Featured Commentary

Obesity is a major health issue affecting both developed and developing countries. In Europe, it is estimated that about one-third of coronary heart disease (CHD) and ischaemic stroke and almost 60% of hypertensive disease are attributed to increased body mass index (BMI).¹ The increasing prevalence of obesity among children adolescents across the region – and globally - is a major cause of concern.² In spite of efforts aimed at increasing awareness and preventive measures, prevalence increases to rise. Studies showing that the emergence of atherosclerotic disease can occur early in life, with children displaying fatty streaks in their arteries, underscore the need for an early preventive approach to address this problem.

Data from the Metabolic, Lifestyle, and Nutrition Assessment in Young Adults (MELANY) study in more than 37,000 apparently healthy young men provides new insights into the association of BMI during adolescence and future risk of CHD and type 2 diabetes. BMI at age 17 years was independently predictive of documented angiographic disease. Of particular note, the increased risk of CHD was evident at BMI criteria typically considered normal.³

The study was conducted in male Israeli army subjects. Height and weight were measured at age 17 years and every 3 to 5 years thereafter if the subjects remained in the army. In adolescents, BMI ranged from 17.3 (10^th percentile) to 27.6 (90^th percentile). In adulthood, the range was between 21.4 and 30.6.

Over a mean follow-up, of 17.4 years, there were 1173 incident cases of type 2 diabetes and 327 cases of angiographically documented CHD (>50% stenosis in at least one coronary artery). After adjustment for age, family history and other cardiovascular risk factors, BMI levels at the 80^th percentile (22.4-23.4) and above were associated with significantly increased risk for diabetes. The limit was lower when considering angiographic CHD risk, when BMI levels at the 30^th percentile (19.0 to 19.7) were associated with significantly increased risk (Fig 1).  In subjects with higher BMI at age 17 years, losing weight during adulthood did not completely reverse this risk.

When analysed as a continuous variable in a multivariate model, each 1 unit increase in BMI:

• increased the risk of diabetes by 9.8% (Hazard ratio 1.10, 95% CI 1.08-1.12)
• Increased the risk of CHD by 12.0% (95% CI 1.12, 95% CI 1.07-1.18).

Both BMI in adolescence (17 years) and adulthood (around 30 years) were significantly associated with risk of future CHD. In contrast, only BMI in adulthood was associated with increased risk for type 2 diabetes.

The study does have a number of limitations, in that it relates to male army personnel, and used BMI rather than waist circumference as a measure of obesity.

However, even accounting for these, the results adds further to evidence of an association of cardiometabolic abnormalities in adolescence and risk for CHD in adulthood.^4,5 The data underline the relevance of a higher BMI in adolescence to future heart disease risk, even if the individual subsequently loses weight. However, what is new from this study, is that previously regarded criteria for a ‘normal’ or ‘healthy’ BMI in adolescence are indeed associated with increased risk for atherosclerotic disease and CHD in adulthood. This suggests that these criteria merit further scrutiny and definition.

Which is a better marker of CV risk: apoB, LDL-C or non-HDL-C?

There is ongoing debate as to whether non-HDL-C or apolipoprotein (apo)B are preferable to LDL-C in predicting CV risk. A new meta-analysis suggests that that the use of apoB is preferable and, in routine application could have important implications for the prevention of CVD.⁶

ApoB vs. Non-HDL-C: what does each represent?

• Non-HDL-C: the sum of cholesterol in atherogenic apoB lipoprotein particles
• ApoB: the number of atherogenic apoB lipoprotein particles

Previously, the Emerging Risk Factors Collaboration ⁷ concluded that non-HDL-C and apoB were interchangeable with LDL-C as predictors of CV risk. The analysis was based on 68 prospective population-based studies of cardiovascular risk involving 302,430 participants without known history of CHD, mainly from Western Europe and North America, representing therefore the most extensive analysis of this question to date.

The current meta-analysis included 15 independent analyse; 12 reports including 233,455 subjects and 22,950 events were analysed. The relative risk reduction for vascular events from 12 population-based studies suggested a hierarchy with apoB the most accurate marker of CV risk (Fig 2).

Fig 2. Increasing order of lipid indices (hazard ratios and 95% CI) as a marker of CV risk

Based on data from the US National Health and Nutrition Examination Survey, estimates of benefit suggest that targeting non-HDL-C instead of LDL-C could prevent a further 300,000 clinical events over 10 years; and targeting apoB instead of LDL-C could prevent a further 500,000 events. The authors therefore make the case for routine monitoring of apoB in CV disease prevention, given that clinical measurement is now more accessible, reliable and robust. In support, it is notable that recently updated Canadian guidelines recommend the use of apoB in clinical practice, with a recommended target of <80 mg/dL.⁸

Primary prevention of CVD in Europe: far from optimal

Management of CV risk factors in primary prevention needs to improve according to the results of the EURIKA (European Study on Cardiovascular Risk Prevention and Management in Usual Daily Practice). The study also highlights disparities in CV risk management across Europe.⁹

EURIKA was a cross-sectional study conducted in 7641 outpatients without CVD (mean age 63.2 years, 48% male) enrolled by centres in 12 European countries (Austria, Belgium, France, Germany, Greece, Norway, Russia, Spain, Sweden, Switzerland, Turkey and the UK). Patients had at least one major CV risk factor, as defined by the most recent published European guidelines for CVD prevention.¹⁰  

The prevalence of CV risk factors is summarised below. Despite the primary prevention setting, 40.1% were at high risk (as estimated by SCORE). However, this figure varied across the countries, lowest in Greece (27.3%) and highest in Sweden (57.3%).

Among patients receiving treatment for CV risk factors, control was less than optimal; less than 50% of treated patients achieved target blood pressure (<140/90mmHg); lipids (total cholesterol <5 mmol/L and LDL-C <3.0 mmol/L); or HbA1c <6.5%. Of note, less than one-third of obese patients receiving lifestyle advice achieved a BMI <30 (Fig 3). Even after treatment, about one-third of patients remained at high CV risk.

Fig 3. Despite high treatment rates, achievement of guideline recommended goals was far from optimal

Criteria for dyslipidemia only took into account control of total cholesterol and LDL-C and not other lipid abnormalities (HDL-C, non-HDL-C and triglycerides). It is likely therefore that the current data represent an overestimate of the proportion of dyslipidemic patients who were adequately controlled. This is of relevance, given that the prevalence of the low HDL-C and/or elevated triglycerides phenotype is increasing as a result of the global diabetes and obesity epidemic.

Guidelines recommend lifestyle intervention as an important first step for the management of cardiometabolic abnormalities. However, in the study while most patients received lifestyle advice, less than 50% received written information about a healthy diet and less than one-third were referred to a dietician  These data suggest that while the importance of lifestyle intervention is recognised by clinicians, there remains a clear deficit in implementing practical changes that would benefit patients.

Anti-inflammatory effects of HDL

HDL exhibit a range of biological activities which are implicated in their athero-vasculo protective functions. Recent data implicate HDL – and apoA-I – in the regulation of neutrophil activation.¹¹ Emerging evidence suggests that neutrophils are key players in the inflammatory process of atherosclerosis; activated neutrophils are associated with acute coronary syndromes and increased numbers of circulating neutrophils are a risk marker of cardiovascular outcomes.^12,13

In an in vitro setting, HDL and apo A-I were shown to inhibit CD11b neutrophil expression and activation, adhesion and spreading under flow conditions, and migration. These anti-inflammatory effects were also observed in vivo. Infusion of apoA-I in a murine model of inflammation inhibited leukocyte recruitment to the endothelium.  In patients with peripheral vascular disease, infusion of reconstituted (r)HDL was associated with an elevation in plasma levels of HDL-C together with reduction in neutrophil activation, as measured by the change in CD11b membrane expression. The latter findings are consistent with reduction in monocyte activation previously observed following infusion of rHDL in patients with peripheral vascular disease.¹⁴

The results of this study using both in vitro and in vivo approaches adds to increasing evidence of multiple anti-inflammatory effects of HDL and apoA-I, which are of relevance to mediation of atheroprotective effects.