of the Women’s Health Study.[6]

Researchers investigated whether exercise influenced the association between common SNPs and plasma levels of HDL cholesterol. Of 58 SNPs in nine genes that showed a genome wide-association with HDL cholesterol levels, seven SNPs on three loci had effects on HDL cholesterol that were modulated by exercise. The strongest evidence was for SNPs at the LPL, LIPC and CETP genes.

The frequency of physical activity modulated these effects. In active women (physical activity > 8.8 metabolic equivalents hours/week) the increase in HDL cholesterol associated with LIPC and CETP variants was greater than in less active women. However, for LPL variants, the results were counterintuitive, in that larger effects were observed in less active than more active women.

Further analyses investigated the clinical implications of these findings. In women with the minor-allele LPL polymorphism, regular exercise was associated with a lower risk of myocardial infarction (MI) (Hazard ratio 0.51, 95% CI 0.30-0.86), whereas in women without this polymorphism, regular exercise had no association with MI risk (Hazard ratio 1.13, 95% CI 0.79-1.61). By contrast, the impact of the minor-allele CETP polymorphism on MI risk was similar irrespective of exercise frequency (Hazard ratio 0.72, 95% CI 0.57-0.92).

Overall, these data are consistent with current understandings that the relationship between variation in key lipid genes and HDL cholesterol levels is complex, subject to environmental influences, and may not necessarily translate to reduction in coronary risk.

The relevance of insulin resistance in low HDL/elevated triglycerides dyslipidemia

Dyslipidemia characterised by a low plasma level of HDL cholesterol and elevated triglycerides is commonly associated with cardiometabolic abnormalities, including insulin resistance. Observational studies have also shown that the presence of insulin resistance is not only independently predictive of this dyslipidemia, but also is associated with elevated coronary heart disease (CHD) risk.[7] However, whether this dyslipidemic profile is also associated with increased CHD risk independent of insulin resistance, was the focus of this report from the community-based Framingham Heart Study.[8]

This analysis included data from 2,910 non-diabetic individuals from the Framingham Offspring Study, who were followed-up for an average of 14 years for first occurrence of coronary events (nonfatal or fatal MI or CHD death). Low HDL cholesterol and elevated triglycerides were defined as either below or above, respectively, the median values at the baseline examination. For HDL cholesterol, median values were 56 mg/dL in women, 42 mg/dL in men and 49 mg/dL overall. For triglycerides, the corresponding median values were 108, 121 and 112 mg/dL. Insulin resistance was defined by the upper quartile of HOMA-IR in sex-pooled subjects with diabetes.

Multivariate Cox regression analyses, adjusted for other cardiovascular risk factors, showed that the presence of insulin resistance together with the lowest values of HDL cholesterol and the highest values of triglycerides was associated with increased coronary risk (p<0.001). In the absence of insulin resistance, neither low HDL cholesterol nor elevated triglycerides were associated with increased CHD risk. However, in secondary analyses increasing continuous HDL cholesterol was significantly associated with decreasing risk of CHD, with or without insulin resistance. There was no significant association between log triglycerides and CHD risk in individuals without insulin resistance.

The results of this analysis are not unexpected considering the close metabolic relationships between these two lipids. The atherogenic dyslipidemic profile of low HDL cholesterol-elevated triglycerides in insulin resistance appears to be driven by CETP-mediated hetero-exchange of triglycerides from apolipoprotein (apo) B lipoproteins with cholesteryl ester from apo A-I lipoproteins, together with dissociation of apo A-I from triglyceride-enriched HDL and subsequent clearance via the kidney.[9] However, the study findings do not implicate insulin resistance as directly causal for CHD, irrespective of this dyslipidemia.

The study also has a number of limitations, not least of which is the selection of the cutoffs for low HDL or elevated triglycerides. It should be borne in mind that these values are not consistent with levels proposed in guidelines as indicative of increased cardiovascular risk. For example, in the latest published European guidelines for cardiovascular disease prevention, an HDL cholesterol value ≤1.0 mmol/L (40 mg/dL) in men and ≤1.2 mmol/l (45 mg/dL) in women, and triglycerides ≥1.7 mmol/L (150 mg/dL) are thought to be indicative of increased cardiovascular risk. Further investigation of the association of atherogenic dyslipidemia, as defined by these criteria, insulin resistance and coronary risk is merited.

Study provides rationale for universal screening for FH in children

Early identification and treatment of familial hypercholesterolemia (FH) are key to reducing the risk of premature cardiovascular disease. Mutations in 3 genes (low-density lipoprotein receptor [LDLR], apo B [APOB] and proprotein convertase subtilisin/kexin 9 [PCSK9] are responsible for the majority of cases. However, there remains ongoing controversy that numerous other mutations – so far unidentified –  are also responsible for FH in a sizable proportion of patients.

The current study[10] aimed to provide information that may resolve this debate by determining the proportion of children with FH who had mutations in the three main genes (LDLR, APOB and PCSK9).  Inclusion criteria for FH included LDL-C levels >95th percentile for age and sex and autosomal dominant inheritance pattern of hypercholesterolemia, defined as at least one biological parent on treatment for hypercholesterolemia and a family history of hypercholesterolemia and cardiovascular disease. Children with a body mass index >75th percentile for age and sex, who were referred to the lipid clinic via the national cascade screening programme and who were from families with a known molecular diagnosis were excluded.

The clinical implications of these findings are highly relevant.  These results provide a rationale for a universal screening programme, which would be able to differentiate a diagnosis of FH in children with elevated LDL cholesterol levels, from other dyslipidemias (such as familial combined hyperlipidemia and dyslipidemia associated with obesity).[11] The crucial need to detect and treat FH early is underscored by the very high risk of premature cardiovascular disease in such subjects.  At the current time, statins remain the treatment of choice in this setting, given their extensive evidence-base supportive of efficacy and safety, even in children.

New model of atherosclerosis regression

Regression of atherosclerotic plaque remains the ‘holy grail’ for therapeutic intervention. To achieve this, an appropriate model of human atherosclerosis is essential. The Reversa mouse, which combines a standard model of human atherosclerosis (i.e. LDL-receptor deficient) together with a genetic ‘switch’ that inactivates microsomal triglyceride transfer protein, which is required for hepatic secretion of atherogenic apo B-containing lipoproteins, is an appropriate approach. This is a clinically relevant model as it enables researchers to mimic both elevated LDL cholesterol levels associated with hyperlipidemia and treatment strategies aimed at lowering these levels. A recent study using this model provided important insights.[12]

Reversa mice were fed an atherogenic diet for 16 weeks, allowing for the development of arterial plaques, thus mimicking the development of advanced human coronary artery disease. Half the animals were then switched to a chow diet and treated with polyinosinic-polycytidylic acid (pIpC) which resulted in inactivation of the gene for microsomal triglyceride transfer protein, and consequently elimination of apoB-100 containing lipoproteins from the plasma and normalisation of plasma cholesterol levels (regarded as baseline).  This treated group therefore simulated aggressive lipid management. Both treated and control animals were sacrificed after 3, 6, 14, 28 and 56 days from baseline.

The key findings of the study are summarised. The change in plaque size was modest. This may be a consequence of a decrease in matrix degradation and/or stimulation of collagen synthesis and consequent stabilisation of the plaque.

In subsequent experiments, treatment with pioglitazone, a peroxisome proliferator-activated receptor-γ agonist further increased the expression of anti-inflammatory markers associated with M2 macrophages and reduced expression of plasminogen activator inhibitor-1 in mouse plaques.

The Reversa mouse offers a convenient model to help in understanding the molecular mechanisms underlying plaque regression. It also provides the possibility for investigating novel agents that may have potential therapeutic benefit. 

Call to Action for cardiovascular disease prevention in women

The European Society of Cardiology (ESC) has highlighted the need for urgent action to reduce gender disparities in cardiovascular disease (CVD) prevention and management, in a special issue of the European Heart Journal.  According to the World Health Organisation, CVD in Europe accounts for 55% of deaths in women versus 43% of deaths in men.

The call to action focused on two key studies. Researchers at the University of Bologna, Italy evaluated data from 6,558 patients (4,471 men and 2,087 women) from the Canadian Acute Coronary Syndromes Registry I and II. Age was independently associated with lower use of beta blockers (odds ratio 0.83; p<0.001) and lipid-lowering agents (OR 0.80; p<0.001) at discharge. There was also an independent association between heart failure (Killip class 2 or greater) and beta-blocker underutilisation (OR 0.67; p<0.001), which was much more striking among women.[13]

In the second study,[14] researchers from Uppsala University Hospital, Uppsala, Sweden analysed data from the Swedish Coronary Angiography and Angioplasty Register (SCAAR) between 2006 and 2008. Data from 7,195 men and 5,005 women with suspected coronary artery disease (CAD) after chest pain were included.

There was clear evidence of overuse of coronary angiography, especially in younger women. In younger patients (<59 years) 78.8% of women vs. 42.3% of men who underwent angiography were shown to have no significant CAD (p<0.001). However, only 4.2% of women vs. 18.2% of men were diagnosed with left main or three-vessel disease (p<0.001).

The ESC first launched the “Women at Heart” programme in 2005. Since this time, the Society has been active in promoting research into the specific problems relating to CVD in women.

References

1. Trichopoulou A, Bamia C, Trichopoulous D. Mediterranean diet and survival among patients with coronary heart disease in Greece. Arch Intern Med 2005; 165: 929-35.

2. Giugliano D, Esposito K. Mediterranean diet and metabolic diseases. Curr Opin Lipidol 2008; 19: 63-8.

3. Salas-Salvadó. J, Bullo M, Babio N et al. Reduction in the incidence of type 2 diabetes with the Mediterranean Diet: Results of the PREDIMED-Reus Nutrition Intervention Randomized trial. Diabetes Care 2011; 34:14-9.

4. Buckland G, Bach A, Serra-Majern L. Obesity and the Mediterranean diet: a systematic review of observational and intervention studies. Obes Rev 2008;9:582-93.

5. Kastorini CM, Milionis HJ, Esposito K, et al. The effect of Mediterranean diet on metabolic syndrome and its components. J Am Coll Cardiol 2011; 57:1299-313.

6. Ahmad T, Chasman DI, Buring JE et al. Physical activity modifies the effect of LPL, LIPC, and CETP polymorphisms on HDL-C levels and the risk of myocardial infarction in women of European ancestry. Circ Cardiovasc Genet 2011;4:74-80.

7. Pyorala M, Miettinen H, Laakso M, Pyorala K. Plasma insulin and all-cause, cardiovascular, and noncardiovascular mortality: the 22-year follow-up results of the Helsinki Policemen Study. Diabetes Care 2000;23:1097-1102.

8. Robins SJ, Lyass A, Zachariah JP et al. Insulin resistance and the relationship of a dyslipidemia to coronary heart disease. The Framingham Heart Study. Arterioscler Thromb Vasc Biol 2011;31:doi:10.1161/atvbaha.110.219055.

9. Chapman MJ, Redfern JS, McGovern ME, Giral P. Niacin and fibrates in atherogenic dyslipidemia: pharmacotherapy to reduce cardiovascular risk. Pharmacol Ther 2010;126:314-45.

10. van der Graaf A, Avis HJ, Kusters M et al. Molecular basis of autosomal dominant hypercholesterolemia. Assessment in a large cohort of hypercholesterolemic children. Circulation 2011;123:1167-73.

11. Kwiterovich PO. Clinical implications of the molecular basis of familial hypercholesterolemia and other inherited dyslipidemias. Circulation 2011;123:1153-5.

12. Feig JE, Parathath S, Rong JX et al. Reversal of hyperlipidemia with a genetic switch favorably affects the content and inflammatory state of macrophages in atherosclerotic plaque. Circulation 2011;123:989-98.

13. Bugiardini R, Yan AT, Yan RT, et al. Factors influencing underutilization of evidence-based therapies for women. Eur Heart J 2011; DOI:10.1093/eurheartj/ehr027. Available at: http://eurheartj.oxfordjournals.org. Accessed 11 March 2011.

14. Johnston N, Schenck-Gustafsson K, Lagerqvist B, et al. Are we using cardiovascular medications and coronary angiography appropriately in men and women with chest pain? Eur Heart J 2011; DOI:10.1093/eurheartj/ehr009. Available at: http://eurheartj.oxfordjournals.org. Accessed 11 March 2011.   

Article © Jane Stock, freelance medical writer and journalist.
March 2011