Lipoprotein(a) in health and disease

Elevated plasma levels of Lp(a) do seem to influence the progression of atherosclerosis. Evidence is emerging that certain apo(a) isoforms may be more atherogenic than others, and in transgenic mice free apo(a) has been shown to be associated with accelerated atherosclerosis. Currently it is not known whether treating elevated Lp(a) levels will reduce progression of atherosclerosis and, as therapeutic options are limited, mass screening of Lp(a) levels in populations is not indicated. The presence of raised Lp(a) levels, however, warrants aggressive treatment to reduce other cardiovascular risk factors. Continuing research to investigate the relationship of the apo(a) gene to other genes, including the plasminogen gene and apo(a)-related genes, will add further information pertaining to the evolution, function, regulation and clinical implications of Lp(a).     

Lipoprotein Lp(a) excess and coronary heart disease

A pharmacokinetic study of all-trans retinoic acid (ATRA) was performed in 8 patients with various types of leukemia and MDS. After oral administration at a dose of 30 mg/m2, the mean peak plasma concentration was 430 ng/ml and was reached at 150 min. In one patient who failed to respond a very low plasma ATRA level was seen. Though the plasma ATRA exposure decreased significantly with daily drug administration, an intermittent schedule of ATRA administration would yield higher plasma drug concentrations. We treated 2 patients with refractory acute promyelocytic leukemia (APL) in a pilot study of ATRA followed by intensive chemotherapy (APL-ATRA protocol). Two patients successfully achieved complete remission with ATRA after failing under conventional chemotherapy. Based on the pharmacokinetic study of ATRA, an intermittent schedule of ATRA in addition to chemotherapy suggests an effective regimen for children with APL. Phase II trials to evaluate the role of intermittent schedules of ATRA are planned in Children's Cancer and Leukemia Study Group.     

Lipoprotein (a) and plasminogen in atherosclerosis

The aim of this study was to evaluate plasma levels of lipoprotein (a) [LP(a)] and plasminogen in patients affected with atherosclerotic disease and to understand the mutual relationships. Eighty-four patients affected with atherosclerosis were examined and divided as follows: group I, 24 patients with peripheral arteriopathy; group II, 40 patients with ischemic heart disease (myocardial infarction and/or angina pectoris); group III, 20 patients with multi-infarct dementia; group IV (control group) with 20 healthy young subjects. The results show that Lp(a) plasma levels, in atherosclerotic patients, are higher than 30 mg/dl, while the plasminogen levels are lower than 80 mg/dl. There is an inverse correlation between these two data. Moreover, a different behaviour of Lp(a) and plasminogen rate related to age of patients, to number of atherosclerotic lesions or to acuteness of ischemic heart disease, was observed.     

Lipoprotein(a) concentration and molecular weight of apolipoprotein(a) in patients with cerebrovascular disease and diabetes mellitus

Plasma lipoprotein(a) [Lp(a)] concentrations are genetically determined, and hyper-Lp(a)-emia is an independent risk factor for atherosclerosis and thrombosis. To study the implications of Lp(a) in cerebrovascular disease (CVD) and diabetes mellitus (DM), we examined plasma Lp(a) levels and molecular weights of apolipoprotein(a) [apo(a)] in 118 patients with CVD, and 125 cases with DM. Although mean Lp(a) concentrations were higher in those cases with atherothrombotic brain infarction than in those with brain hemorrhage and lacunar infarction, the difference was not statistically significant. Lp(a) levels were significantly higher in the DM cases treated with insulin and in those treated with oral hypoglycemic agents than in those on diet therapy alone, suggesting that insulin and oral agents modulate apo(a) expression. Lp(a) concentrations correlated significantly with the low-molecular-weight isoforms of apo(a) in all CVD and DM groups.     

Lipoprotein(a) in android obesity and NIDDM

OBJECTIVE: To assess the level of serum lipoprotein(a) [Lp(a)] in nonobese and obese NIDDM subjects with android body distribution. RESEARCH DESIGN AND METHODS: Serum Lp(a) levels were measured in 30 long-standing NIDDM patients (duration of diabetes 12.5 +/- 3 years, mean +/- SD), with 15 of the patients being obese of android distribution (BMI > 30 kg/m2 and waist-to-hip ratio > 0.8). In addition, there were 15 android obese nondiabetic subjects and 10 healthy subjects serving as the control group. RESULTS: All groups of patients in this study (diabetic, obese, and obese diabetic) showed significantly higher levels of Lp(a) than the healthy control group. Lp(a) concentrations were significantly higher in NIDDM patients with android type of obesity than in nondiabetic androids (24.1 +/- 5.6 vs. 14.8 +/- 2.4 mg/dl, P < 0.001). Significantly greater levels of Lp(a) were found in nonobese subjects with diabetes when compared with obese subjects without diabetes (22.3 +/- 4.1 vs. 14.8 +/- 2.4 mg/dl, P < 0.001). Furthermore, Lp(a) serum concentrations were not dependent on the degree of glycemic control (controlled NIDDM 23.6 +/- 5.0 vs. uncontrolled NIDDM 21.4 +/- 2.7 mg/dl, NS), but were much greater in subjects with diabetes complicated by vascular disease (complicated 26.3 +/- 5.0 vs. uncomplicated 20.5 +/- 2.7 mg/dl, P < 0.001). No correlation was found between Lp(a) and other lipid parameters in this study. CONCLUSIONS: Lp(a) levels are significantly elevated in both android-obese and nonobese NIDDM patients regardless of the degree of glycemic control. Lp(a) is an independent risk factor showing greater elevations in those subjects complicated with diabetic vascular diseases.     

Lipoprotein(a) and general risk factors in patients with angiographically assessed peripheral arterial disease

High lipoprotein(a) [Lp(a)] has been observed in patients with ischemic heart disease and cerebrovascular disease. Lp(a) is actually thought to be an independent risk factor for coronary disease. We therefore carried out a case-control study, evaluating plasma Lp(a) in 61 patients with angiographically documented peripheral arterial disease (PAD) and in 61 age- and sex-matched patients with no cardiovascular disease. General risk factors for vascular disease were also taken into account. Lp(a) was significantly higher in patients than controls (257.0 +/- 34.8 vs 146.5 +/- 23.5 mg/l p < 0.05), as were cigarette smoking, diabetes, cholesterolemia, fibrinogenemia and the waist-to-hip circumference ratio. Stepwise logistic regression analysis showed that, in addition to cigarette smoking, diabetes, cholesterol and fibrinogen, Lp(a) is a significant independent risk indicator for PAD. This result suggests that high plasma Lp(a) is associated with enhanced risk of PAD and must therefore be evaluated alongside traditional risk factors.     

Lipoprotein(a) and diabetes. An update

On the basis of the available data (much of which is contradictory), I suggest that the following might summarize the role of Lp(a) in diabetes currently. 1. Lp(a) in IDDM: Concentrations are probably elevated. Concentrations are probably related to metabolic control. Concentrations are increased with microalbuminuria. 2. Lp(a) in NIDDM: Concentrations are not elevated. Concentrations do not change with metabolic control. Too few data exist to make an assessment of relation of Lp(a) to microalbuminuria in NIDDM. 3. Lp(a) and CHD in diabetes: Little current evidence shows that Lp(a) is a risk factor for CHD in diabetes. More studies--especially prospective studies with larger numbers of subjects--need to be done.     

Lipoprotein(a) interactions with lipid and nonlipid risk factors in early familial coronary artery disease

An interaction between high plasma lipoprotein(a) [Lp(a)], unfavorable plasma lipids, and other risk factors may lead to very high risk for premature CAD. Plasma Lp(a), lipids, and other coronary risk factors were examined in 170 cases with early familial CAD and 165 control subjects to test this hypothesis. In univariate analysis, relative odds for CAD were 2.95 (P < .001) for plasma Lp(a) above 40 mg/dL. Nearly all the risk associated with elevated Lp(a) was found to be restricted to persons with historically elevated plasma total cholesterol (6.72 mmol/L [260 mg/dL] or higher) or with a total/HDL cholesterol ratio > 5.8. Nonlipid risk factors were also found to at least multiply the risk associated with Lp(a). When Lp(a) was over 40 mg/dL and plasma total/HDL cholesterol > 5.8, relative odds for CAD were 25 (P = .0001) in multiple logistic regression. If two or more nonlipid risk factors were also present (including hypertension, diabetes, cigarette smoking, high total homocysteine, or low serum bilirubin), relative odds were 122 (P < 1 x 10(-12)). The ability of nonlipid risk factors to increase risk associated with Lp(a) was dependent on at least a mildly elevated total/HDL cholesterol ratio. In conclusion, high Lp(a) was found to greatly increase risk only if the total/HDL cholesterol ratio was at least mildly elevated, an effect exaggerated by other risk factors. Aggressive lipid lowering in those with elevated Lp(a) therefore appears indicated.     

Lipoprotein (a): effect of detraining

Plasma levels of lipoprotein (a), total cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol, apo-protein Al and apoprotein B were evaluated for 8 long-distance runners during the XXIII New York Marathon, with blood samples being taken before and after the race, and after one month of detraining. After detraining lipoprotein (a) increased significantly both with respect to basal values and especially with respect to immediately post-race values. Negligible and predictable modifications of the other metabolic parameters evaluated, were observed. No correlation was found between lipoprotein (a) and the anthropometrical data and metabolic parameters considered.     

Lipoprotein (a) concentrations in patients with various dyslipidaemias

The results of operative treatment of 45 flexible flat feet (29 patients) using the sinus tarsi spacer are reported. Although radiological improvement in both the talar declination and the ground-navicular distance was found, our patients suffered from pain and functional impairment for an average period of 5 months. An unacceptably high rate of spacer dislocation was noted. Furthermore, the literature indicates spontaneous improvement as the natural history of flexible flat feet. We therefore no longer advise the sinus tarsi spacer as a routine treatment for flexible flat feet.     

Lipoprotein(a)--possible role in the fibrinolysis process

The clinical and epidemiological features of 120 episodes of Streptococcus pyogenes bacteraemia in St. Thomas' Hospital between 1970 and 1997 were analysed. One-third of episodes were nosocomial. M1 was the most common serotype, and 29% of strains were non-typable. There was a variety of presenting features, but nearly half of the patients had cellulitis, 15% were shocked, and 6% had necrotic infections. There was no focus of infection in 13%. 54% of patients had an underlying disease, and 23% of infections were associated with a medical procedure or device. The mortality rate was 19%, and was associated with shock, coma, no focus of infection, and underlying disease. Since 1989, the annual incidence has more than doubled, and M1 strains and necrotic infections have increased, but the mortality rate and the proportion of patients presenting with shock have decreased, and the increase in cases involved many different M-types.     

Lipoprotein(a) as a risk factor for ischemic heart disease: metaanalysis of prospective studies

Although in vitro studies support a pathophysiologic role for lipoprotein(a) [Lp(a)] in the development of atherosclerosis, and retrospective studies consistently report that there is a relationship between Lp(a) and ischemic heart disease (IHD), the conclusions drawn from prospective studies about this relationship have been inconsistent. To address this issue, we have performed a metaanalysis of data available from prospective studies. Lp(a) concentrations expressed as mass units vary markedly between studies, reflecting the need for assay standardization. In 12 of 14 prospective studies, Lp(a) concentrations are higher in subjects who later develop IHD (cases) than in those who do not (controls), although there is variation in the size of the effect. Sample storage temperature may contribute to this variability. When the studies are analyzed collectively, Lp(a) concentrations are significantly higher in cases than in controls, and the extent of the effect is similar in men and women. These findings provide evidence in support of a causal role for Lp(a) in the development of atherosclerosis. Measurement of Lp(a) may be useful to guide management of individuals with a family history of IHD or with existing disease. The separation in values between cases and controls is not, however, sufficient to allow the use of Lp(a) as a screening test in the general population.     

Lipoprotein(a): a link between thrombosis and atherosclerosis?

Lipoprotein(a) (Lp(a)) represents a class of plasma lipoproteins similar to low-density lipoprotein (LDL), but containing an unique apolipoprotein(a) with striking homology to plasminogen. Plasma Lp(a) is inherited as a quantitative genetic trait, with a continuous distribution in Caucasian populations (< 10-2000 mg/l), where high levels are associated with an increased risk of atherosclerotic disease. The physiological role of Lp(a) is unknown, and the metabolism is obscure. Plasma Lp(a) is apparently resistent to diets and drug therapy, and LDL-apheresis is currently the most effective way of reducing plasma Lp(a). However, clinical benefits of lowering plasma Lp(a) have not been demonstrated, and specific therapeutic goals cannot be recommended at present. The structural similarity between apo(a) and plasminogen has generated several experimental observations indicating a prothombogenic and proatherogenic role of Lp(a), but the exact pathophysiological mechanisms have not been determined.     

Lipoprotein(a) is an independent risk factor for coronary artery disease in NIDDM patients in South India

OBJECTIVE: Asian Indians have been reported to have very high prevalence rates of coronary artery disease (CAD) in the absence of traditional risk factors. Recently, elevated levels of lipoprotein(a) [Lp(a)] have been reported to be associated with premature CAD in migrant Asian Indians. However, there are very little data regarding Lp(a) in CAD patients from the Indian subcontinent and virtually none in individuals with NIDDM. The objective of this study was to assess the role of Lp(a) as a marker for CAD in South Indian NIDDM patients. RESEARCH DESIGN AND METHODS: We estimated serum Lp(a) in 100 control subjects, 100 NIDDM patients without CAD, and 100 NIDDM patients with CAD. Lp(a) values were transformed into natural logarithms. Statistical analysis included Student's t test, one-way analysis of variance, and chi2 test. Multiple logistic regression analysis was used to identify associations with CAD. RESULTS: Lp(a) levels were significantly higher in NIDDM patients with CAD compared with NIDDM patients without CAD and control subjects (geometric mean 24.6, 15.1, and 19.4 mg/dl, respectively, P < 0.05). Results of logistic regression analysis showed that Lp(a), age, and HDL were associated with CAD. In NIDDM patients with CAD, there was no correlation between Lp(a) and serum cholesterol, triglyceride, or HDL cholesterol levels, but there was a weak association with LDL cholesterol and systolic blood pressure. CONCLUSIONS: The data suggests that serum Lp(a) is an independent risk factor for CAD in NIDDM patients in South India.     

Lipoprotein (a) and cholesterol in body builders using anabolic androgenic steroids

A 67-year-old Taiwanese woman with multilocular hydatid cysts of the liver presented with a 5-month history of intermittent right upper abdominal discomfort. Abdominal ultrasonography and computed tomography showed multiple cysts in both lobes of the liver. Subsequent selective celiac angiography revealed an avascular space-occupying lesion in the right lobe. She underwent a radical excision of the cyst by total closed (without opening the wall) cystopericystectomy over segments 4, 5 and 6. Histologic study of the lesions showed three structural components: 1) an outer acellular laminated membrane, 2) a thin nucleated germinal membrane and 3) several protoscolices with Echinococcus granulosus suckers. The patient has been well for 5 years since her discharge. Although hydatid cysts of the liver are extremely rare in Taiwan, they may cause life-threatening complications and mortality. Making a preoperative diagnosis is important and is only possible if this rare disease is kept in mind.     

Lipoprotein(a) in patients with carotid atherosclerosis and ischemic cerebrovascular disorders

Two novel peptides, named PACAP (pituitary adenylate cyclase activating polypeptide) containing 38 (PACAP38) and 27 residues (PACAP27) were recently isolated from ovine hypothalami. In order to investigate the pituitary cell type(s) that bear a receptor for PACAP, PACAP38 was biotinylated and used for cytochemical examination of binding. The cells were also identified by immunocytochemical methods using the antisera against each of the rat anterior pituitary hormones or an antiserum against S-100 protein, a marker for pituitary folliculo-stellate (FS) cells. Biotinylated PACAP38 (biot-PACAP) exhibited adenylate cyclase stimulating activity (ACSA) comparable to PACAP38 in rat pituitary cell cultures, and displaced the bound 125I-PACAP27 to the rat pituitary membrane preparation to the same extent as PACAP38. After 2-4 days of culture, dispersed rat pituitary cells were incubated with varying concentrations of biot-PACAP at room temperature or 4 degrees C. The bound biot-PACAP38 was visualized by avidin-biotin-peroxidase complex (ABC) method with nickel intensification. Biot-PACAP-positive and pituitary hormone or S-100-positive cells were counted. More than 90% of S-100-positive cells bound biot-PACAP38. A considerable number of GH and PRL cells and a lesser number of ACTH cells also bound biot-PACAP38, whereas only a few identified LH, FSH, or TSH cells bound biot-PACAP38. These results suggest that FS cells are a major target cell type for PACAP. A recent study from our laboratory demonstrated that PACAP stimulated the release of interleukin (IL)-6 in rat pituitary cell cultures. FS cells are known to produce IL-6.     

Lipoprotein (a) in children with chronic renal failure treated conservatively

The aim of this study was to evaluate serum lipid abnormalities, particularly lipoprotein (a), [Lp(a)] as an independent risk factor for cardiovascular disease in children with mild and moderate renal failure. Study were performed on 14 children of whom serum creatinine levels were above 265.3 mumol/l and 32 patients with serum creatinine levels below 265.3 mumol/l. Control group consisted of 27 healthy age-matched subjects. All children were tested for concentration of serum Lp(a), total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (C-LDL) and high density lipoprotein cholesterol (C-HDL). It was found a significantly increase in Lp(a), TC, C-LDL and significantly decrease in C-HDL in children with more advanced renal insufficiency compared to the control. In children with mild renal failure concentration of serum Lp(a) also increased but not significantly. Patients in this group had elevated serum TC and decreased C-HDL. These results suggest that even in the early stages of renal insufficiency in children abnormalities of lipoprotein are present. Such abnormalities, particularly Lp(a) might contribute to accelerated atherosclerosis in this patients.     

Lipoprotein(a) in endurance athletes, power athletes, and sedentary controls

Elevated concentrations of lipoprotein(a) [Lp(a)] have been shown to be an independent risk factor for atherosclerotic disease. Physical activity and physical fitness have been shown to improve lipoprotein metabolism and reduce the risk of coronary artery disease. Studies on the influence of physical activity and physical fitness on Lp(a) levels including a large number of endurance as well as power athletes have not been performed before. Therefore, we determined parameters of physical fitness (maximal oxygen consumption), physical activity, and lipoproteins in 105 endurance athletes, 57 power athletes, and 87 sedentary young men. As expected, we found that endurance athletes with a good physical fitness had significantly higher concentrations of high-density lipoprotein cholesterol than power athletes and sedentary controls. Regarding mean Lp(a) levels (rocket immunoelectrophoresis), however, there were no significant differences between endurance athletes, power athletes, and sedentary controls. Even when including only those with Lp(a) values > 10 mg.dl-1, no differences were observed between the groups. These findings indicate that intensive training over years and good aerobic fitness improve the ratio of low-density lipoprotein to high-density lipoprotein cholesterol but have no or only minor effects on Lp(a) concentrations.     

Lipoprotein(a) and the cardiovascular risk during estrogen-progestin replacement therapy in postmenopause

A homogeneous group of 37 patients, aged between 52 and 61 years was considered in relationship to the metabolic response during hormonal replacement therapy (HRT). A free endocrinological-metabolic pathology control group, formed by 40 patients, who were not treated with any therapy, was also considered. Study-trial was comprehensive of a 123 months follow-up, with some periods of study at 0, +6, +12 months. Metabolic responses of lipoprotein(a) and apolipoprotein A and B during the different follow-up steps were determined. Total and fractioned cholesterol and triglycerides were also determined. Significant correlations were shown between Lipo(a) and Apo B and also between Lipo(a) and LDL in both groups considered Lipoprotein(a) was determined by ELISA methodic and turbidimetric methodic. The aim of our study was to verify the importance of the new markers of the atheromatous risk. The reduction of lipoproteins middle value observed in the HRT group shows a little, but however present, estrogens action to the Lipo(a) itself. This fact testifies to the benefit of the use of HRT in post-menopause also as reg ards an evaluated cardiovascular risk inhibition.