The importance of the relation between lipoprotein(a) and lipids for development of atherosclerosis and cardiovascular disease

DEAR SIR, Life-style modification and drug therapy is regularly used in primary and secondary prevention of cardiovascular disease in order to lower LDL cholesterol (LDL-C) and triglycerides and increase HDL cholesterol (HDL-C). These interventions does not normally change the strongly inherited lipoprotein(a) [Lp(a)] level. There is still a disagreement in the literature on the usefulness of Lp(a) determinations when lipid intervention is considered. We feel that Lp(a) should always be included in order to define high risk individuals and families and the extent of cholesterol reduction needed. To fully explain that view a more extensive discussion is needed. However, unpublished results of a comparison of two previously studied male populations add further support to our opinion. Results from a study of 653 healthy 30–33-year-old white male population from Northern Sweden, investigated in 1978 and a study of 161 healthy black male population who in 1990 were blood donors at the Ilembula Lutheran Hospital in south-west Tanzania were compared. In the ordinary procedure for blood donation in the hospital a HIV test was performed using an ELISA method with reagents from Organon. Only blood from blood donors who were tested negative was included in the study. Serum was immediately frozen and shipped by air to Sweden. Lipids and Lp(a) were analysed by comparable techniques as previously described [1]. The studies were reviewed and approved by the Institutional Review Boards. All black male population were Bantus living in the catchment area of the hospital. The majority were farmers working in the fields where all procedures were carried out manually. Walking was the main way of transportation and many were walking far distances. The staple food in the area consisted of a thick maize porridge (ugali), usually eaten with beans or vegetables like spinach, tomatoes and onions. Eggs were consumed to some extent. The intake of fat was low and the main source of fat was derived from sunflower oil and peanuts. Only a very low portion of food was of animal origin and fish was uncommon. Very few fruits were grown in the area and canned food was essentially not available. Consumption of local beer was common. Smoking was rare and those who smoked consumed only a few cigarettes per day. Obesity was very rare. The hospital had 265 beds and 13 000–17 000 admissions per year. During the last 15 years before this study no patient with acute myocardial infarction (AMI) had been seen in the hospital and other atherosclerotic manifestations were extremely rare. It seems very unlikely that a diagnosis of AMI would have been overlooked as both sudden death and sudden onset of chest pain was very rare amongst patients attending the hospital. On the contrary, hypertension was not uncommon and stroke were regularly seen in hypertensive patients. A much higher cholesterol level was found amongst the Swedish male population and triglycerides were also higher than amongst the male population in Tanzania. Although HDL-C was higher in the Swedish male population the percent HDL-C was significantly higher amongst the Tanzanian male population (Table 1). No inverse correlation was found between triglycerides and HDL-C in the black male population. The highly significant correlation between cholesterol and HDL-C in the Tanzanian male population was not found in the Swedish male population (Table 2; Fig. 1). As found previously [2] the median Lp(a) level was much higher in black than in white male population (322 vs. 81 mg L–1; P < 0.001). Scatter plot showing distribution of cholesterol and HDL-C in black and white male population, respectively. A comparison between all black male population and a subgroup of white male population with reasonably similar characteristics (nonsmoking male population with cholesterol <5.0 mmol L–1 and BMI <22.2) was hampered by the fact that only 5.2% (n=34) of the white Swedish male population were found in that group. In this subgroup, a highly significant correlation (r=0.81; P=0.002) between cholesterol and HDL-C was found amongst male population with Lp(a) higher than the median level of 81 mg L–1 (n=12), whilst no correlation was found amongst male population (n=22) with lower Lp(a) levels (r=–0.20; NS) (Fig. 2). This is probably related to the finding in many previous studies of a significantly lower triglyceride level in individuals with high Lp(a) levels than in individuals with low Lp(a) levels [3]. Scatter plot showing distribution of cholesterol and HDL-C amongst selected nonsmoking white male population with cholesterol <5.0 mmol L–1 and BMI <22.2. A highly significant correlation (r=0.81; P=0.002) between cholesterol and HDL-C was found amongst male population with Lp(a) higher than the median level of 81 mg L–1 (n=12), whilst no correlation was found amongst male population with lower Lp(a) levels (r=–0.20; NS). High-density lipoprotein protects against the development of atherosclerosis by facilitating the transport of cholesterol from peripheral cells back to the liver for removal from the body, i.e. the ‘reverse cholesterol transport’. A high correlation between total cholesterol and HDL-C in the lower range of cholesterol distribution may mean that there is a balance between deposition of cholesterol in the arterial wall and efflux of cholesterol from the arterial wall leading to a protection against cholesterol accumulation in the artherial intima and against atherosclerosis. Apparently, a high Lp(a) level is not a risk factor for AMI in the studied black male subpopulation in Tanzania. The reason for that is most certainly the low cholesterol level and the comparatively high HDL-C/cholesterol ratio. A further reason is probably also the high correlation between cholesterol and HDL-C amongst black male population in Tanzania who have a very high mean Lp(a) level. This is a further indication that Lp(a) may have evolved a long time ago as a beneficial factor that may have promoted a higher bone density [4] and a more efficient wound healing [5] because of the additional local cholesterol supply from Lp(a) and a more efficient reverse cholesterol transport. This regulation may have been lost when the abundant high cholesterol food supply led to unphysiologically high cholesterol, LDL-C and triglyceride levels and low HDL-C levels. The consequence is an increased accumulation of cholesterol in peripheral tissues, especially in individuals with inherited high Lp(a) levels, which in the arterial intima leads to the development of vulnerable plaques, prone to rupture. In areas like in Northern Sweden, with high mean cholesterol levels, Lp(a) is a major risk factor for cardiovascular disease in male population with an attributable risk percent as high as 31% in prospective studies [6, 7]. These new findings add further support for the urgent need for life-style changes in the western world, aiming at lipid lowering, increased exercise, weight reduction and reduction of smoking in the population as a prerequisite in the important primary prevention of cardiovascular disease. It is also important to find ways to protect the native African population with a low prevalence of atherosclerotic manifestations from the adverse effects of a change to a western life-style.