Lipoprotein (a) and risk of cardiovascular disease in patients with metabolic syndrome in a population of familial hypercholesterolaemia (2006)

Dear Sir,Liprotein (a) [Lp(a)] is known to increase the risk of cardiovascular disease (CVD). A meta-analysis of prospective studies indicated that plasma Lp(a) concentration is an independent risk factor for coronary heart disease (CHD) [1]. The Prospective Epidemiological Study of Myocardial Infarction (PRIME), a cohort study that included 9133 men also showed Lp(a) as a predictor of CHD risk [2]. Heterozygous familial hypercholesterolaemia (FH) is a common hereditary disorder of lipoprotein metabolism (prevalence 1 : 400). We recently showed Lp(a) to be a risk factor for CVD in 2400 Dutch patients with FH [3]. In recent years various studies have reported that the metabolic syndrome is associated with an increase in CVD [4-9]. It is unknown if measuring Lp(a) has an additive prognostic value on top of having metabolic syndrome. The objective or our study was to determine whether along with the presence of metabolic syndrome there was an additional risk associated with the presence of higher levels of Lp(a) in this high-risk population which included patients inducted from 27 clinics around the Netherlands. The database for the current study is the molecular diagnostic centre for nationwide FH screening in the Netherlands, located at the Academic Medical Centre, the University of Amsterdam. A total of 2400 patients fulfilled the diagnostic criteria for FH and were included in the study. The inclusion and exclusion criteria for participation in the study and details of the data collection are outlined and discussed in detail previously [3, 10, 11]. The Ethics Institutional Review Board of each participating hospital approved the protocol. Metabolic syndrome was defined as per National Cholesterol Education Program (NCEP) Adult Treatment Plan (ATP III) criteria [12] along with the recently suggested modifications [13]. We did not have waist circumference information so we substituted for body mass index (BMI) and based our cut-off on a recent NHANES III analysis [14]. A diagnosis required the concomitant presence of three or more of the following risk factors: (i) elevated triglycerides (≥1.7 mmol L−1); (ii) low HDL cholesterol (men <1.03 mmol L−1; women <1.29 mmol L−1); (iii) fasting glucose ≥5.55 mmol L−1 or medication use for diabetes; (iv) Systolic blood pressure (BP) ≥130 mmHg or diastolic BP ≥85 mmHg or medication use for hypertension; (v) BMI ≥30 kg m−2 for men and ≥25 kg m−2 for women. Total CVD was defined by the presence of at least one of the following: (i) CHD, (ii) cerebrovascular disease and (iii) peripheral vascular disease. The criteria to define each one of these three end-points have been explained in detail previously [3]. Differences in clinical characteristics between patients with and without metabolic syndrome were tested with chi-square statistics or independent sample t-tests where appropriate. We analysed the lifetime risk of CVD in these patients. The relative risks were estimated from a Cox regression analysis which modelled the lifetime hazard of events, thus we looked at the risk of CVD events starting at birth and ended for each individual at the date of the first occurrence of established CVD. Patients without CVD were censored at the date of the last lipid clinic visit or at the date of death attributable to other causes. We verified any vascular end-point that may have occurred before presentation to the vascular lipid clinics. The following variables were entered into the analyses: gender, smoking (time-dependent), LDL cholesterol and statin therapy. For smoking we implemented a linearly decreasing risk effect for the 3 years after cessation [15]. Analyses were performed using SPSS (version 10.1; Chicago, IL, USA) and SAS software (version 8.02; Cary, NC, USA). P < 0.05 was considered to be statistically significant. Of 2400 patients with FH, we had all five variables to make a diagnosis of metabolic syndrome and Lp(a) levels in 1292 patients. The characteristics of patient population according to tertiles of Lp(a) is described in Table 1. In the multivariate Cox regression model we showed that as opposed to patients without metabolic syndrome, patients with metabolic syndrome had an increased risk for CVD (RR 1.54, 95% CI 1.22–1.96). When additionally stratifying by tertiles of Lp(a), compared to patients without metabolic syndrome and the lowest tertile of Lp(a) the patients with metabolic syndrome were at an increased risk of CVD in both first (RR 1.56, 95% CI 1.02–2.39) and third tertile (RR 2.70, 95% CI 1.79–4.07) of Lp(a). Wiklund et al. [16] and Seed et al. [17] have shown that an elevated level of Lp(a) is a strong risk factor for CHD in patients with FH. Previously we have shown in the same population of FH patients that Lp(a) conferred a risk of 1.50 (95% CI 1.2–1.79) [3]. In the present study we show that presence of metabolic syndrome in the highest tertile of Lp(a) additionally increased the risk for CVD to 2.70 (1.79–4.07). Lipoprotein (a) is a cholesterol-rich lipoprotein with structural similarities to LDL [18], but contain apo(a) and apoB in a 1 : 1 molar ratio. A recent study showed that the apoB/AI ratio and the metabolic syndrome were both independent long-term predictors of myocardial infarction [19]. Another study has shown that increased levels of Lp(a) were independently associated with risk of CHD amongst diabetic women [20]. There are limitations to our study. Our results are derived from patients referred to lipid clinics and therefore caution is required when interpreting the results. Patients at the highest risk might have died before visiting a lipid clinic, which might have caused underestimation of our results. However, in mortality analyses we rarely observed such early deaths [21]. Further studies are required to explore this possible relationship between Lp(a) and risk of CVD in patients with metabolic syndrome in a population of FH. The use of novel risk markers to recognize and prevent CVD is becoming increasingly important. With recent emphasis on the metabolic syndrome as an independent risk factor for CVD, it is important to explore whether measuring of any additional markers would work synergistically to provide additional prognostic value for future risk of CVD. No conflict of interest was declared.