Elevation Of Lp Research Articles

Increased Lp(a) levels in a Caribbean family. Case report and literature review

Background and Aims : Lipoprotein (a) (Lp(a)) is a macromolecule synthesized by the liver, whose serum levels are determined genetically by the LPA gene (1-4). It’s associated with increased atherosclerotic risk (1, 2) when levels rise above 50 mg/dl independently of ethnicity (5). The cardiovascular risk (CVR) related to Lp(a) are associated with LDL-C. In patients with familiar hypercholesterolemia, the elevation of Lp(a) increase the risk of cardiovascular event at an early age (6,7). Levels above 180 mg/dl of Lp(a) are considered very high-risk patients (8).

*A Novel ABCG8 Variant and Apo(A) Short Isoform Associated with Premature Atherosclerosis and Familial Hypercholesterolemia Phenocopy.

Lead Author's Financial Disclosures Nothing to disclose. Study Funding None. Background/Synopsis We report a patient with a rare ABCG8 mutation, that when combined with Apo(a) short isoforms may represent a familial hypercholesterolemia (FH) phenocopy. Objective/Purpose A 44-year-old African American male with prior myocardial infarction (MI) at the age 24 with subsequent coronary artery bypass graft who had rapid progression of atherosclerosis despite having a corrected LDL of zero. Methods Lp(a) was 127 mg/dL and LDL was 40 mg/dL and he had been on evolocumab and rosuvastatin. The corrected LDL accounts for the cholesterol contained in Lp(a) using the formula LDLcorr =LDL- 0.3x Lp(a) mass. Thus, his LDLcorr was zero. He underwent genetic testing with GBinsight which demonstrated he had Apo(a) short isoforms, which is associated with elevated Lp(a). He was also heterozygous for an extremely rare ABCG8 variant p.Gly212Glu (rs1318623110) which has not been previously reported. This variant is predicted to be deleterious and Gly212 is highly conserved across vertebrates. Mutations in ABCG5 or ABCG8 can be associated with increased LDL and risk for CAD. In addition, elevation of Lp(a) can be associated with 3 to 4 folds increased risk. This novel mutation, along with the elevated Lp(a) may help to explain his FH phenocopy presentation. Results We hypothesized that his premature disease progression may have been secondary to inflammation, atherogenesis or prothrombosis associated with Lp(a) with the added potentially deleterious effect of the ABCG8 mutation. His clinical course with his first MI at age 24 mimics that of FH, thus making him a phenocopy. We enrolled him in the randomized Lp(a)HORIZON trial evaluating the effect of pelacarsen in lowering Lp(a). However, he subsequently had an episode of unstable angina requiring additional intervention. Conclusions When assessing patients with suspected FH, mutations in genes other than LDLR, APOB, and PCSK9 should be evaluated. In this case, a mutation in ABCG8 gene along with Apo(a) short form isoforms may help explain the patient's disease progression and FH phenocopy presentation. In addition, ezetimibe may be beneficial in patients with ABCG5/8 mutation. His marked disease progression despite having a LDLcorr of zero highlights the importance of considering factors other than just LDL. Nothing to disclose.

Intracoronary Thrombus in a Patient with Elevated Lp(a) Levels and COVID-19

Lead Author's Financial DisclosuresNothing to disclose.Study FundingNone.Background/SynopsisLp(a) is elevated in 20% of the population and is associated with increased risk for myocardial infarctions and strokes. In patients with COVID-19, Lp(a) is upregulated as a response to the systemic inflammatory infection which can potentially increase the risk for atherothrombotic events. The following case presents the first report of a patient with elevated Lp(a) levels and COVID-19 who presented with an acute MI and evidence for intracoronary thrombus.Objective/Purpose49-year-old male with past medical history of thoracic aortic aneurysm recently diagnosed with COVID-19 presented to ED with chest pain. EKG showed ST-segment elevation in the anterior leads with a 12.7 troponin score. Patient underwent emergent cardiac catheterization that showed 90% ulcerated thrombotic lesion in the proximal LAD. The thrombus was demonstrated by both angiography and IVUS. Thrombectomy, angioplasty, and stenting were performed. There was embolization of thrombus to the distal LAD. Echocardiogram revealed LVEF 55% with apical hypokinesis. He was started on DAPT, statin, and rivaroxaban due to the high risk of recurrent coronary thrombosis. His Lp(a) was 200 nmol/L. (Normal < 75 nmol/L).MethodsN/A.ResultsCases of patients with COVID-19 and elevated Lp(a) presenting with acute MI and intracoronary thrombus have yet to be reported. Elevated Lp(a) level is thought to increase the risk of cardiovascular events and venous thromboembolism through anti-fibrinolytic and pro- atherosclerotic properties. Acute, transient elevations in Lp(a) secondary to IL-6 production have been observed in inflammatory states, such as COVID-19 infections. A cohort study of 146 COVID-19 patients in the Netherlands observed a mean increase in Lp(a) of 16.9mg/dL from baseline over a course of 21 days during hospitalization In a retrospective study of patients admitted with COVID-19, 5.6% of 531 experienced arterial thrombosis, 9 of which suffered myocardial infarction. In patients similar to ours with COVID- 19 and elevated Lp(a), there may be elevated risk of similar events and providers should remain vigilant for potential complications. It is possible that acutely elevated Lp(a) levels contribute to arterial thrombotic events in the coronaries during COVID-19 infection.ConclusionsIn patients presenting with COVID-19 and acute myocardial infarction, we recommend that clinicians measure Lp(a) level and evaluate for intracoronary thrombi to correlate our findings.

Lipoprotein(a) and Cardiovascular Disease Prevention across Diverse Populations.

Lipoprotein(a) (Lp(a)) is a highly proatherogenic lipid fraction that is genetically determined and minimally responsive to lifestyle or behavior changes. Mendelian randomization studies have suggested a causal link between elevated Lp(a) and heart disease, stroke, and aortic stenosis. There is substantial inter-ethnic variation in Lp(a) levels, with persons of African descent having the highest median values. Monitoring of Lp(a) has historically been limited by lack of standardization of assays. With the advent of novel therapeutic modalities to lower Lp(a) levels including proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors and targeted antisense oligonucleotides, it is increasingly important to screen patients who have family or personal history of atherosclerotic cardiovascular disease for elevations in Lp(a). Further study is needed to establish a causal relationship between elevated Lp(a) and cardiovascular disease across diverse ethnic populations.

Actual situation of lipoprotein apheresis in patients with elevated lipoprotein(a) levels

An elevation of lipoprotein(a) (Lp(a)) is an internationally recognized atherogenic risk factor, documented in epidemiological studies, in studies with Mendelian randomization and in genome-wide association studies (GWAS). At present, no drug is available to effectively reduce its concentration. In Germany, an elevation of Lp(a) associated with progressive cardiovascular diseases is officially recognized as an indication for a lipoprotein apheresis (LA). The number of patients who were treated with LA with this abnormality was steadily increasing in the years 2013–2016 – the official data are reported. In all new patients, who started to be treated at our LA center in 2017 (n = 20) the increased Lp(a) was a main indication for extracorporeal therapy, though some of them also showed clearly elevated LDL cholesterol (LDL-C) concentrations despite being treated with a maximal tolerated lipid-lowering drug therapy. A diabetes mellitus was seen in 5 patients. The higher was the Lp(a) level before the first LA session, the higher was the cardiovascular risk. Lp(a) concentrations measured before LA sessions were usually about 20% lower than those before the start of the LA therapy. Acutely, Lp(a) levels were reduced by about 70%. Following LA sessions the Lp(a) levels increased and in the majority reach pre-session concentrations after one week. Thus a weekly interval is best for the patients, but a few may need two sessions per week to stop the progress of atherosclerosis. The interval mean values were about 39% lower than previous levels. Several papers had been published showing a higher efficiency of LA therapy on the incidence of cardiovascular events in patients with high Lp(a) values when comparing with hypercholesterolemic patients with normal Lp(a) concentrations. Russian specific anti-Lp(a) columns positively affected coronary atherosclerosis. PCSK9 inhibitors reduce Lp(a) concentrations in many patients and in this way have a positive impact on cardiovascular outcomes. In the future, an antisense oligonucleotide against apolipoprotein(a) may be an alternative therapeutic option, provided a clear-cut reduction of cardiovascular events will be demonstrated.

P6196Lipoprotein (a) and cardiovascular risk: are women at increased risk?

Abstract Introduction Coronary artery disease (CAD) is the leading cause of death worldwide, placing a major economic and resource burden on health and public health systems, so efforts are being made to accurately predict risk for major adverse cardiac events (MACE). The field of risk prediction and CAD prevention continues to evolve with the identification of novel risk factors and biomarkers, such as lipoprotein a [Lp)a]. Almost 20% of the population has elevated circulating levels of Lp(a), which is recognized as an independent risk factor for CAD, stroke, peripheral arterial disease, and aortic stenosis. Importantly, studies showed that this was particularly true for women. Objective To evaluate if the elevation of Lp(a) is associated with MACE in female, male or both. Materials and methods Case control study of 3050 subjects from the GENEMACOR study population. In female population (n=676): cases were 341 patients with at least one &gt;75% coronary stenosis (median age 55.7±7.2) and 335 normal controls (median age 55.8±6) adjusted by age with cases. In male population (n=2374): 1278 patients with at least one &gt;75% coronary stenosis (median age 52.7±8) and 1096 controls (median age 51.9±8) also adjusted by age. χ2 and T student tests were used to analyze the demographic, laboratorial, angiographic and anthropometric characteristics of the population. Lipoprotein (a) was determined by immunoturbidimetry. High Lp(a) level was considered if superior to 30 mg/dl. Logistic regression was used to evaluate Lp(a) as a risk factor for CAD in total, female and male populations. Results In female population 44.0% patients vs 21.2% controls (p&lt;0.000) had Lp(a)&gt;30mg/dl. In male population 39.4% patients vs 23.8% controls (p&lt;0.000) had Lp(a)&gt;30mg/dl. In total population Lp(a)&gt;30mg/dl was a predictor for CAD (OR 2.24, 95% CI: 1.91–2.62, p&lt;0.0001). Analyzing by gender, Lp(a)&gt;30mg/dl was also a predictor for CAD either in male (OR 2.08, 95% CI: 1.74–2.5, p&lt;0.0001) or female population (OR 2.92, 95% CI: 2.08–4.09, p&lt;0.0001). Conclusions As opposed to other studies, in our population elevated Lp(a) levels (&gt;30mg/dl) were associated with elevated CAD risk, in both men and women. We conclude that Lp(a) can be considered an independent risk factor for CAD disease in our population, and further strategies for Lp(a) reduction may indeed translate in improved outcomes in CAD disease.

The Relationship between the serum total bilirubin level and the severity of coronary artery disease in chronic stable angina patients

An elevation of lipoprotein(a) (Lp(a)) is an internationally recognized atherogenic risk factor, documented in epidemiological studies, in studies with Mendelian randomization and in genome-wide association studies (GWAS). At present, no drug is available to effectively reduce its concentration. In Germany, an elevation of Lp(a) associated with progressive cardiovascular diseases is officially recognized as an indication for a lipoprotein apheresis (LA). The number of patients who were treated with LA with this abnormality was steadily increasing in the years 2013–2016 – the official data are reported. In all new patients, who started to be treated at our LA center in 2017 (n = 20) the increased Lp(a) was a main indication for extracorporeal therapy, though some of them also showed clearly elevated LDL cholesterol (LDL-C) concentrations despite being treated with a maximal tolerated lipid-lowering drug therapy. A diabetes mellitus was seen in 5 patients. The higher was the Lp(a) level before the first LA session, the higher was the cardiovascular risk. Lp(a) concentrations measured before LA sessions were usually about 20% lower than those before the start of the LA therapy. Acutely, Lp(a) levels were reduced by about 70%. Following LA sessions the Lp(a) levels increased and in the majority reach pre-session concentrations after one week. Thus a weekly interval is best for the patients, but a few may need two sessions per week to stop the progress of atherosclerosis. The interval mean values were about 39% lower than previous levels. Several papers had been published showing a higher efficiency of LA therapy on the incidence of cardiovascular events in patients with high Lp(a) values when comparing with hypercholesterolemic patients with normal Lp(a) concentrations. Russian specific anti-Lp(a) columns positively affected coronary atherosclerosis. PCSK9 inhibitors reduce Lp(a) concentrations in many patients and in this way have a positive impact on cardiovascular outcomes. In the future, an antisense oligonucleotide against apolipoprotein(a) may be an alternative therapeutic option, provided a clear-cut reduction of cardiovascular events will be demonstrated.

Statin therapy increases lipoprotein(a) levels.

Lipoprotein(a) [Lp(a)] is elevated in 20-30% of people. This study aimed to assess the effect of statins on Lp(a) levels. This subject-level meta-analysis includes 5256 patients (1371 on placebo and 3885 on statin) from six randomized trials, three statin-vs.-placebo trials, and three statin-vs.-statin trials, with pre- and on-treatment (4-104 weeks) Lp(a) levels. Statins included atorvastatin 10 mg/day and 80 mg/day, pravastatin 40 mg/day, rosuvastatin 40 mg/day, and pitavastatin 2 mg/day. Lipoprotein(a) levels were measured with the same validated assay. The primary analysis of Lp(a) is based on the log-transformed data. In the statin-vs.-placebo pooled analysis, the ratio of geometric means [95% confidence interval (CI)] for statin to placebo is 1.11 (1.07-1.14) (P < 0.0001), with ratio >1 indicating a higher increase in Lp(a) from baseline in statin vs. placebo. The mean percent change from baseline ranged from 8.5% to 19.6% in the statin groups and -0.4% to -2.3% in the placebo groups. In the statin-vs.-statin pooled analysis, the ratio of geometric means (95% CI) for atorvastatin to pravastatin is 1.09 (1.05-1.14) (P < 0.0001). The mean percent change from baseline ranged from 11.6% to 20.4% in the pravastatin group and 18.7% to 24.2% in the atorvastatin group. Incubation of HepG2 hepatocytes with atorvastatin showed an increase in expression of LPA mRNA and apolipoprotein(a) protein. This meta-analysis reveals that statins significantly increase plasma Lp(a) levels. Elevations of Lp(a) post-statin therapy should be studied for effects on residual cardiovascular risk.

Apolipoprotein C-III Inhibition with Volanesorsen in Patients with Hypertriglyceridemia (COMPASS): a Randomized, Double-Blind, Placebo-controlled Trial

An elevation of lipoprotein(a) (Lp(a)) is an internationally recognized atherogenic risk factor, documented in epidemiological studies, in studies with Mendelian randomization and in genome-wide association studies (GWAS). At present, no drug is available to effectively reduce its concentration. In Germany, an elevation of Lp(a) associated with progressive cardiovascular diseases is officially recognized as an indication for a lipoprotein apheresis (LA). The number of patients who were treated with LA with this abnormality was steadily increasing in the years 2013–2016 – the official data are reported. In all new patients, who started to be treated at our LA center in 2017 (n = 20) the increased Lp(a) was a main indication for extracorporeal therapy, though some of them also showed clearly elevated LDL cholesterol (LDL-C) concentrations despite being treated with a maximal tolerated lipid-lowering drug therapy. A diabetes mellitus was seen in 5 patients. The higher was the Lp(a) level before the first LA session, the higher was the cardiovascular risk. Lp(a) concentrations measured before LA sessions were usually about 20% lower than those before the start of the LA therapy. Acutely, Lp(a) levels were reduced by about 70%. Following LA sessions the Lp(a) levels increased and in the majority reach pre-session concentrations after one week. Thus a weekly interval is best for the patients, but a few may need two sessions per week to stop the progress of atherosclerosis. The interval mean values were about 39% lower than previous levels. Several papers had been published showing a higher efficiency of LA therapy on the incidence of cardiovascular events in patients with high Lp(a) values when comparing with hypercholesterolemic patients with normal Lp(a) concentrations. Russian specific anti-Lp(a) columns positively affected coronary atherosclerosis. PCSK9 inhibitors reduce Lp(a) concentrations in many patients and in this way have a positive impact on cardiovascular outcomes. In the future, an antisense oligonucleotide against apolipoprotein(a) may be an alternative therapeutic option, provided a clear-cut reduction of cardiovascular events will be demonstrated.

Lipoprotein (a) in calcific aortic valve disease: from genomics to novel drug target for aortic stenosis

Calcific aortic stenosis (AS) is the most common form of valve disease in the Western world and affects over 2.5 million individuals in North America. Despite the large burden of disease, there are no medical treatments to slow the development of AS, due at least in part to our incomplete understanding of its causes. The Cohorts for Heart and Aging Research in Genetic Epidemiology extra-coronary calcium consortium reported a genome-wide association study demonstrating that genetic variants in LPA are strongly associated with aortic valve (AV) calcium and clinical AS. Using a Mendelian randomization study design, it was demonstrated that the effect of this genetic variant is mediated by plasma lipoprotein (a) [Lp(a)], directly implicating elevations in Lp(a) as a cause of AV calcium and progression to AS. This discovery has sparked intense interest in Lp(a) as a modifiable cause for AV disease. Herein, we will review the mounting epidemiological and genetic findings in support of Lp(a)-mediated valve disease, discuss potential mechanisms underlying this observation, and outline the steps to translate this discovery to a much needed novel preventive and/or therapeutic strategy for AV disease.

Factors inducing cardiovascular events in patients treated by lipoprotein apheresis

Lipoprotein apheresis is indicated in patients at high risk for cardiovascular disease due to severe hyperlipoproteinemia, which is not adequately controlled by diet and medication. This extracorporeal therapy reduces the event rate, although it does not completely abolish new events. We compared atherogenic risk factors in patients who were treated in 2009 and 2010 with lipoprotein apheresis and who suffered events (n 20) with patients who did not (n 44). Among the 45 cardiovascular events that occurred four were strokes, one was myocardial infarction, and two were bypass operations (one coronary and one peripheral). The following risk factors were found to be associated with events: male gender, coexisting diabetes/glucose intolerance and elevation of Lp(a) concentrations. In addition, the history of previous cardiovascular events, the efficiency of the lipoprotein apheresis therapy as judged by the reduction rates of LDL-C and of Lp(a), and the duration of the extracorporeal treatment (patients with events had started treatment with lipoprotein apheresis more recently) may play a role. We did not observe any influence of family history, of the underlying lipid disorder or lipid levels, of arterial hypertension or of smoking habits. Evidently, apheresis therapy of longer duration (more than two years) stabilizes the cardiovascular situation of the patients. Patients on apheresis therapy should be regularly assessed with respect to their risk factor and vascular situation. Lipoprotein apheresis therapy is important for the reduction of cardiovascular events, but optimization of additional modifiable risk factors should also be undertaken.

Serum lipid profile in psoriatic patients: correlation between vascular adhesion protein 1 and lipoprotein (a)

Psoriasis is a chronic inflammatory skin disease characterized by excessive cellular replication. Apolipoproteins are genetically determined molecule whose role has been implied in cardiovascular pathology. Vascular adhesion protein-1 (VAP-1) is an adhesion molecule with an enzymatic activity that partakes in the migration process of lymphocytes into sites of inflammation. Our purpose was to evaluate the plasma lipid profiles, apolipoproteins (A1, B) and Lp (a) and VAP-1 in order to compare the lipid profile in psoriatic patients with non-affected persons and correlation between VAP-1 and Lp (a). We determined serum concentrations of lipids, lipoproteins , apolipoproteins and VAP-1 in 90 patients with psoriasis and 90 age matched controls. Serum Lp (a), apo A1 and apo B were measured by immunoprecipitation assays, and the lipids and lipoproteins were measured by enzymatic methods.The VAP-1 were measured by ELISA method. The mean levels of total cholesterol, LDL, apo B and VAP-1 in patients with psoriasis were found to be significantly higher than those of healthy subjects (P<0.05. In psoriatic patients, elevation of VAP-1 correlated with elevation of Lp (a) (p = 0.025). This study shows that high serum lipid level and VAP-1, is significantly more common in psoriasis. This fact may be responsible for higher prevalence of cardiovascular accident in psoriatic patients.

High lipoprotein(a) serum levels in three CADASIL families

We read with interest the paper by Gong et al. [1] on the clinical and genetic features of a cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) family with high values of lipoprotein(a) [Lp(a)]. They concluded that elevated Lp(a) levels might have contributed to the cerebrovascular phenotype in their family. We would like to report our three CADASIL families with elevated Lp(a) levels (Table 1). The mutations, all different from that reported by Gong and colleagues [1], are reported in Table 1. Lp(a) levels were measured for various reasons in eight members of these CADASIL families by the same laboratory, and found elevated in seven (Table 1) (one patient already reported) [2]. Patients had various association of other vascular risk factors. Symptomatic patients showed the typical clinical manifestations of the disease. Cerebral MRI picture was that typical of the disease, with different severity degrees of white matter lesions, also in accordance with the subjects’ ages. In only one of the patients with a history of stroke or in those who underwent vessel evaluation (ultrasound, MR angiography, or digital subtraction angiography) was evidence of large vessel pathology found. One 70-year-old man with dyslipidemia had mild carotid atherosclerosis. All the strokes were of the lacunar type, and no nonlacunar infarct was detected on cerebral MRI. In one patient, MRI revealed a cerebellar arteriovenous malformation, which was later found associated on digital subtraction angiography with a vertebral artery aneurysm. This case has already been reported [3]. All the members of these families have now been followed up for more than 10 years. In conclusion, we did not find clinical or radiological features suggestive of significant large vessel disease in any of our patients affected by CADASIL and with elevated Lp(a) levels. In our opinion, the finding of elevated Lp(a) levels in NOTCH3 mutations carriers seems to be incidental, of doubtful clinical significance, and does not appear to contribute to the cerebrovascular phenotype. However, our data are too limited to get definitive conclusions. While an elevated Lp(a) level is known as a risk factor for ischemic heart disease, its role is less clearly defined in cerebrovascular diseases [4]. In the recent Guidelines for the Primary Prevention of Stroke, elevation of Lp(a) level was included among the less well documented cerebrovascular risk factors (recommendation for treatment in primary prevention of ischemic stroke: class IIb; level of evidence B) [4]. Considering our small series and also Gong et al.’s report in which only one family member presented with large vessel pathology, we believe that systematic screening for elevated Lp(a) levels in CADASIL patients is not recommended. A few cases of large vessel pathology have been reported in this small vessel disease [5]. The value of Lp(a) levels evaluation in these patients remains to be elucidated. R. Valenti and S. Nannucci contributed equally to this work.

ENDOTHELIN 1 AND PROSTACYCLIN ATTENUATE INCREASES IN HYDRAULIC PERMEABILITY CAUSED BY PLATELET-ACTIVATING FACTOR IN RATS

We have previously documented that endothelin 1 (ET-1) and prostacyclin (PGI2) decrease basal state hydraulic permeability (Lp). The aim of this study was to investigate the ability of ET-1 and PGI2 to modulate transendothelial fluid flux during situations in which Lp was artificially elevated with platelet-activating factor (PAF). We hypothesized that ET-1 and PGI2 administration before PAF exposure would prevent the increase in Lp secondary to PAF. In addition, in a potentially more clinically relevant situation, we also hypothesized that ET-1 and PGI2 administration after PAF exposure would attenuate the increase in Lp secondary to PAF. Microvascular Lp was measured in rat mesenteric postcapillary venules. Exposure to 10 nM PAF increased Lp 4-fold (P < 0.001). If the administration of 80 pM ET-1 or 10 microM PGI2 was completed before PAF exposure, no PAF-associated increase in Lp was observed (P < 0.001). The administration of ET-1 or PGI2 after PAF exposure attenuated the peak increase in Lp caused by PAF alone by 55% and 57%, respectively (P < 0.001). We conclude that ET-1 and PGI2 administration before PAF exposure prevents PAF-induced elevations in Lp, and in a more clinically relevant situation, ET-1 and PGI2 administered after PAF exposure attenuate the PAF-induced increase in Lp. Endothelin 1 and PGI2 receptors may provide important therapeutic targets for decreasing the microvascular fluid leak-associated morbidity resulting from shock and sepsis.

Increased occurrence of marked elevations of lipoprotein(a) in ageing, hypercholesterolaemic men with low testosterone

Objective. We previously examined the inverse relationship between total serum testosterone (T) and the occurrence of the metabolic syndrome in ageing men using baseline data from two lipid treatment studies. We further examined baseline data from a subset of US men participating in one of these two studies to assess the relationship between T and the cardiovascular risk factor lipid, lipoprotein(a) [Lp(a)].Methods. Baseline T, lipid, glycaemic and anthropometric data were obtained from 107 men (mean age: 55 years). Inclusion criteria included low-density lipoprotein cholesterol ≥3.4–4.9 mmol/l and triglycerides ≤4.0 mmol/l. Baseline Lp(a) levels were examined across the following baseline T subgroups: <15 nmol/l (low/low-normal T) and ≥15 nmol/l (normal T).Results. There was an overall trend for a higher incidence of clinically significant Lp(a) elevations in men with low T; 17.1% of men in the low/low-normal T subgroup had an Lp(a) level ≥3 times the upper limit of normal compared to 8.1% in the normal T subgroup.Conclusions. The data from this descriptive analysis suggest that ageing men with low serum T levels may have an increase in marked elevations in Lp(a), which would be expected to be associated with a significant increase in their cardiovascular event risk.

Serum lipid levels associated with increased risk for cardiovascular disease is associated with highly active antiretroviral therapy (HAART) in HIV-1 infection

The long-term effects of fat metabolism, storage and utilization in HIV-1 infected patients on highly active antiretroviral therapy (HAART) including a protease inhibitor are profound and cause increasing concern. The main importance of these lipid/metabolic disorders lies in their assumed contribution to an increased risk of coronary heart disease (CHD). In the general population increased levels of lipoprotein(a) [Lp(a)] constitute an independent risk factor for CHD by itself as well as in combination with increased levels of cholesterol and low density lipoprotein (LDL)-cholesterol, respectively. Two hundred and fifty-six patients with 27 +/- 7 months HAART and 84 treatment-naive HIV-1 positive patients were screened for cardiovascular risk factors. The subjective perception of fat wasting and/or accumulation in different sites of the body, which was possible to evaluate in 235 patients on HAART and 73 treatment-naive patients, the levels of plasma triglycerides (TG), cholesterol, LDL and high-density lipoproteins (HDL)-cholesterol, LDL/HDL ratio and Lp(a) were measured. Of the patients on HAART, 42% (98/235) reported abnormal fat distribution as compared with 4% (3/73) of the treatment-naive patients (P<0.0001). The levels of TG, cholesterol and LDL-cholesterol, but not HDL-cholesterol or Lp(a) were higher (P<0.0001) in the HAART group as compared with the naive group. Very high Lp(a) levels (> 700 mg/l) were more common among HAART patients as compared with naive, 14% (36/256) vs 2% (2/83); P=0.0022. The Lp(a) levels correlated to the levels of LDL-cholesterol, but not to total cholesterol, HDL-cholesterol or TG, and did not differ between patients with and without subjective perception of abnormal fat distribution. A significant number of the HAART patients had very high levels of Lp(a) and various combinations of increased lipid values associated with considerably increased risk for CHD. The elevation of Lp(a) did not relate to any other clinical or laboratory parameter than to LDL-cholesterol.

Lipoprotein(a) and apolipoprotein(a) isoforms and proteinuria in patients with moderate renal failure

Atherosclerotic diseases are a major cause of death in patients with renal failure. Increased serum concentrations of lipoprotein(a) [Lp(a)] have been established as a genetically controlled risk factor for these diseases and have been demonstrated in patients with moderate renal failure, suggesting that this lipoprotein contributes to the increased cardiovascular risk seen in these patients. Variable alleles at the apolipoprotein(a) [apo(a)] gene locus are the main determinants of the serum Lp(a) level in the general population. The purpose of this study was to investigate apo(a) isoforms in patients with moderate renal failure and mild proteinuria (less than 1.0 g/day). In 250 consecutive subjects recruited at a hypertension clinic, we assessed the renal function by 24-hour creatinine clearance, proteinuria, and microalbuminuria, as well as the prevalence of atherosclerotic disease, and we also measured apo(a) isoforms, serum albumin, and Lp(a) concentrations. Moderate impairment of renal function (creatinine clearance, 30 to 89 ml/min per 1.73 m2 of body surface area) was found in 97 patients. Lp(a) levels were significantly greater in patients with moderate renal failure (21.7+/-23.9 mg/dl) as compared with patients with normal renal function (15.6+/-16.4 mg/dl, P<0.001), and an inverse correlation was observed between log Lp(a) and creatinine clearance (r = -0.181, P <0.01). However, no difference was found in the frequency of low molecular weight apo(a) isoforms between patients with normal (25.5%) and impaired (27.8%) renal function. Only patients with the smallest size apo(a) isoforms exhibited significantly elevated levels of Lp(a), whereas the large-size isoforms had similar concentrations in patients with normal and impaired renal function. No significant relationship was found between serum Lp(a) and proteinuria. Clinical and laboratory evidence of one or more events attributed to atherosclerosis was found in 9.8% of patients with normal renal function and 25.8% of patients with moderate renal failure (P<0.001). These results indicate that renal failure per se or other genes beside the apo(a) gene locus are responsible for the elevation of serum Lp(a) levels in patients with moderate impairment of renal function. The elevation of Lp(a) levels occurs independently of the level of proteinuria and may contribute to the risk for atherosclerotic disease in these patients.

Cyclosporin A has divergent effects on plasma LDL cholesterol (LDL-C) and lipoprotein(a) [Lp(a)] levels in renal transplant recipients. Evidence for renal involvement in the maintenance of LDL-C and the elevation of Lp(a) concentrations in hemodialysis patients.

Cardiovascular disease is the major cause of mortality in renal transplant recipients. Plasma levels of low-density lipoprotein cholesterol (LDL-C) are often elevated following renal transplantation, and the immunosuppressant cyclosporin A has been implicated as a predisposing factor for posttransplantation hyperlipidemia. Lipoprotein(a) [Lp(a)] is an LDL-like lipoprotein particle; elevated levels of Lp(a) provide an independent and significant risk factor for cardiovascular disease. Plasma concentrations of Lp(a) vary greatly among individuals, and the mechanisms that govern changes in their levels in transplant patients are unknown. The effect(s) of cyclosporin A on Lp(a) was studied in two groups of renal transplantation patients. In group I plasma lipoproteins including Lp(a) were measured before and after successful renal transplantation; this group received both prednisone and cyclosporin A for immunosuppression. Group II patients were studied after renal transplantation and received prednisone alone for immunosuppression. Following surgery, group I patients demonstrated increased plasma concentrations of LDL-C (mean +/- SEM range, 111 +/- 6 to 142 +/- 17 mg/dL; P < .005). In contrast, plasma Lp(a) levels for this group were markedly decreased after renal transplantation (median, 34.3 to 19.7 mg/dL). Patients not treated with cyclosporin A (group II) exhibited mean LDL-C and median Lp(a) levels (118 +/- 42 and 33.1 mg/dL, respectively) that were remarkably similar to those observed before renal transplantation (group I). These data confirm that hyperlipidemia following renal transplantation is associated with cyclosporin A therapy and show that this drug has opposing effects on plasma Lp(a) and LDL-C accumulations.(ABSTRACT TRUNCATED AT 250 WORDS)

Lipoprotein (a): A Risk Factor for Peripheral Vascular Disease

Lipoprotein (a) [Lp(a)] is a serum protein that has been reported to be predictive of complications from coronary and cerebrovascular atherosclerotic disease. This study was designed to compare plasma levels of Lp(a) in 100 white male patients with and without peripheral vascular disease (PVD) and to determine the role of Lp(a) as a risk factor for PVD independent of known risk factors such as cigarette smoking (CIG), diabetes mellitus (DM), and coronary artery disease (CAD). Patients with PVD (mean age = 67.6 years, n = 50) had a statistically significant (p = 0.04) elevation of Lp(a) (29.8 +/- 3.9 mg/dl) as compared to patients without PVD (20.0 +/- 2.9 mg/dl (mean age = 68.3 years, n = 50). Further analysis revealed that patients with PVD had a significantly higher incidence of CIG (86% vs. 68%, p = 0.03), DM (34% vs. 14%, p = 0.02), and CAD (52% vs. 30%, p = 0.02) than those without PVD. However, there was no statistically significant difference in Lp(a) levels in patients with CIG or CAD compared to those without. Patients with DM had significantly (p = 0.04) lower levels of Lp(a) (17.8 +/- 3.5 mg/dl) than those without DM (27.1 +/- 3.0 mg/dl). Stepwise regression analysis of these various risk factors for PVD revealed that Lp(a) was the strongest significant individual predictor for the presence of PVD (R2 = 0.07) as compared to DM (R2 = 0.05) and CIG (R2 = 0.04). We conclude that there is a significant correlation of Lp(a) levels and the incidence of PVD, which is independent of other major risk factors for PVD.

Elevated plasma lipoprotein(a) in patients with the nephrotic syndrome.

To examine the influence of the nephrotic syndrome on lipoprotein(a) [Lp(a)], a plasma lipoprotein associated with atherosclerotic cardiovascular disease independently of low-density lipoproteins. Factors that modulate plasma Lp(a) concentrations are poorly understood. A total of 62 patients: 47 with primary kidney disease and 15 with diabetic nephropathy. Lipoprotein(a) levels were determined by enzyme-linked immunosorbent assay. Because apo(a) phenotype has a significant effect on Lp(a) levels, apo(a) isoforms were determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, Western blotting, and immunoblotting; the data were compared with a healthy control group. Nephrotic patients had significantly higher Lp(a) levels (mean, +/- SE, 69 +/- 10 mg/dL; median, 46 mg/dL, < 0.01) compared with 91 healthy controls (mean, 18 +/- 2 mg/dL; median 9 mg/dL). Sixty percent of the patients and 18% of the controls had values greater than 30 mg/dL. Lipoprotein(a) levels correlated significantly with apolipoprotein B, serum cholesterol, and low-density lipoprotein cholesterol but showed no correlation with creatinine, albumin, or proteinuria. Within all apo(a) isoform classes, higher concentrations of Lp(a) were seen in the nephrotic patients compared with controls (P < 0.05). Finally, in nine patients with primary kidney disease and elevated Lp(a) levels, remission of the nephrotic syndrome was induced using immunosuppressive drugs and Lp(a) values decreased dramatically (pretreatment mean, 90 +/- 15 mg/dL versus remission mean, 31 +/- 8 mg/dL). A decrease in Lp(a) levels was also observed when patients with diabetic nephropathy progressed to end-stage renal disease (nephropathy mean, 56 +/- 11 mg/dL versus dialysis mean, 34 +/- 10 mg/dL; n = 7). Most patients with the nephrotic syndrome have Lp(a) concentrations that are substantially elevated compared with controls of the same apo(a) isoform. Because Lp(a) concentrations are substantially reduced when remission of the nephrotic syndrome is induced, it is likely that the nephrotic syndrome results directly in elevation of Lp(a) by an as yet unknown mechanism. The high levels of Lp(a) in the nephrotic syndrome could cause glomerular injury as well as increase the risk for atherosclerosis and thrombotic events associated with this disorder.