Lipoprotein(a) and apolipoprotein(a) isoform size: Associations with angiographic extent and severity of coronary artery disease, and carotid artery plaque.
Ooi Esther Mm,Ellis Katrina L,Barrett P Hugh R,Watts Gerald F,Hung Joseph,Beilby John P,Thompson Peter L,Stobie Paul,McQuillan Brendan M
BACKGROUND AND AIMS:Lipoprotein(a) [Lp(a)] is an emerging genetic risk factor for cardiovascular disease (CVD). We examined whether plasma Lp(a) concentration and apolipoprotein(a) [apo(a)] isoform size are associated with extent and severity of coronary artery disease (CAD), and the presence of carotid artery plaque. METHODS:We included in our study male participants (n = 263) from a cohort with angiographically defined premature CAD (Carotid Ultrasound in Patients with Ischemic Heart Disease). The angiographic extent and severity of CAD were determined by the modified Gensini and Coronary Artery Stenosis≥20% (CAGE) scores. Carotid artery plaque was assessed by bilateral carotid B-mode ultrasound. Apo(a) isoform size was determined by LPA Kringle IV-2 copy number (KIV-2 CN). RESULTS:Lp(a) concentration, but not KIV-2 CN, was positively associated with the Gensini score. The association remained significant following adjustment for conventional CVD risk factors (all p < 0.05). Lp(a) concentration and elevated Lp(a) [≥50 mg/dL] were positively associated with the CAGE≥20 score, independent of conventional CVD risk factors. KIV-2 C N Q1 (lowest KIV-2 CN quartile) was associated with CAGE≥20 score and KIV-2 CN, with the CAGE≥20 score in those without diabetes. In multivariate models that included phenotypic familial hypercholesterolemia or low-density lipoprotein cholesterol, Lp(a) concentration, but not KIV-2 CN, was independently associated with the Gensini and CAGE≥20 scores. No significant associations between Lp(a) concentration and KIV-2 CN with carotid artery plaque were observed. CONCLUSIONS:Lp(a) concentration, but not apo(a) isoform size, is independently associated with angiographic extent and severity of CAD. Neither Lp(a) nor apo(a) isoform size is associated with carotid artery plaque.
Oxidized phospholipids as a unifying theory for lipoprotein(a) and cardiovascular disease.
Boffa Michael B,Koschinsky Marlys L
Nature reviews. Cardiology
Epidemiological and clinical studies over the past decade have firmly established that elevated plasma concentrations of lipoprotein(a) (Lp(a)) are an important, independent and probably causal risk factor for the development of cardiovascular diseases. Whereas a link between Lp(a) levels and atherosclerotic cardiovascular disease (ASCVD) has been appreciated for decades, the role of Lp(a) in calcific aortic valve disease (CAVD) and aortic stenosis has come into focus only in the past 5 years. ASCVD and CAVD are aetiologically distinct but have several risk factors in common and similar pathological processes at the cellular and molecular levels. Oxidized phospholipids, which modify Lp(a) primarily by covalent binding to its unique apolipoprotein(a) (apo(a)) component, might hold the key to Lp(a) pathogenicity and provide a mechanistic link between ASCVD and CAVD. Oxidized phospholipids colocalize with apo(a)-Lp(a) in arterial and aortic valve lesions and directly participate in the pathogenesis of these disorders by promoting endothelial dysfunction, lipid deposition, inflammation and osteogenic differentiation, leading to calcification. The advent of potent Lp(a)-lowering therapies provides the opportunity to address directly the causality of Lp(a) in ASCVD and CAVD and, more importantly, to provide both a novel approach to reduce the residual risk of ASCVD and a long-sought medical treatment for CAVD.
Prognostic value of lipoprotein (a) level in patients with coronary artery disease: a meta-analysis.
Wang Zhimiao,Zhai Xincheng,Xue Mei,Cheng Wenjuan,Hu Hesheng
Lipids in health and disease
BACKGROUND:Elevated lipoprotein (a) is recognized as a risk factor for incident cardiovascular events in the general population and established cardiovascular disease patients. However, there are conflicting findings on the prognostic utility of elevated lipoprotein (a) level in patients with coronary artery disease (CAD).Thus, we performed a meta-analysis to evaluate the prognostic value of elevated lipoprotein (a) level in CAD patients. METHODS AND RESULTS:A systematic literature search of PubMed and Embase databases was conducted until April 16, 2019. Observational studies reporting the prognostic value of elevated lipoprotein (a) level for cardiac events (cardiac death and acute coronary syndrome), cardiovascular events (death, stroke, acute coronary syndrome or coronary revascularisation), cardiovascular death, and all-cause mortality in CAD patients were included. Pooled multivariable adjusted risk ratio (RR) and 95% confidence interval (CI) for the highest vs. the lowest lipoprotein (a) level were utilized to calculate the prognostic value. Seventeen studies enrolling 283,328 patients were identified. Meta-analysis indicated that elevated lipoprotein (a) level was independently associated with an increased risk of cardiac events (RR 1.78; 95% CI 1.31-2.42) and cardiovascular events (RR 1.29; 95% CI 1.17-1.42) in CAD patients. However, elevated lipoprotein (a) level was not significantly associated with an increased risk of cardiovascular mortality (RR 1.43; 95% CI 0.94-2.18) and all-cause mortality (RR 1.35; 95% CI 0.93-1.95). CONCLUSIONS:Elevated lipoprotein (a) level is an independent predictor of cardiac and cardiovascular events in CAD patients. Measurement of lipoprotein (a) level has potential to improve the risk stratification among patients with CAD.
High lipoprotein(a) and high risk of mortality.
Langsted Anne,Kamstrup Pia R,Nordestgaard Børge G
European heart journal
AIMS:Several lipoprotein(a)-lowering therapies are currently being developed with the long-term goal of reducing cardiovascular disease and mortality; however, the relationship between lipoprotein(a) and mortality is unclear. We tested the hypothesis that lipoprotein(a) levels are associated with risk of mortality. METHODS AND RESULTS:We studied individuals from two prospective studies of the Danish general population, of which 69 764 had information on lipoprotein(a) concentrations, 98 810 on LPA kringle-IV type 2 (KIV-2) number of repeats, and 119 094 on LPA rs10455872 genotype. Observationally, lipoprotein(a) >93 mg/dL (199 nmol/L; 96th-100th percentiles) vs. <10 mg/dL (18 nmol/L; 1st-50th percentiles) were associated with a hazard ratio of 1.50 (95% confidence interval 1.28-1.76) for cardiovascular mortality and of 1.20 (1.10-1.30) for all-cause mortality. The median survival for individuals with lipoprotein(a) >93 mg/dL (199 nmol/L; 96th-100th percentiles) and ≤93 mg/dL (199 nmol/L; 1st-95th percentiles) were 83.9 and 85.1 years (log rank P = 0.005). For cardiovascular mortality, a 50 mg/dL (105 nmol/L) increase in lipoprotein(a) levels was associated observationally with a hazard ratio of 1.16 (1.09-1.23), and genetically with risk ratios of 1.23 (1.08-1.41) based on LPA KIV2 and of 0.98 (0.88-1.09) based on LPA rs10455872. For all-cause mortality, corresponding values were 1.05 (1.01-1.09), 1.10 (1.04-1.18), and 0.97 (0.92-1.02), respectively. Finally, for a similar cholesterol content increase, lipoprotein(a) was more strongly associated with cardiovascular and all-cause mortality than low-density lipoprotein, implying that the mortality effect of high lipoprotein(a) is above that explained by its cholesterol content. CONCLUSION:High levels of lipoprotein(a), through corresponding low LPA KIV-2 number of repeats rather than through high cholesterol content were associated with high risk of mortality. These findings are novel.
Current and future role of lipoprotein(a) in preventive cardiology.
Berman Adam N,Blankstein Ron
Current opinion in cardiology
PURPOSE OF REVIEW:The purpose of this review is to highlight our emerging understanding of lipoprotein(a) [Lp(a)]'s role in atherosclerotic cardiovascular disease (ASCVD), its structure-function relationship, and promising developments within the therapeutic pipeline. RECENT FINDINGS:Elevated levels of Lp(a) are strongly associated with an increased risk of coronary heart disease, calcific aortic valve stenosis, and ischemic stroke. With circulating levels almost exclusively genetically mediated, increased levels of Lp(a) contribute significantly to the residual cardiovascular disease risk in individuals with otherwise well controlled risk factors. The unique structure of Lp(a) - comprised of a genetically heterogeneous apolipoprotein(a) molecule bound to an LDL-like moiety - provides insight into its pathogenic role in cardiovascular disease and also complicates its accurate measurement. Emerging therapies targeting the apolipoprotein(a) component of Lp(a) have the potential to revolutionize the management of individuals with elevated Lp(a). SUMMARY:With promising therapies on the horizon, there has been a renewed focus on the role of Lp(a) in ASCVD. Given Lp(a)'s strong and independent association with key cardiovascular outcomes, it is hopeful that these promising targeted therapies will add another therapeutic option for the prevention of cardiovascular disease.
Lipoprotein(a): An underrecognized genetic risk factor for malignant coronary artery disease in young Indians.
Enas Enas A,Varkey Basil,Dharmarajan T S,Pare Guillaume,Bahl Vinay K
Indian heart journal
Malignant coronary artery disease (CAD) refers to a severe and extensive atherosclerotic process involving multiple coronary arteries in young individuals (aged <45 years in men and <50 years in women) with a low or no burden of established risk factors. Indians, in general, develop acute myocardial infarction (AMI) about 10 years earlier; AMI rates are threefold to fivefold higher in young Indians than in other populations. Although established CAD risk factors have a predictive value, they do not fully account for the excessive burden of CAD in young Indians. Lipoprotein(a) (Lp(a)) is increasingly recognized as the strongest known genetic risk factor for premature CAD, with high levels observed in Indians with malignant CAD. High Lp(a) levels confer a twofold to threefold risk of CAD-a risk similar to that of established risk factors, including diabetes. South Asians have the second highest Lp(a) levels and the highest risk of AMI from the elevated levels, more than double the risk observed in people of European descent. Approximately 25% of Indians and other South Asians have elevated Lp(a) levels (≥50 mg/dl), rendering Lp(a) a risk factor of great importance, similar to or surpassing diabetes. Lp(a) measurement is ready for clinical use and should be an essential part of all CAD research in Indians.
Lipoprotein(a) - the cardiovascular risk factor: significance and therapeutic possibilities.
About 20 % of the population has raised Lp(a) concentrations and evidence suggests that high levels of Lp(a) are an independent cardiovascular risk factor. Both the European Society of Cardiology and the European Atherosclerosis Society recommend measuring Lp(a) values in intermediate to high-risk patients for risk stratification, as well as in patients already under statin treatment and with recurrent clinical events as a residual risk factor that calls for lipid-lowering therapy intensification. Strategies used to lower Lp(a) concentrations have either been partially disappointing in the past or lack cardiovascular outcome data. Therefore, Lp(a) has often been considered as a nonmodifiable cardiovascular risk factor. New and consistent data retrieved from the PCSK9 inhibitor trials now suggest that Lp(a) can be decreased effectively by roughly 30 %, while emerging data from apo(a) antisense therapy trials suggest that selective and potent Lp(a) reduction is a feasible treatment approach in the future. The impact of such decreases on the occurrence of cardiovascular outcomes, independent from LDL-C, could, if established, herald Lp(a) in the treatment of atherosclerosis. Key words: alirocumab - atherosclerosis - cardiovascular disease - evolocumab - hypercholesterolaemia - lipoprotein(a) - lipoprotein apheresis.
Lipoprotein(a): An independent, genetic, and causal factor for cardiovascular disease and acute myocardial infarction.
Enas Enas A,Varkey Basil,Dharmarajan T S,Pare Guillaume,Bahl Vinay K
Indian heart journal
Lipoprotein(a) [Lp(a)] is a circulating lipoprotein, and its level is largely determined by variation in the Lp(a) gene (LPA) locus encoding apo(a). Genetic variation in the LPA gene that increases Lp(a) level also increases coronary artery disease (CAD) risk, suggesting that Lp(a) is a causal factor for CAD risk. Lp(a) is the preferential lipoprotein carrier for oxidized phospholipids (OxPL), a proatherogenic and proinflammatory biomarker. Lp(a) adversely affects endothelial function, inflammation, oxidative stress, fibrinolysis, and plaque stability, leading to accelerated atherothrombosis and premature CAD. The INTER-HEART Study has established the usefulness of Lp(a) in assessing the risk of acute myocardial infarction in ethnically diverse populations with South Asians having the highest risk and population attributable risk. The 2018 Cholesterol Clinical Practice Guideline have recognized elevated Lp(a) as an atherosclerotic cardiovascular disease risk enhancer for initiating or intensifying statin therapy.
Lipoprotein apheresis for lipoprotein(a) and cardiovascular disease.
Moriarty Patrick M,Gray Jessica V,Gorby Lauryn K
Journal of clinical lipidology
BACKGROUND:Elevated lipoprotein(a) [Lp(a)] is an independent risk factor for cardiovascular disease (CVD). In the United States, lipoprotein apheresis (LA) therapy is approved for patients with familial hypercholesterolemia. Germany uses LA therapy for patients with an Lp(a) > 60 mg/dL, normal low-density lipoprotein cholesterol (LDL-C) levels, and CVD. LA therapy in this population demonstrated a >70% reduction in CVD events. In the United States, LA is only approved for patients with elevated LDL-C levels, regardless of Lp(a) level. OBJECTIVE:The objective of the study was to evaluate clinical significance of Lp(a) reduction with LA therapy in the United States. METHODS:A retrospective cohort study at one LA site in the United States evaluated 14 CVD patients with elevated Lp(a) and near normal LDL-C levels. Patient data was analyzed to demonstrate possible clinical benefit in reducing Lp(a) levels with LA to mitigate risk of major adverse cardiovascular events. RESULTS:Pre-LA patients' mean LDL-C and Lp(a) were 80 mg/dL and 138 mg/dL, respectively. LA therapy demonstrated a reduction of mean LDL-C to 29 mg/dL and Lp(a) to 51 mg/dL. These represent a percent reduction of 64% and 63% for LDL-C and Lp(a), respectively. There was a 94% reduction in major adverse cardiovascular events over a mean treatment period of 48 months. CONCLUSION:The treatment of CVD patients with an elevated Lp(a) and near normal LDL-C with LA in a U.S. treatment center demonstrated a significant reduction in future CVD events. LA should be considered for patients in the United States suffering from an elevated Lp(a) and progressive CVD.
Lipoprotein(a) Levels and the Risk of Myocardial Infarction Among 7 Ethnic Groups.
Paré Guillaume,Çaku Artuela,McQueen Matthew,Anand Sonia S,Enas Enas,Clarke Robert,Boffa Michael B,Koschinsky Marlys,Wang Xingyu,Yusuf Salim,
BACKGROUND:Lipoprotein(a) [Lp(a)] levels predict the risk of myocardial infarction (MI) in populations of European ancestry; however, few data are available for other ethnic groups. Furthermore, differences in isoform size distribution and the associated Lp(a) concentrations have not fully been characterized between ethnic groups. METHODS:We studied 6086 cases of first MI and 6857 controls from the INTERHEART study that were stratified by ethnicity and adjusted for age and sex. A total of 775 Africans, 4443 Chinese, 1352 Arabs, 1856 Europeans, 1469 Latin Americans, 1829 South Asians, and 1221 Southeast Asians were included in the study. Lp(a) concentration was measured in each participant using an assay that was insensitive to isoform size, with isoform size being assessed by Western blot in a subset of 4219 participants. RESULTS:Variations in Lp(a) concentrations and isoform size distributions were observed between populations, with Africans having the highest Lp(a) concentration (median=27.2 mg/dL) and smallest isoform size (median=24 kringle IV repeats). Chinese samples had the lowest concentration (median=7.8 mg/dL) and largest isoform sizes (median=28). Overall, high Lp(a) concentrations (>50 mg/dL) were associated with an increased risk of MI (odds ratio, 1.48; 95% CI, 1.32-1.67; P<0.001). The association was independent of established MI risk factors, including diabetes mellitus, smoking, high blood pressure, and apolipoprotein B and A ratio. An inverse association was observed between isoform size and Lp(a) concentration, which was consistent across ethnic groups. Larger isoforms tended to be associated with a lower risk of MI, but this relationship was not present after adjustment for concentration. Consistent with variations in Lp(a) concentration across populations, the population-attributable risk of high Lp(a) for MI varied from 0% in Africans to 9.5% in South Asians. CONCLUSIONS:Lp(a) concentration and isoform size varied markedly between ethnic groups. Higher Lp(a) concentrations were associated with an increased risk of MI and carried an especially high population burden in South Asians and Latin Americans. Isoform size was inversely associated with Lp(a) concentration, but did not significantly contribute to risk.
Lipoprotein(a) in the Evaluation of Cardiovascular Risk in the Portuguese Population.
Meireles-Brandão Joaquim A,Meireles-Brandão Lúcia R,Coelho Rui,Rocha-Gonçalves Francisco R
Acta medica portuguesa
INTRODUCTION:High values of lipoprotein(a), related to atherosclerosis progression, are often considered a marker of thrombosis. We assessed the lipoprotein(a) profile in a group of patients with high vascular risk and no cardiovascular events, established its correlation with other cardiovascular risk factors and inferred the results for patients with metabolic disorders and, at least, two risk factors. MATERIAL AND METHODS:This longitudinal observational study included 516 patients, who had at least two cardiovascular risk factors and regularly attended, for at least two years, the outpatient consultations at a clinic of metabolism and vascular risk for primary prevention. Sociodemographic, clinical and anthropometric parameters were obtained at the baseline visit. Hepatic morphology was assessed in 509 patients (98.6%) by ultrasonography. The 10-year vascular risk was estimated using Framingham risk score, atherosclerotic cardiovascular disease and systematic coronary risk evaluation tables. RESULTS:Significant correlations were found between lipoprotein(a) levels and the addressed vascular risk factors, as well as between lipoprotein(a), and Framingham risk score, atherosclerotic cardiovascular disease and systematic coronary risk evaluation charts. Lipoprotein(a) values were also considerably higher in patients with steatosis. DISCUSSION:Increased lipoprotein(a) values were directly associated with all markers of cardiovascular risk and with non-alcoholic hepatic steatosis. CONCLUSION:Due to its high availability and low cost, lipoprotein(a) should become part of the routine evaluation of patients at vascular risk.
Prognostic impact of lipoprotein(a) levels during lipid management with statins after ST-elevation acute myocardial infarction.
Mitsuda Takayuki,Uemura Yusuke,Ishii Hideki,Tanaka Akihito,Takemoto Kenji,Koyasu Masayoshi,Ishikawa Shinji,Shibata Rei,Watarai Masato,Murohara Toyoaki
Coronary artery disease
The causal relationship of lipoprotein(a) with cardiovascular disease has been established. However, clinical impacts of lipoprotein(a) levels on adverse vascular events in patients with established coronary artery disease who are undergoing statin treatment have not been fully elucidated. We measured lipoprotein(a) levels of 668 consecutive patients with ST-elevated myocardial infarction upon admission and reevaluated lipoprotein(a) of 189 of these patients during statin treatment at least 6 months later than the date of index ST-elevated myocardial infarction. Changes in lipoprotein(a) and associations between lipoprotein(a) levels and the incidence of major adverse cardiac and cerebrovascular event for 3 years were examined. Lipoprotein(a) at baseline was an independent predictor of 3-year major adverse cardiac and cerebrovascular event after ST-elevated myocardial infarction. Levels of lipoprotein(a) at follow-up were slightly but significantly elevated despite improvements in other lipid parameters due to statin treatment. Furthermore, higher levels of lipoprotein(a) achieved with statin treatment were also associated with the subsequent incidence of major adverse cardiac and cerebrovascular event over 3 years, regardless of whether or not the LDL-cholesterol levels were below 100 mg/dl. In conclusion, lipoprotein(a) levels during lipid management by statin are also predictive of adverse vascular events in Japanese patients with ST-elevated myocardial infarction.
Lipoprotein(a) Concentration and Risks of Cardiovascular Disease and Diabetes.
Gudbjartsson Daniel F,Thorgeirsson Gudmundur,Sulem Patrick,Helgadottir Anna,Gylfason Arnaldur,Saemundsdottir Jona,Bjornsson Eythor,Norddahl Gudmundur L,Jonasdottir Aslaug,Jonasdottir Adalbjorg,Eggertsson Hannes P,Gretarsdottir Solveig,Thorleifsson Gudmar,Indridason Olafur S,Palsson Runolfur,Jonasson Fridbert,Jonsdottir Ingileif,Eyjolfsson Gudmundur I,Sigurdardottir Olof,Olafsson Isleifur,Danielsen Ragnar,Matthiasson Stefan E,Kristmundsdottir Snaedis,Halldorsson Bjarni V,Hreidarsson Astradur B,Valdimarsson Einar M,Gudnason Thorarinn,Benediktsson Rafn,Steinthorsdottir Valgerdur,Thorsteinsdottir Unnur,Holm Hilma,Stefansson Kari
Journal of the American College of Cardiology
BACKGROUND:Lipoprotein(a) [Lp(a)] is a causal risk factor for cardiovascular diseases that has no established therapy. The attribute of Lp(a) that affects cardiovascular risk is not established. Low levels of Lp(a) have been associated with type 2 diabetes (T2D). OBJECTIVES:This study investigated whether cardiovascular risk is conferred by Lp(a) molar concentration or apolipoprotein(a) [apo(a)] size, and whether the relationship between Lp(a) and T2D risk is causal. METHODS:This was a case-control study of 143,087 Icelanders with genetic information, including 17,715 with coronary artery disease (CAD) and 8,734 with T2D. This study used measured and genetically imputed Lp(a) molar concentration, kringle IV type 2 (KIV-2) repeats (which determine apo(a) size), and a splice variant in LPA associated with small apo(a) but low Lp(a) molar concentration to disentangle the relationship between Lp(a) and cardiovascular risk. Loss-of-function homozygotes and other subjects genetically predicted to have low Lp(a) levels were evaluated to assess the relationship between Lp(a) and T2D. RESULTS:Lp(a) molar concentration was associated dose-dependently with CAD risk, peripheral artery disease, aortic valve stenosis, heart failure, and lifespan. Lp(a) molar concentration fully explained the Lp(a) association with CAD, and there was no residual association with apo(a) size. Homozygous carriers of loss-of-function mutations had little or no Lp(a) and increased the risk of T2D. CONCLUSIONS:Molar concentration is the attribute of Lp(a) that affects risk of cardiovascular diseases. Low Lp(a) concentration (bottom 10%) increases T2D risk. Pharmacologic reduction of Lp(a) concentration in the 20% of individuals with the greatest concentration down to the population median is predicted to decrease CAD risk without increasing T2D risk.
Lipoprotein(a) levels and risk of cardiovascular disease events in individuals with diabetes mellitus or prediabetes: The Atherosclerosis Risk in Communities study.
Saeed Anum,Sun Wensheng,Agarwala Anandita,Virani Salim S,Nambi Vijay,Coresh Josef,Selvin Elizabeth,Boerwinkle Eric,Jones Peter H,Ballantyne Christie M,Hoogeveen Ron C
BACKGROUND AND AIMS:Diabetes increases risk for atherosclerotic cardiovascular disease (ASCVD). Current guidelines do not recommend measuring lipoprotein(a), another ASCVD risk factor, in these individuals. We examined the association of lipoprotein(a) levels with incident ASCVD events in persons with and without diabetes or prediabetes. METHODS:Lipoprotein(a) and other ASCVD risk factors were measured at baseline (1996-1998) in the biracial Atherosclerosis Risk in Communities study; participants without prevalent ASCVD (coronary heart disease or stroke) were monitored ∼15 years for incident ASCVD events. RESULTS:Of 9871 eligible participants (mean age 63 years; 5816 women; 2155 African Americans), 1543 had diabetes and 3615 had prediabetes. Cumulative ASCVD incidence rates (event/1000-person years) were higher in participants with diabetes (26%) or prediabetes (13%) than in nondiabetic individuals (10%, p < 0.001). When comparing highest to lowest lipoprotein(a) categories (≥50 mg/dL vs. ≤10 mg/dL), increasing lipoprotein(a) levels were significantly associated with increasing incident ASCVD events in Caucasian participants with prediabetes (hazard ratio [HR] = 1.35; 95% confidence interval [CI] 1.07-1.69); p = 0.03) and diabetes (HR = 1.42; 95% CI 1.10-1.84; p < 0.01), but not those with normal fasting blood glucose. Adding lipoprotein(a) to Pooled Cohort Equation variables improved risk prediction in persons with diabetes (Δ in area under the receiver operating characteristic curve [AUC] 0.0087, net reclassification index [NRI] 0.1761) and prediabetes (ΔAUC 0.0025, NRI 0.0938). CONCLUSIONS:In this biracial cohort, elevated lipoprotein(a) levels in Caucasian individuals with diabetes or prediabetes were associated with further increased ASCVD risk. Adding lipoprotein(a) to traditional risk factors improved ASCVD risk prediction.
Lipoprotein(a) plasma levels are not associated with survival after acute coronary syndromes: An observational cohort study.
Roth Christian,Krychtiuk Konstantin A,Gangl Clemens,Schrutka Lore,Distelmaier Klaus,Wojta Johann,Hengstenberg Christian,Berger Rudolf,Speidl Walter S
BACKGROUND:Lipoprotein(a) [Lp(a)] is associated with coronary artery disease in population studies, however studies on its predictive value in patients with cardiovascular disease, in particular after acute coronary syndromes (ACS), are conflicting. The aim of this study was to investigate whether Lp(a) is associated with survival after ACS. METHODS AND RESULTS:We analyzed Lp(a) measurement in 1,245 patients who underwent coronary angiography for ACS. The median follow-up for cardiovascular and all-cause mortality was 5.0 (IQR 3.2-8.0) years. 655 (52.6%) presented with ST-segment elevation myocardial infarction (STEMI), 424 (34.1%) with Non-ST-segment elevation myocardial infarction (NSTEMI) and 166 (13.3%) underwent coronary angiography for unstable angina. Cardiovascular mortality was 9.1% and all-cause mortality was 15.7%. Patients were stratified into four groups to their Lp(a) levels. (≤15mg/dL, >15-30mg/dL, >30-60mg/dL, and >60mg/dL). Multivessel disease was significantly more common in patients with Lp(a)>60mg/dL (p<0.05). Increased levels of Lp(a) were not associated with cardiovascular mortality (HR compared with Lp(a) ≤15mg/dL were 1.2, 1.2, and 1.0, respectively; p = 0.69) and not with all-cause mortality (HR compared with Lp(a) ≤15mg/dL were 1.2, 1.2, and 1.2, respectively; p = 0.46). CONCLUSIONS:Lp(a) levels at time of ACS were neither associated with cardiovascular nor with all-cause mortality. Although Lp(a) has been shown to be associated with incidence of coronary artery disease, this study does not support any role of Lp(a) as a risk factor for mortality after ACS. This should be taken into account for development of outcome studies for agents targeting Lp(a) plasma levels.
Lipoprotein(a) in Patients Undergoing Transcatheter Aortic Valve Replacement.
Ma Gary S,Wilkinson Michael J,Reeves Ryan R,Yeang Calvin,DeMaria Anthony N,Cotter Bruno,Patel Mitul,Mahmud Ehtisham,Tsimikas Sotirios
Lipoprotein(a) [Lp(a)] is a genetically determined risk factor for calcific aortic valve stenosis (CAVS) for which transcatheter aortic valve replacement (TAVR) is increasingly utilized as treatment. We evaluated the effect of a program to increase testing of and define the prevalence of elevated Lp(a) among patients undergoing TAVR. Educational efforts and incorporation of a "check-box" Lp(a) order to the preoperative TAVR order set were instituted. Retrospective chart review was performed in 229 patients requiring TAVR between May 2013 and September 2018. Of these patients, 57% had an Lp(a) level measured; testing rates increased from 0% in 2013 to 96% in 2018. Lipoprotein(a) testing occurred in 11% of patients before and in 80% of patients after the "check-box" order set ( P < .001). The prevalence of elevated Lp(a) (≥30 mg/dL) was 35%; these patients had a higher incidence of coronary artery disease requiring revascularization compared with patients with normal Lp(a) (65% vs 47%; P = .047). Patients with Lp(a) ≥30 mg/dL also had higher incidence of paravalvular leak compared with those with normal Lp(a) (13% vs 4%; P = .04). This study defines the prevalence of elevated Lp(a) in advanced stages of CAVS and provides a practice pathway to assess procedural complications and long-term outcomes of TAVR in patients with elevated Lp(a) levels.
Lipoprotein(a) and mortality-a high risk relationship.
Klingel Reinhard,Heibges Andreas,Fassbender Cordula
Clinical research in cardiology supplements
Lipoprotein(a) (Lp(a)) is an independent cardiovascular risk factor playing a causal role for atherosclerotic cardiovascular disease (ASCVD). Early or progressive ASCVD or a familial predisposition are key findings which can be associated with Lp(a)-hyperlipoproteinemia (Lp(a)-HLP). The German guideline for the indication of lipoprotein apheresis in patients with Lp(a)-HLP has proved to be of value to identify patients at highest risk, using the composite of a Lp(a) threshold >60 mg/dl (>120 nmol/l) and clinical ASCVD progression despite effective LDL-C lowering therapy. In particular for such patients it appears to be plausible that Lp(a)-associated risk would increase cardiovascular mortality as the most important part of total mortality in Western populations. By the majority of existing investigations an association of Lp(a) concentration on total or cardiovascular mortality was demonstrated. However, inconsistency in the findings between studies exists without a clear trend for any study feature to explain this. Genetic homogeneity of the population, long-term follow-up, and clinically guided selection of patients might be important to further clarify the impact of Lp(a) concentration on progression of ASCVD, and finally total or cardiovascular mortality. LDL and Lp(a) particles exhibit a mutual effect modification on related ASCVD risk. Therefore, LDL-C levels and concomitant LDL-C lowering treatment must be considered in this context. Prospective evaluation is needed to document that specific Lp(a)-lowering additional to targeted LDL-C lowering will in fact reduce cardiovascular or total mortality.
Impact of Lipoprotein (a) Levels on Long-Term Outcomes in Patients With Coronary Artery Disease and Left Ventricular Systolic Dysfunction.
Shitara Jun,Kasai Takatoshi,Konishi Hirokazu,Endo Hirohisa,Wada Hideki,Doi Shinichiro,Naito Ryo,Tsuboi Shuta,Ogita Manabu,Dohi Tomotaka,Okazaki Shinya,Miyauchi Katsumi,Daida Hiroyuki
Circulation journal : official journal of the Japanese Circulation Society
BACKGROUND:Serum levels of lipoprotein (a) (Lp(a)) could be a risk factor for adverse events in patients with coronary artery disease (CAD). However, the effect of Lp(a) on long-term outcomes in patients with left ventricular (LV) systolic dysfunction, possibly through the increased likelihood for development of heart failure (HF), remains to be elucidated. This study aimed to determine the prognostic impact of Lp(a) in patients with CAD and LV systolic dysfunction. Methods and Results: A total of 3,508 patients who underwent percutaneous coronary intervention were candidates. We analyzed 369 patients with LV systolic dysfunction (defined as LV ejection fraction <50%). They were assigned to groups according to a median level of Lp(a) (i.e., high Lp(a), ≥21.6 mg/dL, n=185; low Lp(a), <21.6 mg/dL, n=184). The primary outcome was a composite of all-cause death and readmission for acute coronary syndrome and/or HF. The median follow-up period was 5.1 years. Cumulative event-free survival was significantly worse for the group with high Lp(a) than for the group with low Lp(a) (P=0.005). In the multivariable analysis, a high Lp(a) level was an independent predictor of the primary outcomes (hazard ratio, 1.54; 95% confidence interval, 1.09-2.18; P=0.014). CONCLUSIONS:A high Lp(a) value could be associated with long-term adverse clinical outcomes among patients with CAD and LV systolic dysfunction.
Lipoprotein(a) Reduction in Persons with Cardiovascular Disease.
Tsimikas Sotirios,Karwatowska-Prokopczuk Ewa,Gouni-Berthold Ioanna,Tardif Jean-Claude,Baum Seth J,Steinhagen-Thiessen Elizabeth,Shapiro Michael D,Stroes Erik S,Moriarty Patrick M,Nordestgaard Børge G,Xia Shuting,Guerriero Jonathan,Viney Nicholas J,O'Dea Louis,Witztum Joseph L,
The New England journal of medicine
BACKGROUND:Lipoprotein(a) levels are genetically determined and, when elevated, are a risk factor for cardiovascular disease and aortic stenosis. There are no approved pharmacologic therapies to lower lipoprotein(a) levels. METHODS:We conducted a randomized, double-blind, placebo-controlled, dose-ranging trial involving 286 patients with established cardiovascular disease and screening lipoprotein(a) levels of at least 60 mg per deciliter (150 nmol per liter). Patients received the hepatocyte-directed antisense oligonucleotide AKCEA-APO(a)-L, referred to here as APO(a)-L (20, 40, or 60 mg every 4 weeks; 20 mg every 2 weeks; or 20 mg every week), or saline placebo subcutaneously for 6 to 12 months. The lipoprotein(a) level was measured with an isoform-independent assay. The primary end point was the percent change in lipoprotein(a) level from baseline to month 6 of exposure (week 25 in the groups that received monthly doses and week 27 in the groups that received more frequent doses). RESULTS:The median baseline lipoprotein(a) levels in the six groups ranged from 204.5 to 246.6 nmol per liter. Administration of APO(a)-L resulted in dose-dependent decreases in lipoprotein(a) levels, with mean percent decreases of 35% at a dose of 20 mg every 4 weeks, 56% at 40 mg every 4 weeks, 58% at 20 mg every 2 weeks, 72% at 60 mg every 4 weeks, and 80% at 20 mg every week, as compared with 6% with placebo (P values for the comparison with placebo ranged from 0.003 to <0.001). There were no significant differences between any APO(a)-L dose and placebo with respect to platelet counts, liver and renal measures, or influenza-like symptoms. The most common adverse events were injection-site reactions. CONCLUSIONS:APO(a)-L reduced lipoprotein(a) levels in a dose-dependent manner in patients who had elevated lipoprotein(a) levels and established cardiovascular disease. (Funded by Akcea Therapeutics; ClinicalTrials.gov number, NCT03070782.).
Elevated lipoprotein (a) levels are associated with the acute myocardial infarction in patients with normal low-density lipoprotein cholesterol levels.
Cai Gaojun,Huang Zhiying,Zhang Bifeng,Yu Lei,Li Li
Elevated lipoprotein (a) [Lp(a)] and coronary artery disease (CAD) risk has been renewed interested in recent years. However, the association between Lp(a) and acute myocardial infarction (AMI) risk in patients with normal low-density lipoprotein cholesterol (LDL-C) levels has yet to been established. A hospital-based observational study including 558 AMI patients and 1959 controls was conducted. Lp(a) level was significantly higher in AMI patients with normal LDL-C levels than that in non-CAD group (median: 134.5 mg/l 108 mg/l, <0.001). According to Lp(a) quartiles (Q1, <51 mg/l; Q2, 51-108 mg/l; Q3, 108-215 mg/l; Q4, ≥215 mg/l), the incidence of AMI increased with the elevated Lp(a) quartiles (<0.001 and for trend<0.001). Logistic regression analysis suggested that patients with Q3 and Q4 of Lp(a) values had 1.666 (95%CI = 1.230-2.257, <0.001) and 1.769 (95%CI = 1.305-2.398, < 0.001) folds of AMI risk compared with patients with Q1, after adjusting for traditional confounders. Subgroup analyses stratified by gender and age showed that the association only existed in male and late-onset subgroups. In addition, we analyzed the association of Lp(a) with AMI risk in different cut-off values (cut-off 1 = 170 mg/l, cut-off 2 = 300 mg/l). A total of 873 (34.68%) and 432 (17.16%) participants were measured to have higher Lp(a) levels according to cut-off 1 and cut-off 2, respectively. Participants with high Lp(a) levels had 1.418- (cut-off1, 95%CI = 1.150-1.748, <0.001) and 1.521- (cut-off 2, 95%CI = 1.179-1.963, < 0.001) folds of AMI risk compared with patients with low Lp(a) levels. The present large-scale study revealed that elevated Lp(a) levels were associated with increased AMI risk in Chinese population with normal LDL-C levels.
Impact of Lipoprotein(a) on Long-Term (Mean 6.2 Years) Outcomes in Patients With Three-Vessel Coronary Artery Disease.
Xu Na,Jiang Lin,Xu Lianjun,Tian Jian,Zhang Ce,Zhao Xueyan,Feng Xinxing,Wang Dong,Zhang Yin,Sun Kai,Xu Jingjing,Liu Ru,Xu Bo,Zhao Wei,Hui Rutai,Gao Runlin,Gao Zhan,Song Lei,Yuan Jinqing
The American journal of cardiology
The aim of the cohort study was to investigate the relation between plasma lipoprotein(a) (Lp[a]) and long-term clinical outcomes in patients with three-vessel disease (TVD) after the following treatment strategies, including medical therapy alone, percutaneous coronary intervention, and coronary artery bypass grafting. A total of 6,175 consecutive patients with angiographically confirmed TVD and available baseline Lp(a) data were included in this study. Based on the median level of Lp(a) at admission, the patient was divided into 2 subgroups. Primary endpoint was major adverse cardiovascular events (MACE), of which all-cause death, myocardial infarction, and unplanned revascularization were all included. In general, the median value of Lp(a) reached 13.76 mg/dl for all patients. The median follow-up time of all patients was 6.2 years. For MACE, a total of 1,433 cases were generated, accounting for 23.2%, including 804 (13.0%) all-cause death, 302 (4.9 %) myocardial infarction, and 494 (8.0%) unplanned revascularization. For the incidence of MACE, the high Lp (a) and low Lp (a) groups were 24.3% to 22.1% (p = 0.015), respectively. When the risk factors were adjusted, the multivariate analysis showed that high Lp(a) levels was an independent predictor of primary outcome (adjusted hazard ratio 1.169, 95% confidence interval 1.046 to 1.306, p = 0.006). Except for gender group, there is a relatively consistent correlation in the various subgroups. In conclusion, plasma Lp(a) is a potential biomarker for risk stratification and prognosis in patients diagnosed with TVD.
[Association between lipoprotein (a) level and chronic cardio-renal syndrome in elderly patients].
Wang Y,Wang Q Y,Guan C,Zhang X,Guo Y F
Zhonghua xin xue guan bing za zhi
To explore the relationship between lipoprotein(a) [Lp(a)] and chronic cardio-renal syndrome (CRS) in elderly patients. Chronic heart failure (CHF) patients age ≥ 65 years old, who hospitalized in the department of Cardiology of Hebei General Hospital from December 2017 to October 2019, were included in this study. According to the estimate glomerular filtration rate (eGFR) level, patients were divided into CRS group (eGFR<60 ml·min·1.73 m) and CHF group (eGFR ≥60 ml·min·1.73 m). The blood index and basic disease information were collected and compared. Left ventricular ejection fraction (LVEF) were measured by echocardiography. The correlation between clinical indicators and cardio-renal function (LVEF and eGFR) was assessed. The multivariate logistic regression analysis was used to evaluate the related risk factors of CRS in elderly patients; subgroup logistic regression analysis was performed according to the basic disease of patients to assess the relationship between Lp(a) and CRS. A total of 172 elderly patients (85 males (49.4%), aged 79 (71, 84) years) were finally enrolled. Among them, 88 cases (51.2%) were in CRS group and 84 cases (48.8%) were in CHF group. Age (80 (74, 84) years old vs. 74 (70, 82) years old) and LP (a) levels (222.0 (112.0, 445.3) mg/L vs. 155.0 (97.0, 348.7) mg/L) were significantly higher in the CRS group than in the CHF group (<0.05). Lp(a) levels were negatively correlated with LVEF (=-0.155, =0.043) and eGFR (=-0.220, =0.004) in total cohort. In the subgroup analysis of patients with 2 high-incidence basic diseases (coronary heart disease and hypertension), Lp(a) was negatively correlated with LVEF (=-0.250, =0.007) in the coronary heart disease group, and negatively correlated with eGFR (=-0.233, =0.013) in the hypertension group. Multivariate logistic regression analysis showed that age ( = 1.069, : 1.017-1.124, = 0.009) and Lp(a) ( = 3.719, : 1.339-10.326, = 0.012) were independent correlates of CRS. The results of logistic regression analysis showed that Lp(a) was an independent correlative factor of CRS in the subgroups of coronary heart disease (=3.207, : 1.129-9.108, =0.029) and hypertension (=3.054, : 1.086-8.587, =0.034). Serum Lp(a) level is independently related with CRS in elderly patients.
Plasma Lipoprotein(a) Concentration Is Associated With the Coronary Severity but Not With Events in Stable Coronary Artery Disease Patients: A Chinese Cohort Study.
Zhou Bing-Yang,Sun Di,Wang Chun,Wu Na-Qiong,Guo Yuan-Lin,Zhu Cheng-Gang,Gao Ying,Liu Geng,Dong Qian,Li Jian-Jun
Heart, lung & circulation
BACKGROUND:Although lipoprotein(a) (Lp(a)) has been regarded as an independent risk factor for atherosclerotic cardiovascular disease (ASCVD), its predictive role in outcomes in stable coronary artery disease (CAD) has been undetermined. The aim of the present study was to investigate the relations of Lp(a) to the coronary severity and events in Chinese patients with angiography-proven stable CAD. METHODS:A total of 3,278 patients with stable CAD were consecutively enrolled and the coronary severity was evaluated by the Gensini Score (GS) system. Patients were divided into two groups according to the median of GS: high GS group (n=1,585) and low GS group (n=1,693). The associations of continuous Lp(a), Lp(a) ≥300mg/L, and tertiles of Lp(a) with GS and events were respectively evaluated. RESULTS:Patients in the high GS group had significantly higher concentrations of Lp(a). In addition, the multivariate Cox regression analysis indicated that elevated Lp(a) (odds ratio: 1.164, 95% confidence interval: 1.005-1.349), Lp(a) ≥300mg/L (odds ratio: 1.200, 95% confidence interval: 1.028-1.401), and the highest tertile of Lp(a) (odds ratio: 1.205, 95% confidence interval: 1.010-1.438) were statistically associated with GS after adjusted for potential confounders. However, although 215 (6.56%) events were established during a median of follow-up over 10,170 patient-years, no relationship between Lp(a) and events was found. CONCLUSIONS:In this Chinese cohort study on stable CAD with moderate sample size and follow-up duration, data showed that Lp(a) was significantly associated with the coronary severity while not with cardiovascular events, similar to several studies, suggesting that further study is needed regarding the role of Lp(a) in ASCVD.
Lipoprotein(a) as an Old and New Causal Risk Factor of Atherosclerotic Cardiovascular Disease.
Tada Hayato,Takamura Masayuki,Kawashiri Masa-Aki
Journal of atherosclerosis and thrombosis
Lipoprotein(a) [Lp(a)], discovered in 1963, has been associated with atherosclerotic cardiovascular disease (ASCVD) independent of other traditional risk factors, including LDL cholesterol. Lp(a) is an apolipoprotein B (apoB)-containing lipoprotein, which contains an LDL-like particle. Unlike LDL, which is a primary therapeutic target to decrease ASCVD, current guidelines recommend measuring Lp(a) for risk assessments because there is no clear evidence demonstrating the clinical benefit of decreasing Lp(a) using classical drugs such as niacin. However, recent Mendelian randomization studies indicate that Lp(a) causally correlates with ASCVD. In addition, novel drugs, including PCSK9 inhibitors, as well as antisense oligonucleotide for apo(a), have exhibited efficacy in decreasing Lp(a) substantially, invigorating a discussion whether Lp(a) could be a novel therapeutic target for further ASCVD risk reduction. This review aims to provide current understanding, and future perspectives, of Lp(a), which is currently considered a mere biomarker but may emerge as a novel therapeutic target in future clinical settings.
Lipoprotein(a) as a key target in combined therapeutic approaches for cardiovascular disease.
Brandão Joaquim A Meireles,Meireles-Brandão Lúcia R,Coelho Rui,Rocha-Gonçalves Francisco
Revista portuguesa de cardiologia : orgao oficial da Sociedade Portuguesa de Cardiologia = Portuguese journal of cardiology : an official journal of the Portuguese Society of Cardiology
INTRODUCTION AND OBJECTIVE:Lipoprotein(a) [Lp(a)] is an independent cardiovascular risk factor but is closely associated with other similar risk factors that are manageable with appropriate treatment and guidance. We aimed to study the impact of using combined therapy for managing Lp(a) levels in patients at high cardiovascular risk but without major adverse cardiovascular events, in primary prevention. METHODS:We conducted a retrospective observational study in 516 patients randomly selected from a group of 1677 patients who attended cardiovascular risk and metabolism consultations between 1995 and 2015. The disorders observed and therapies used were classified into nosological and pharmacological groups, respectively. Cardiovascular risk was calculated based on the Framingham risk score, the European Society of Cardiology's SCORE and the American College of Cardiology's ASCVD Risk Estimator, and changes in patients' lifestyle were assessed. RESULTS:Significant differences (p<0.001) were found in almost all metabolic variables, except fasting insulin and C-peptide. Lp(a) levels were also significantly reduced (p<0.001). Carotid intima-media thickness improved, decreasing from 2.90 mm to 1.40 mm; however, there was no reduction in the number of cases of vascular stenosis. Of patients with hepatic steatosis (85.5%), 40.7% presented hepatomegaly, but liver function was only altered in a few patients (14.5%). Lipid-lowering therapy, especially statins, significantly decreased Lp(a), benefiting from synergy with other treatments. CONCLUSIONS:Lp(a) is a key overall indicator of vascular risk and should be considered a therapeutic target. Besides a healthy lifestyle, primary prevention should include combined drug therapies to address all cardiovascular risk factors and to delay the atherosclerotic process.
Lipoprotein (a) and 10-year Cardiovascular Disease Incidence in Apparently Healthy Individuals: A Sex-based Sensitivity Analysis from ATTICA Cohort Study.
Kouvari Matina,Panagiotakos Demosthenes B,Chrysohoou Christina,Georgousopoulou Ekavi N,Yannakoulia Mary,Tousoulis Dimitrios,Pitsavos Christos
The association between lipoprotein (a) (Lp(a)) and 10-year first fatal/nonfatal cardiovascular disease (CVD) risk in apparently healthy men and women was evaluated. The ATTICA prospective study was conducted during 2001-2012 and included n = 1514 men and n = 1528 women (age >18 years) from the greater Athens area, Greece. Follow-up CVD assessment (2011-2012) was achieved in n = 2020 participants (n = 317 cases); baseline Lp(a) was measured in n = 1890 participants. The recommended threshold of 50 mg/dL was used to define abnormal Lp(a) status. Ten-year CVD-event rate was 14% and 24% in participants with Lp(a) <50 and Lp(a) ≥50 mg/dL, respectively. Multivariate analysis revealed that participants with Lp(a) ≥50 mg/dL versus Lp(a) <50 mg/dL had about 2 times higher CVD risk (hazard ratio (HR) = 2.18, 95% confidence interval (CI) 1.11, 4.28). The sex-based analysis revealed that the independent Lp(a) effect was retained only in men (HR = 2.00, 95% CI 1.19, 2.56); in women, significance was lost after adjusting for lipid markers. Sensitivity analyses revealed that Lp(a) increased CVD risk only in case of abnormal high-density lipoprotein cholesterol, apolipoprotein A1, and triglycerides as well as low adherence to Mediterranean diet. Certain patient characteristics may be relevant when considering Lp(a) as a therapeutic or risk-prediction target.
Lipoprotein(a) and coronary artery disease in Chinese postmenopausal female patients: a large cross-sectional cohort study.
Liu Shuo-Lin,Wu Na-Qiong,Guo Yuan-Lin,Zhu Cheng-Gang,Gao Ying,Sun Jing,Xu Rui-Xia,Liu Geng,Dong Qian,Li Jian-Jun
Postgraduate medical journal
BACKGROUND:It has been reported that lipoprotein(a) (Lp(a)) is associated with the risk of cardiovascular disease. The present study aimed to examine the association of Lp(a) levels with the presence and severity of coronary artery disease (CAD) in female patients. METHODS:A total of 3712 female patients who received coronary angiography were consecutively enrolled. The levels of Lp(a) were measured and compared among patients with or without CAD, myocardial infarction and menopause. Spearman correlation analysis and logistic regression analysis were used to examine the association of Lp(a) with the presence of CAD and the severity of coronary atherosclerosis assessed by Gensini score (GS). RESULTS:The average of Lp(a) levels was elevated as age increased in female subjects. Notably, women after menopause had higher Lp(a) levels compared with that before menopause (16.8 mg/dL (IQR 7.54-41.12 mg/dL) vs 14.7 mg/dL (IQR 6.72-30.82 mg/dL), p=0.002). Furthermore, multiple logistic regression analysis identified that Lp(a)>30 mg/dL was an independent risk factor of CAD in the postmenopausal females (OR: 1.33, 95% CI: 1.08 to 1.63, p=0.007). Finally, Lp(a) had a positive correlation with GS (r=0.11, p<0.001), and Lp(a)>30 mg/dL was an independent risk factor for high GS (OR: 1.43, 95% CI: 1.14 to 1.79, p=0.02) in the postmenopausal females. CONCLUSION:Circulating Lp(a) levels were independently associated with the presence and severity of CAD in the postmenopausal females, suggesting that Lp(a) may be useful for prevention and risk-stratification of CAD in female individuals.
Lipoprotein(a) as Orchestrator of Calcific Aortic Valve Stenosis.
Schnitzler Johan G,Ali Lubna,Groenen Anouk G,Kaiser Yannick,Kroon Jeffrey
Aortic valve stenosis (AVS) is the most prevalent valvular heart disease in the Western World with exponentially increased incidence with age. If left untreated, the yearly mortality rates increase up to 25%. Currently, no effective pharmacological interventions have been established to treat or prevent AVS. The only treatment modality so far is surgical or transcatheter aortic valve replacement (AVR). Lipoprotein(a) [Lp(a)] has been implicated as a pivotal player in the pathophysiology of calcification of the valves. Patients with elevated levels of Lp(a) have a higher risk of hospitalization or mortality due to the presence of AVS. Multiple studies indicated Lp(a) as a likely causal and independent risk factor for AVS. This review discusses the most important findings and mechanisms related to Lp(a) and AVS in detail. During the progression of AVS, Lp(a) enters the aortic valve tissue at damaged sites of the valves. Subsequently, autotaxin converts lysophosphatidylcholine in lysophosphatidic acid (LysoPA) which in turn acts as a ligand for the LysoPA receptor. This triggers a nuclear factor-κB cascade leading to increased transcripts of interleukin 6, bone morphogenetic protein 2, and runt-related transcription factor 2. This progresses to the actual calcification of the valves through production of alkaline phosphatase and calcium depositions. Furthermore, this review briefly mentions potentially interesting therapies that may play a role in the treatment or prevention of AVS in the near future.
Lipoprotein(a) - Marker for cardiovascular risk and target for lipoprotein apheresis.
Klingel Reinhard,Heigl Franz,Schettler Volker,Roeseler Eberhard,Grützmacher Peter,Hohenstein Bernd,Vogt Anja,Fassbender Cordula,Heibges Andreas,Julius Ulrich
Lipoprotein(a) (Lp(a)) consists of an LDL particle whose apolipoprotein B (apoB) is covalently bound to apolipoprotein(a) (apo[a]). An increased Lp(a) concentration is a causal, independent risk factor for atherosclerotic cardiovascular disease (ASCVD) and a predictor of incident or recurrent cardiovascular events. Although Lp(a) was first described as early as 1963, only the more recent results of epidemiological, molecular, and genetic studies have led to this unequivocal conclusion. More than 20% of Western populations have elevated Lp(a) values. Lp(a) concentrations should be always part of the lipid profile when ASCVD risk is assessed. However, presence of other risk factors, laboratory findings, medical history and family history must be considered to conclude on its clinical relevance in an individual patient. Early or progressive ASCVD or a familial predisposition are key findings which can be associated with elevated Lp(a). The cholesterol portion contained in Lp(a) is also included in the various methods of LDL-C measurement. To assess proximity to the cardiovascular risk related target value for LDL-C, appropriate correction should be applied when high Lp(a) values are obtained to estimate the LDL-C that can actually be treated by lipid lowering drugs. Initial study data show that antisense oligonucleotides, which selectively decrease apolipoprotein(a), are promising as future treatment options. Currently, lipoprotein apheresis, which has a reimbursement guideline in Germany, is the therapy of choice for patients with Lp(a)-associated progressive ASCVD, with the aim of sustained prevention of further cardiovascular events.
Lipoprotein(a) and Atherosclerotic Cardiovascular Disease: Current Understanding and Future Perspectives.
Wu M F,Xu K Z,Guo Y G,Yu J,Wu Y,Lin L M
Cardiovascular drugs and therapy
PURPOSE:To review current knowledge of elevated lipoprotein(a) [Lp(a)] levels in relation to atherosclerotic cardiovascular disease (ASCVD) and discuss their potential use as biomarkers and therapeutic approaches in clinical practice. METHODS:We summarized the current understanding and recent advances in the structure, metabolism, atherogenic mechanisms, standardized laboratory measurement, recommended screening populations, and prognostic value of Lp(a), with a special focus on the current potential treatment approaches for hyperlipoprotein(a)emia in patients with ASCVD. RESULTS:Lp(a) is composed of LDL-like particle and characteristic apolipoprotein(a) [apo(a)] connected by a disulfide bond. Substantial evidence shows that elevated plasma Lp(a) level is a heritable, independent, and possibly causal risk factor for ASCVD through its proatherogenic, proinflammatory, and potentially prothrombotic properties. Current guidelines recommend Lp(a) measurement for patients with an intermediate-high risk of ASCVD, familial hypercholesterolemia, a family history of early ASCVD or elevated Lp(a), and progressive ASCVD despite receiving optimal therapy. Traditional Lp(a)-lowering approaches such as niacin, PCSK9 inhibitors, mipomersen, lomitapide, and lipoprotein apheresis were associated with a non-specific and limited reduction of Lp(a), intolerable side effects, invasive procedure, and high expense. The phase 2 randomized controlled trial of antisense oligonucleotide against the apo(a) encoding gene LPA mRNA showed that IONIS-APO(a)-L could specifically reduce the level of Lp(a) by 90% with good tolerance, which may become a promising candidate for the prevention and treatment of ASCVD in the future. CONCLUSIONS:It is reasonable to measure Lp(a) levels to reclassify ASCVD risk and manage individuals with elevated Lp(a) to further reduce the residual risk of ASCVD, especially with IONIS-APO(a)-L.
Lipoprotein(a) and calcific aortic valve stenosis: A systematic review.
Guddeti Raviteja R,Patil Shantanu,Ahmed Aiza,Sharma Arindam,Aboeata Ahmed,Lavie Carl J,Alla Venkata Mahesh
Progress in cardiovascular diseases
Calcific aortic valve stenosis (AS) is the most common form of acquired valvular heart disease needing intervention and our understanding of this disease has evolved from one of degenerative calcification to that of an active process driven by the interplay of genetic factors and chronic inflammation modulated by risk factors such as smoking, hypertension and elevated cholesterol. Lipoprotein(a) [Lp (a)] is a cholesterol rich particle secreted by the liver which functions as the major lipoprotein carrier of phosphocholine-containing oxidized phospholipids. Lp(a) levels are largely genetically determined by polymorphisms in the LPA gene. While there is an extensive body of evidence linking Lp(a) to atherosclerotic cardiovascular disease, emerging evidence now suggests a similar association of Lp(a) to calcific AS. In this article, we performed a systematic review of all published literature to assess the association between Lp(a) and calcific aortic valve (AV) disease. In addition, we review the potential mechanisms by which Lp(a) influences the progression of valve disease. Our review identified a total of 21 studies, varying from case-control studies, prospective or retrospective observational cohort studies to Mendelian randomized studies that assessed the association between Lp(a) and calcific AS. All but one of the above studies demonstrated significant association between elevated Lp(a) and calcific AS. We conclude that there is convincing evidence supporting a causal association between elevated Lp(a) and calcific AS. In addition, elevated Lp(a) predicts a faster hemodynamic progression of AS, and increased risk of AV replacement, especially in younger patients. Further research into the clinical utility of Lp(a) as a marker for predicting the incidence, progression, and outcomes of sclerodegenerative AV disease is needed.
Prognostic Value of Lipoprotein(a) Levels in Patients Undergoing Coronary Angiography for Premature Acute Coronary Syndromes.
Wang Le,Cong Hongliang,Zhang Jingxia,Hu Yuecheng,Wei Ao,Zhang Yingyi
Little is known about the association between lipoprotein(a) [Lp(a)] levels and future ischemic cardiovascular events in patients with premature acute coronary syndrome (ACS). A total of 1464 consecutive patients who underwent coronary angiography for premature ACS (males <45 years and females <55 years) were enrolled in this study. Patients were divided into quartiles according to serum Lp(a) levels (Q1: ≤11.1 nmol/L; Q2: 11.1-27.7 nmol/L; Q3: 27.7-79.3 nmol/L; and Q4: >79.3 nmol/L). Major adverse cardiovascular events (MACEs) increased with Lp(a) quartiles after 2-year follow-up (among quartiles, respectively; = .001). Kaplan-Meier curves revealed significant differences in event-free survival rates among Lp(a) quartile groups ( = .001). Multivariate Cox proportional hazards regression analysis indicated that serum Lp(a) level was an independent predictor of MACE either as a continuous variable (hazard ratio [HR]: 1.002, 95% confidence interval [CI]: 1.001-1.004; = .009) or as a categorical variable (HR: 1.443, 95% CI: 1.074-1.937; = .015). Furthermore, Lp(a) levels (as a variable) significantly improved the prognostic value for MACE. These findings suggest that Lp(a) measurement has value for cardiovascular risk stratification in patients with premature ACS.
Lipoprotein(a) levels are associated with coronary severity but not with outcomes in Chinese patients underwent percutaneous coronary intervention.
Xu Na,Tang Xiao-Fang,Yao Yi,Jia Si-da,Liu Yue,Zhao Xue-Yan,Chen Jue,Gao Zhan,Yang Yue-Jin,Gao Run-Lin,Xu Bo,Yuan Jin-Qing
Nutrition, metabolism, and cardiovascular diseases : NMCD
BACKGROUND AND AIMS:The association between lipoprotein(a) [Lp(a)] levels and the risk of cardiovascular disease is of great interest but still controversial. This study sought to investigate the impact of Lp(a) on coronary severity and long-term outcomes of patients who undergo percutaneous coronary intervention (PCI). METHODS AND RESULTS:A total of 6714 consecutive patients who received PCI were enrolled to analyze the association between Lp(a) and coronary severity and major adverse cardiovascular and cerebrovascular events (MACCE). Patients were divided into tertiles according to Lp(a) levels on admission. Coronary severity was evaluated by SYNTAX scoring system. The MACCE included recurrent myocardial infarction, unplanned target vessel revascularization, stent thrombosis, ischemic stroke and all-cause mortality. Significantly, Lp(a) levels were positively associated with coronary severity (p < 0.001). Multivariate logistic regression analyses showed Lp(a) was an independent predictor of intermediate to high SYNTAX score. During an average of 874 days follow-up, 755 patients presented with MACCE (11.25%) were reported. The incidence rates of MACCE, all-cause mortality, cardiac death, target vessel revascularization, recurrent myocardial infarction, stent thrombosis, stroke and bleeding were not statistically different among the Lp(a) tertile groups. Furthermore, both Kaplan-Meier and Cox regression analyses found no relationship between Lp(a) and cardiovascular outcomes (p > 0.05). CONCLUSION:Lp(a) is an independent predictor of the prevalence of more complex coronary artery lesions (SYNTAX score ≥ 23) in patients with PCI. In addition, our study has shown that Lp(a) has no relationship with long-term cardiovascular outcomes in Chinese patients with PCI.
Predicting Cardiovascular Outcomes by Baseline Lipoprotein(a) Concentrations: A Large Cohort and Long-Term Follow-up Study on Real-World Patients Receiving Percutaneous Coronary Intervention.
Liu Hui-Hui,Cao Ye-Xuan,Jin Jing-Lu,Zhang Hui-Wen,Hua Qi,Li Yan-Fang,Guo Yuan-Lin,Zhu Cheng-Gang,Wu Na-Qiong,Xu Rui-Xia,Chen Xie-Hui,Li Jian-Jun
Journal of the American Heart Association
Background Although several studies have indicated that lipoprotein(a) is a useful prognostic predictor for patients following percutaneous coronary intervention (PCI), previous observations have somewhat been limited by either small sample size or short-term follow-up. Hence, this study aimed to evaluate the impact of lipoprotein(a) on long-term outcomes in a large cohort of stable coronary artery disease patients after PCI. Methods and Results In this multicenter and prospective study, we consecutively enrolled 4078 stable coronary artery disease patients undergoing PCI from March 2011 to March 2016. They were categorized according to both the median of lipoprotein(a) levels and lipoprotein(a) values of <15 (low), 15 to 30 (medium), and ≥30 mg/dL (high). All patients were followed up for occurrence of cardiovascular events, including cardiovascular death, nonfatal myocardial infarction, and stroke. During an average of 4.9 years of follow-up, 315 (7.7%) cardiovascular events occurred. The events group had significantly higher lipoprotein(a) levels than the nonevents group. Compared with the low lipoprotein(a) group, Kaplan-Meier analysis showed that the high lipoprotein(a) group had a significantly lower cumulative event-free survival rate, and multivariate Cox regression analysis further revealed that the high lipoprotein(a) group had significantly increased cardiovascular events risk. Moreover, adding continuous or categorical lipoprotein(a) to the Cox model led to a significant improvement in C-statistic, net reclassification, and integrated discrimination. Conclusions With a large sample size and long-term follow-up, our data confirmed that high lipoprotein(a) levels could be associated with a poor prognosis after PCI in stable coronary artery disease patients, suggesting that lipoprotein(a) measurements may be useful for patient risk stratification before selective PCI.
Usefulness of Lipoprotein (a) for Predicting Outcomes After Percutaneous Coronary Intervention for Stable Angina Pectoris in Patients on Hemodialysis.
Hishikari Keiichi,Hikita Hiroyuki,Yoshikawa Hiroshi,Abe Fumiyuki,Tsujihata Shihoko,Ito Naruhiko,Kanno Yoshinori,IIya Munehiro,Murai Tadashi,Takahashi Atsushi,Yonetsu Taishi,Sasano Tetsuo
The American journal of cardiology
Serum lipoprotein (a) level is genetically determined and remains consistent during a person's life. Previous studies have reported that people with high lipoprotein (a) level are at a high risk of cardiac events. We investigated the association between lipoprotein (a) levels and clinical outcomes after percutaneous coronary intervention (PCI) for stable angina pectoris (SAP) in hemodialysis (HD) patients. Serum lipoprotein (a) levels were measured on admission in 410 consecutive HD patients who underwent successful PCI for SAP. Patients were divided into 2 groups: low and high group having lipoprotein (a) level <40 mg/dL (n = 297) and ≧40 mg/dL (n = 113) respectively. After PCI, the incidence of major adverse cardiac event (MACE) including cardiac death, nonfatal myocardial infarction, necessity of a new coronary revascularization procedure (coronary bypass surgery, repeat target lesion PCI, PCI for a new non-target lesion) was analyzed. At a median follow-up of 24 months (12 to 37 months), MACE occurred in 188 patients (45.6%). The rate of MACE rate was significantly higher in the high lipoprotein (a) group than in the low lipoprotein (a) group (59.2% vs 40.7%, long-rank test chi-square = 12.3; p < 0.001). Cox analysis showed that high lipoprotein (a) level (Hazard Ratio, 1.62; 95% Confidence Interval, 1.19 to 2.20; p = 0.002) was an independent predictor for MACE after PCI. In conclusion, high lipoprotein (a) level was associated with a higher incidence of MACE after PCI for SAP in HD patients.
Lipoprotein(a) Is Associated with the Presence and Severity of New-Onset Coronary Artery Disease in Postmenopausal Women.
Yan Xiao-Ni,Jin Jing-Lu,Hong Li-Feng,Guo Yuan-Lin,Wu Na-Qiong,Zhu Cheng-Gang,Dong Qian,Li Jian-Jun
Journal of women's health (2002)
Lipid disorder was one of the major risk factors for coronary artery disease (CAD), especially in postmenopausal women, whose lipid profile significantly changed during the transition period to menopause. The aim of the present study was to examine whether plasma lipoprotein(a) [Lp(a)] was a biomarker for predicting the presence and severity of CAD in postmenopausal women. A total of 783 postmenopausal women who had their first angina-like chest pain were enrolled and classified into two groups according to the results of coronary angiography: CAD group ( = 309) and age-matched non-CAD group ( = 309). Patients with CAD were further divided into the three groups based on Gensini score (GS). The relationships of plasma Lp(a) levels to the presence and severity of CAD were evaluated, and the predictive value of Lp(a) for CAD was also examined. CAD group had higher Lp(a) levels when compared to non-CAD ones ( < 0.001). The multivariate logistic regression analysis suggested that Lp(a) was an independent predictor for the presence of CAD ( < 0.001). Plasma levels of Lp(a) were significantly related to GS ( < 0.001). In addition, plasma Lp(a) level was significantly elevated according to the tertiles of GS ( = 0.001) and was independently associated with high GS ( < 0.001). In receiver-operating characteristic analysis for predicting the presence of CAD in postmenopausal women, Lp(a) was found to have the area under the curve of 0.703, with an optimal cutoff value of 255.69 mg/L. Lp(a) is an independent risk factor for predicting the presence and the severity of new-onset CAD in postmenopausal women, suggesting that Lp(a) may be a lipid target for prevention and treatment in such patients.
High Lipoprotein(a) Levels as a Predictor of Major Adverse Cardiovascular Events in Hospitalized-Acute Myocardial Infarction Patients.
Sumarjaya I Dewa Gde Dwi,Nadha I Ketut Badjra,Lestari Anak Agung Wiradewi
Vascular health and risk management
Background:Risk stratification models with incorporation of biochemical markers have received attention recently. In acute myocardial infarction (AMI) one such marker is lipoprotein(a) (Lp(a)). Lp(a) has prothrombotic and proinflammatory properties. High levels of Lp(a) probably contribute to the additional adverse effects in AMI, as it enhances the damaging effect of acute thrombosis. This study aimed to evaluate serum Lp(a) as a predictor of major adverse cardiovascular events (MACE) in hospitalized-acute myocardial infarction patients. Methods:A prospective cohort study was conducted at Sanglah Hospital, Denpasar, during June-August 2018, among 66 people by consecutive sampling. Samples that met the inclusion and exclusion criteria were examined for serum Lp(a) at the time of admission and the occurrence of MACE during hospitalization was observed. Data regarding serum Lp(a), demography, smoking history, dyslipidemia, hypertension, diabetes mellitus, and MACE were collected. Log rank test and Cox proportional hazards regression were conducted with SPSS version 20 for Windows. Results:During observation, MACE occurred in 25 (38%) patients, including cardiogenic shock in 7 (10.6%) patients, heart failure in 20 (30.3%) patients, cardiovascular death in 5 (7, 6%) patients, malignant arrhythmias in 5 (7.6%) patients, and postinfarction angina in 5 (7.6%) patients. After the Log rank test, a significant difference in survival was observed (p = 0.001) between groups of high Lp(a) (survival rate of 60.6 hours; 95% CI 43.3-77.9) and low Lp(a) (average survival of 104.3 hours, 95% CI 91.4-117.2). The hazard ratio of high Lp(a) against MACE was 4.63 (p=0.002), and it increased to 4.69 in multivariate analysis with Cox proportional hazards regression test (p=0.003). Conclusion:The high level of Lp(a) in AMI patients was a risk factor for the occurrence of MACE during hospitalization. Patients with high Lp(a) also had worse survival compared to patients with low Lp(a).
Plasma lipoprotein(a) concentration as an independent predictor of hemodynamic progression of aortic valve stenosis.
Tomova Vesela D,Alexandrova Margarita L,Atanasova Milena A,Tzekova Maria L,Rashev Tihomir R,Ahmad Sarfraz
Molecular and cellular biochemistry
Calcific aortic valve disease (CAVD) is a common cardiovascular disorder of high social significance. This study aimed to identify independent predictors of hemodynamic progression of CAVD. The relationship between some risk factors, including the rs10455872 polymorphism in the intron 25 of the lipoprotein(a) [Lp(a)] coding region and the plasma Lp(a) concentration, and CAVD severity were prospectively examined in 114 patients. Age (p = 0.023), smoking (p = 0.038), lack of obesity (p = 0.005), triglyceride levels (p = 0.039), and plasma Lp(a) (p < 0.0001) levels were found to be significant determinants of stenosis progression. The rs10455872 polymorphism; however, was not found to be a significant factor for neither the stenosis severity (p = 0.773) nor for plasma Lp(a) levels (p = 0.617). We established a highly significant Lp(a) cut-off concentration (21.2 mg/dL) distinguishing the aortic valve calcification without stenosis from the significant stenosis. Plasma Lp(a) concentration was the only independent predictor of disease progression (p < 0.0001). Moreover, patients with plasma levels of Lp(a) ≥ 21.2 mg/dL were 55 times more likely to develop aortic valve stenosis. We conclude that Lp(a) concentration may prove valuable for more reliable identification of patients at risk of accelerated CAVD development. Future studies are desirable to determine whether plasma Lp(a) levels could be used as a potential biomarker for aortic stenosis progression.
Risks of Incident Cardiovascular Disease Associated With Concomitant Elevations in Lipoprotein(a) and Low-Density Lipoprotein Cholesterol-The Framingham Heart Study.
Afshar Mehdi,Rong Jian,Zhan Yang,Chen Hao Yu,Engert James C,Sniderman Allan D,Larson Martin G,Vasan Ramachandran S,Thanassoulis George
Journal of the American Heart Association
Background Elevated lipoprotein(a) is a well-established risk factor for atherosclerotic vascular disease but is not measured in routine clinical care. Screening of high lipoprotein(a) in individuals with moderate elevations of low-density lipoprotein cholesterol (LDL-C) may identify individuals at high risk of cardiovascular disease. Methods and Results We examined 2606 Framingham Offspring participants (median age, 54 years; 45% men) prospectively with a median follow-up of 15 years (n=392 incident cardiovascular events). Individuals with higher (≥100 nmol/L) versus lower lipoprotein(a) were divided into groups based on LDL-C <135 mg/dL versus ≥135 mg/dL. In Cox models, after adjustment for known risk factors, high lipoprotein(a) (≥100 nmol/L) and LDL-C ≥135 mg/dL were each significant predictors of cardiovascular disease (LDL-C ≥135 mg/dL: hazard ratio [HR], 1.34; 95% CI, 1.09-1.64; =0.006; high lipoprotein (a): HR, 1.31; 95% CI, 1.03-1.66; =0.026). Across the groups of high/low lipoprotein (a) and LDL-C ≥135 mg/dL or <135 mg/dL, the absolute cardiovascular disease risks at 15 years were 22.6% (high lipoprotein(a)/LDL-C ≥135 mg/dL, n=248), 17.3% (low lipoprotein(a)/LDL-C ≥135 mg/dL, n=758), 12.7% (high lipoprotein(a)/LDL-C <135 mg/dL, n=275) and 11.5% (low lipoprotein(a)/LDL-C <135 mg/dL, n=1328, reference group). Among individuals with LDL-C ≥135 mg/dL, those with high lipoprotein(a) had a 43% higher risk (HR, 1.43; 95% CI, 1.05-1.97; =0.02). Presence of high lipoprotein(a) with moderate LDL-C levels (135-159 mg/dL) yielded absolute risks equivalent to those with LDL-C ≥160 mg/dL (23.5%, 95% CI, 17.4%-31.3%; and 20.7%, 95% CI, 16.8%-25.3%, respectively). Conclusions Concomitant elevation of LDL-C ≥135 mg/dL and lipoprotein(a) ≥100 nmol/L is associated with a high absolute risk of incident cardiovascular disease. lipoprotein(a) measurement in individuals with moderate elevations in LDL-C, who do not otherwise meet criteria for statins, may identify individuals at high cardiovascular risk.
Elevated Lp(a) (Lipoprotein[a]) Levels Increase Risk of 30-Day Major Adverse Cardiovascular Events in Patients Following Carotid Endarterectomy.
Waissi Farahnaz,Dekker Mirthe,Timmerman Nathalie,Hoogeveen Renate M,van Bennekom Joelle,Dzobo Kim E,Schnitzler Johan G,Pasterkamp Gerard,Grobbee Diederick E,de Borst Gert J,Stroes Erik S G,de Kleijn Dominique P V,Kroon Jeffrey
BACKGROUND AND PURPOSE:General population studies have shown that elevated Lp(a) (lipoprotein[a]) levels are an emerging risk factor for cardiovascular disease and subsequent cardiovascular events. The role of Lp(a) for the risk of secondary MACE in patients undergoing carotid endarterectomy (CEA) is unknown. Our objective is to assess the association of elevated Lp(a) levels with the risk of secondary MACE in patients undergoing CEA. METHODS:Lp(a) concentrations were determined in preoperative blood samples of 944 consecutive patients with CEA included in the Athero-Express Biobank Study. During 3-year follow-up, major adverse cardiovascular events (MACE), consisting of myocardial infarction, stroke, and cardiovascular death, were documented. RESULTS:After 3 years follow-up, Kaplan-Meier cumulative event rates for MACE were 15.4% in patients with high Lp(a) levels (>137 nmol/L; >80th cohort percentile) and 10.2% in patients with low Lp(a) levels (≤137 nmol/L; ≤80th cohort percentile; log-rank test: =0.047). Cox regression analyses adjusted for conventional cardiovascular risk factors revealed a significant association between high Lp(a) levels and 3-year MACE with an adjusted hazard ratio of 1.69 (95% CI, 1.07-2.66). One-third of MACE occurred within 30 days after CEA, with an adjusted hazard ratio for the 30-day risk of MACE of 2.05 (95% CI, 1.01-4.17). Kaplan-Meier curves from time point 30 days to 3 years onward revealed no significant association between high Lp(a) levels and MACE. Lp(a) levels were not associated with histological carotid plaque characteristics. CONCLUSIONS:High Lp(a) levels (>137 nmol/L; >80th cohort percentile) are associated with an increased risk of 30-day MACE after CEA. This identifies elevated Lp(a) levels as a new potential risk factor for secondary cardiovascular events in patients after carotid surgery. Future studies are required to investigate whether Lp(a) levels might be useful in guiding treatment algorithms for carotid intervention.
Lipoprotein (a) and coronary artery calcification: prospective study assessing interactions with other risk factors.
Ong Kwok Leung,McClelland Robyn L,Allison Matthew A,Cushman Mary,Garg Parveen K,Tsai Michael Y,Rye Kerry-Anne,Tabet Fatiha
Metabolism: clinical and experimental
BACKGROUND:Elevated plasma lipoprotein (a) [Lp(a)] and coronary artery calcification (CAC) are established cardiovascular risk factors that correlate with each other. We hypothesized that other cardiovascular risk factors could affect their relationship. METHODS:We tested for interactions of 24 study variables related to dyslipidemia, diabetes, insulin resistance, hypertension, inflammation and coagulation with baseline Lp(a) on change in CAC volume and density over 9.5 years in 5975 Multi-Ethnic Study of Atherosclerosis (MESA) participants, free of apparent cardiovascular disease at baseline. RESULTS:Elevated Lp(a) was associated with larger absolute increase in CAC volume (3.21 and 4.45 mm/year higher for Lp(a) ≥30 versus <30 mg/dL, and Lp(a) ≥50 versus <50 mg/dL, respectively), but not relative change in CAC volume. No association was found with change in CAC density when assessing continuous ln-transformed Lp(a). The association between elevated Lp(a) (≥30 mg/dL) and absolute change in CAC volume was greater in participants with higher circulating levels of interleukin-2 soluble receptor α, soluble tumor necrosis factor alpha receptor 1 and fibrinogen (15.33, 11.81 and 7.02 mm/year in quartile 4, compared to -3.44, -0.59 and 1.91 mm/year in quartile 1, respectively). No significant interaction was found for other study variables. Similar interactions were seen when assessing Lp(a) levels ≥50 mg/dL. CONCLUSIONS:Elevated Lp(a) was associated with an absolute increase in CAC volume, especially in participants with higher levels of selected markers of inflammation and coagulation. These results suggest Lp(a) as a potential biomarker for CAC volume progression.
[Association of lipoprotein (a) with ischemic stroke and stenotic carotid atherosclerosis].
Tmoyan N A,Ezhov M V,Afanasieva O I,Klesareva E A,Afanasieva M I,Balakhonova T V,Pokrovsky S N
Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova
INTRODUCTION:Lipoprotein(a) [Lp(a)] is a genetically determined risk factor of coronary heart disease and its complications. Meanwhile data about the role of Lp(a) in development of ischemic stroke are controversial. AIM:To investigate the association of Lp(a) with atherothrombotic ischemic stroke and stenotic (≥50%) atherosclerosis of carotid arteries. MATERIAL AND METHODS:The study included 490 patients (mean age 60 years, 53% male). The first group comprised 157 patients with ischemic stroke, the second group 68 patients with isolated stenotic atherosclerosis of carotid arteries, but without significant lesion of coronary and low limbs arteries. The control group included 265 patients without stroke, myocardial infarction, stenotic atherosclerosis of coronary, carotid and low limbs arteries according to instrumental examinations. The levels of Lp(a) and lipids were measured in blood serum of all patients. RESULTS:Lp(a) concentration was significantly higher in patients of the first and second groups in comparison with the control group (median [interquartile range]): 24 [9; 48], 20 [8; 55] vs 13 [5; 27] mg/dl, respectively (p<0,05 in both cases). Hyperlipoproteinemia(a) (Lp(a) ≥30 mg/dl) was more frequent in the group with stroke, stenotic atherosclerosis of carotid arteries, than in the control group: 43%, 40% vs 22% (p<0.01 in all cases). In patients with hyperlipoproteinemia(a), odds ratio (OR) for ischemic stroke was 2.7 (95% confidence interval (CI) 1.7-4.1), and OR for stenotic atherosclerosis of carotid arteries was 2.3 (95% CI 1.3-4.0) compared to the patients with Lp(a) level <30 mg/dl (p<0.01 in both cases). In logistic regression analysis adjusted for age, sex, hypertension, type 2 diabetes, smoking and Lp(a) concentration, the hyperlipoproteinemia(a) was associated with ischemic stroke and isolated stenotic carotid atherosclerosis. In the group with severe carotid atherosclerosis, 16 patients (24%) had ischemic stroke. Lp(a) concentration in these patients was higher 36 [20; 59] mg/dl, than in the patients with isolated carotid atherosclerosis without stroke 15 [7; 54] mg/dl (p=0.04). Other risk factors of atherosclerosis did not differ in patients with or without ischemic stroke. CONCLUSION:The study shows the association of elevated level of Lp(a) with ischemic stroke and isolated stenotic atherosclerosis of carotid arteries. In the presence of isolated stenotic carotid atherosclerosis, the median of Lp(a) concentration was significantly higher in patients with ischemic stroke than in patients without stroke.
Lipoprotein(a) and Cardiovascular Diseases - Revisited.
Jang Albert Youngwoo,Han Seung Hwan,Sohn Il Suk,Oh Pyung Chun,Koh Kwang Kon
Circulation journal : official journal of the Japanese Circulation Society
Two decades ago, it was recognized that lipoprotein(a) (Lp(a)) concentrations were elevated in patients with cardiovascular disease (CVD). However, the importance of Lp(a) was not strongly established due to a lack of both Lp(a)-lowering therapy and evidence that reducing Lp(a) levels improves CVD risk. Recent advances in clinical and genetic research have revealed the crucial role of Lp(a) in the pathogenesis of CVD. Mendelian randomization studies have shown that Lp(a) concentrations are causal for different CVDs, including coronary artery disease, calcified aortic valve disease, stroke, and heart failure, despite optimal low-density lipoprotein cholesterol (LDL-C) management. Lp(a) consists of apolipoprotein (apo) B100 covalently bound to apoA. Thus, Lp(a) has atherothrombotic traits of both apoB (from LDL) and apoA (thrombo-inflammatory aspects). Although conventional pharmacological therapies, such as statin, niacin, and cholesteryl ester transfer protein, have failed to significantly reduce Lp(a) levels, emerging new therapeutic strategies using proprotein convertase subtilisin-kexin type 9 inhibitors or antisesnse oligonucleotide technology have shown promising results in effectively lowering Lp(a). In this review we discuss the revisited important role of L(a) and strategies to overcome residual risk in the statin era.
The association of lipoprotein(a) with incident heart failure hospitalization: Atherosclerosis Risk in Communities study.
Agarwala Anandita,Pokharel Yashashwi,Saeed Anum,Sun Wensheng,Virani Salim S,Nambi Vijay,Ndumele Chiadi,Shahar Eyal,Heiss Gerardo,Boerwinkle Eric,Konety Suma,Hoogeveen Ron C,Ballantyne Christie M
BACKGROUND AND AIMS:Lipoprotein(a) [Lp(a)] is a proatherogenic lipoprotein associated with coronary heart disease, ischemic stroke, and more recently aortic stenosis and heart failure (HF). We examined the association of Lp(a) levels with incident HF hospitalization in the Atherosclerosis Risk in Communities (ARIC) study. We also assessed the relationship between Lp(a) levels and arterial stiffness as a potential mechanism for development of HF. METHODS:Lp(a) was measured in 14,154 ARIC participants without prevalent HF at ARIC visit 1 (1987-1989). The association of Lp(a) quintiles with incident HF hospitalization was assessed using Cox proportional-hazards models. Arterial stiffness parameters were stratified based on Lp(a) quintiles, and p-trend was calculated across ordered groups. RESULTS:At a median follow-up of 23.4 years, there were 2605 incident HF hospitalizations. Lp(a) levels were directly associated with incident HF hospitalization in models adjusted for age, race, gender, systolic blood pressure, history of hypertension, diabetes, smoking status, body mass index, heart rate, and high-density lipoprotein cholesterol (quintile 5 vs. quintile 1: hazard ratio [HR] 1.24, 95% confidence interval [CI] 1.09-1.41; p-trend across increasing quintiles <0.01), but not after excluding prevalent and incident myocardial infarction cases (HR 1.07, 95% CI 0.91-1.27; p-trend = 0.70). When adjusted for age, gender, and race, Lp(a) quintiles were not significantly associated with arterial stiffness parameters. CONCLUSIONS:Increased Lp(a) levels were associated with increased risk of incident HF hospitalization. After excluding prevalent and incident myocardial infarction, the association was no longer significant. Lp(a) levels were not associated with arterial stiffness parameters.
Lp(a) (Lipoprotein[a]) Concentrations and Incident Atherosclerotic Cardiovascular Disease: New Insights From a Large National Biobank.
Patel Aniruddh P,Wang Minxian,Pirruccello James P,Ellinor Patrick T,Ng Kenney,Kathiresan Sekar,Khera Amit V
Arteriosclerosis, thrombosis, and vascular biology
OBJECTIVE:Lp(a) (lipoprotein[a]) concentrations are associated with atherosclerotic cardiovascular disease (ASCVD), and new therapies that enable potent and specific reduction are in development. In the largest study conducted to date, we address 3 areas of uncertainty: (1) the magnitude and shape of ASCVD risk conferred across the distribution of lipoprotein(a) concentrations; (2) variation of risk across racial and clinical subgroups; (3) clinical importance of a high lipoprotein(a) threshold to guide therapy. Approach and Results: Relationship of lipoprotein(a) to incident ASCVD was studied in 460 506 middle-aged UK Biobank participants. Over a median follow-up of 11.2 years, incident ASCVD occurred in 22 401 (4.9%) participants. Median lipoprotein(a) concentration was 19.6 nmol/L (25th-75th percentile 7.6-74.8). The relationship between lipoprotein(a) and ASCVD appeared linear across the distribution, with a hazard ratio of 1.11 (95% CI, 1.10-1.12) per 50 nmol/L increment. Substantial differences in concentrations were noted according to race-median values for white, South Asian, black, and Chinese individuals were 19, 31, 75, and 16 nmol/L, respectively. However, risk per 50 nmol/L appeared similar-hazard ratios of 1.11, 1.10, and 1.07 for white, South Asian, and black individuals, respectively. A high lipoprotein(a) concentration defined as ≥150 nmol/L was present in 12.2% of those without and 20.3% of those with preexisting ASCVD and associated with hazard ratios of 1.50 (95% CI, 1.44-1.56) and 1.16 (95% CI, 1.05-1.27), respectively. CONCLUSIONS:Lipoprotein(a) concentrations predict incident ASCVD among middle-aged adults within primary and secondary prevention contexts, with a linear risk gradient across the distribution. Concentrations are variable across racial subgroups, but the associated risk appears similar.
Lipoprotein(a) and Family History Predict Cardiovascular Disease Risk.
Mehta Anurag,Virani Salim S,Ayers Colby R,Sun Wensheng,Hoogeveen Ron C,Rohatgi Anand,Berry Jarett D,Joshi Parag H,Ballantyne Christie M,Khera Amit
Journal of the American College of Cardiology
BACKGROUND:Elevated lipoprotein(a) (Lp[a]) and family history (FHx) of coronary heart disease (CHD) are individually associated with cardiovascular risk, and Lp(a) is commonly measured in those with FHx. OBJECTIVES:The aim of this study was to determine independent and joint associations of Lp(a) and FHx with atherosclerotic cardiovascular disease (ASCVD) and CHD among asymptomatic subjects. METHODS:Plasma Lp(a) was measured and FHx was ascertained in 2 cohorts. Elevated Lp(a) was defined as the highest race-specific quintile. Independent and joint associations of Lp(a) and FHx with cardiovascular risk were determined using Cox regression models adjusted for cardiovascular risk factors. RESULTS:Among 12,149 ARIC (Atherosclerosis Risk In Communities) participants (54 years, 56% women, 23% black, 44% with FHx), 3,114 ASCVD events were observed during 21 years of follow-up. FHx and elevated Lp(a) were independently associated with ASCVD (hazard ratio [HR]: 1.17; 95% confidence interval [CI]: 1.09 to 1.26, and HR: 1.25; 95% CI: 1.12 to 1.40, respectively), and no Lp(a)-by-FHx interaction was noted (p = 0.75). Compared with subjects without FHx and nonelevated Lp(a), those with either elevated Lp(a) or FHx were at a higher ASCVD risk, while those with both had the highest risk (HR: 1.43; 95% CI: 1.27 to 1.62). Similar findings were observed for CHD risk in ARIC, in analyses stratified by premature FHx, and in an independent cohort, the DHS (Dallas Heart Study). Presence of both elevated Lp(a) and FHx resulted in greater improvement in ASCVD and CHD risk reclassification and discrimination indexes than either marker alone. CONCLUSIONS:Elevated plasma Lp(a) and FHx have independent and additive joint associations with cardiovascular risk and may be useful concurrently for guiding primary prevention therapy decisions.
Estimation of the Required Lipoprotein(a)-Lowering Therapeutic Effect Size for Reduction in Coronary Heart Disease Outcomes: A Mendelian Randomization Analysis.
Lamina Claudia,Kronenberg Florian,
Importance:Genetic and epidemiologic data suggest that lipoprotein(a) (Lp[a]) is one of the strongest genetically determined risk factors for coronary heart disease (CHD). Specific therapies to lower Lp(a) are on the horizon, but the required reduction of Lp(a) to translate into clinically relevant lowering of CHD outcomes is a matter of debate. Objective:To estimate the required Lp(a)-lowering effect size that may be associated with a reduction of CHD outcomes compared with the effect size of low-density lipoprotein cholesterol (LDL-C)-lowering therapies. Design, Setting, and Participants:Genetic epidemiologic study using a mendelian randomization analysis to estimate the required Lp(a)-lowering effect size for a clinically meaningful effect on outcomes. We used the effect estimates for Lp(a) from a genome-wide association study (GWAS) and meta-analysis on Lp(a) published in 2017 of 5 different primarily population-based studies of European ancestry. All Lp(a) measurements were performed in 1 laboratory. Genetic estimates for 27 single-nucleotide polymorphisms on Lp(a) concentrations were used. Odds ratios for these 27 single-nucleotide polymorphisms associated with CHD risk were retrieved from a subsample of the CHD Exome+ consortium. Exposures:Genetic LPA score, plasma Lp(a) concentrations, and observations of statin therapies on CHD outcomes. Main Outcomes and Measures:Coronary heart disease. Results:The study included 13 781 individuals from the Lp(a)-GWAS-Consortium from 5 primarily population-based studies and 20 793 CHD cases and 27 540 controls from a subsample of the CHD Exome+ consortium. Four of the studies were similar in age distribution (means between 51 and 59 years), and 1 cohort was younger; mean age, 32 years. The frequency of women was similar between 51% and 55%. We estimated that the required reduction in Lp(a) effect size would be 65.7 mg/dL (95% CI, 46.3-88.3) to reach the same potential effect on clinical outcomes that can be reached by lowering LDL-C by 38.67 mg/dL (to convert to millimoles per liter, multiply by 0.0259). Conclusions and Relevance:This mendelian randomization analysis estimated a required Lp(a)-lowering effect size of 65.7 mg/dL to reach the same effect as a 38.67-mg/dL lowering of LDL-C. However, this estimate is determined by the observed effect estimates of single-nucleotide polymorphisms on Lp(a) concentrations and is therefore influenced by the standardization of the Lp(a) assay used. As a consequence, calculations of the required Lp(a)-lowering potential of a drug to be clinically effective might have been overestimated in the past.
Association of lipoprotein (a) and in-hospital outcomes in patients with acute coronary syndrome undergoing percutaneous coronary intervention.
Wu Baoquan,Zhao Hanjun,Liu Changhua,Lu Hao,Liu Ruishuang,Long Juan,Zhang Zhiling,Zeng Fanfang
: The current study was to evaluate the association of Lipoprotein (a) [Lp(a)] and in-hospital outcomes in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI).: ACS patients undergoing PCI were retrospectively enrolled. Based on Lp(a) level, patients were divided into low (<30 mg/dL) and high (≥30 mg/dL) Lp(a) groups.: Compared to those with low Lp(a), patients with high Lp(a) had larger numbers of coronary arteries ≥70% stenosis and had longer coronary artery lesion (P < 0.05). After adjustment for covariates, high Lp(a) remained associated with higher odds of having coronary artery ≥70% stenosis, type C coronary lesion and pre-PCI TIMI flow grade 1/0. Patients with high Lp(a) had a higher unadjusted odds of acute stent thrombosis (odds ratio [OR] 1.10 and 95% confidence interval [CI] 1.01-2.27), congestive heart failure (OR 1.24 and 95% CI 1.15-2.38) and composite in-hospital outcomes (OR 1.28 and 95% CI 1.18-2.42). After adjustment for covariates, patients with high Lp(a) still had a higher odds of congestive heart failure (OR 1.08 and 95% CI 1.01-1.78) and composite in-hospital outcomes (OR 1.12 and 95% CI 1.04-1.81).: In ACS patients undergoing PCI, compared to those with low Lp(a), patients with high Lp(a) had more severe coronary artery lesion, higher risk of congestive heart failure and composite in-hospital outcomes.
High Level of Lipoprotein(a) as Predictor for Recurrent Heart Failure in Patients with Chronic Heart Failure: a Cohort Study.
Yan Jianlong,Pan Yanbin,Xiao Junhui,Ma Wenxue,Li Li,Zhong Mingjiang,Long Haiquan,Kong Fanliang,Shao Wenming
Arquivos brasileiros de cardiologia
BACKGROUND:Elevated plasma levels of Lipoprotein(a) [Lp(a)] are recognized as a significant risk factor for atherosclerotic vascular disease. However, there are limited data regarding association between Lp(a) and recurrent heart failure (HF) in patients with chronic HF caused by coronary heart disease (CHD). OBJECTIVE:Elevated levels of Lp(a) might have a prognostic impact on recurrent HF in patients with chronic HF caused by CHD. METHODS:A total of 309 patients with chronic HF caused by CHD were consecutively enrolled in this study. The patients were divided into 2 groups according to whether Lp(a) levels were above or below the median level for the entire cohort (20.6 mg/dL): the high Lp(a) group (n = 155) and the low Lp(a) group (n = 154). A 2-sided p < 0.05 was statistically considered significant. RESULTS:During the median follow-up period of 186 days, 31 cases out of a total of 309 patients (10.03%) could not be reached during follow-up. A Kaplan-Meier analysis demonstrated that patients with higher Lp(a) levels had a higher incidence of recurrent HF than those with lower Lp(a) levels (log-rank < 0.0001). A multivariate Cox regression analysis revealed that Lp(a) levels were independently correlated with the incidence of recurrent HF after adjustment of potential confounders (hazard ratio: 2.720, 95 % confidence interval: 1.730-4.277, p < 0.0001). CONCLUSIONS:In Chinese patients with chronic HF caused by CHD, elevated levels of Lp(a) are independently associated with recurrent HF.
HEART UK consensus statement on Lipoprotein(a): A call to action.
Cegla Jaimini,Neely R Dermot G,France Michael,Ferns Gordon,Byrne Chris D,Halcox Julian,Datta Dev,Capps Nigel,Shoulders Carol,Qureshi Nadeem,Rees Alan,Main Linda,Cramb Robert,Viljoen Adie,Payne Jules,Soran Handrean,
Lipoprotein(a), Lp(a), is a modified atherogenic low-density lipoprotein particle that contains apolipoprotein(a). Its levels are highly heritable and variable in the population. This consensus statement by HEART UK is based on the evidence that Lp(a) is an independent cardiovascular disease (CVD) risk factor, provides recommendations for its measurement in clinical practice and reviews current and emerging therapeutic strategies to reduce CVD risk. Ten statements summarise the most salient points for practitioners and patients with high Lp(a). HEART UK recommends that Lp(a) is measured in adults as follows: 1) those with a personal or family history of premature atherosclerotic CVD; 2) those with first-degree relatives who have Lp(a) levels >200 nmol/l; 3) patients with familial hypercholesterolemia; 4) patients with calcific aortic valve stenosis and 5) those with borderline (but <15%) 10-year risk of a cardiovascular event. The management of patients with raised Lp(a) levels should include: 1) reducing overall atherosclerotic risk; 2) controlling dyslipidemia with a desirable non-HDL-cholesterol level of <100 mg/dl (2.5 mmol/l) and 3) consideration of lipoprotein apheresis.