Patients with symptomatic peripheral arterial disease (PAD) are at a very high risk of cardiovascular morbidity and mortality. Elevated lipoprotein(a) levels have been shown to be a risk factor for coronary artery disease (CAD) and stroke. More recently elevated lipoprotein(a) levels have also been demonstrated to be associated with prevalent and incident PAD, and even may be a stronger risk factor for PAD compared with CAD. Lipoprotein apheresis is currently the only efficient way to lower lipoprotein(a) levels. Lipoprotein(a) apheresis has been shown to reduce major coronary events in patients with CAD. There is increasing evidence that lipoprotein(a) apheresis also reduces the rate of major adverse limb events such as peripheral revascularizations and amputations in PAD patients, and improves symptoms of PAD such as pain on exertion. This review summarizes the current knowledge on the clinical role of lipoprotein(a) for PAD and the disease-specific effect of lipoprotein(a) apheresis, and suggests indications for screening for and treating of elevated lipoprotein(a) levels in patients with PAD.

Elevated levels of lipoprotein(a) (Lp(a)) contribute to the risk of early and severe cardiovascular disease (CVD) and Lp(a) is acknowledged as a risk factor to be included in risk assessment. The established lipid-modifying medical therapies do not lower Lp(a) except niacin but no data of endpoint trials are available. Of the new lipid-modifying drugs a few have some impact on Lp(a). Whether the Lp(a) lowering effect contributes to the reduction of CVD events would have to be shown in Lp(a) dedicated trials. None of the available agents is indicated to lower Lp(a). Lipoprotein apheresis lowers levels of Lp(a) significantly by >60% per treatment. Trial data and data of the German Lipoprotein Apheresis Registry show that regular apheresis reduces cardiovascular events. The Apo(a) antisense oligonucleotide is the only approach to specifically lower Lp(a). The IONIS-APO(a)Rx phase 1 and 2 trials showed very substantial decreases of Lp(a) and good tolerability. The hepatospecific variant IONIS-APO(a)-LRx is 30 times more potent. The results of the IONIS-APO(a)-LRx phase 2 trial were presented recently. The highest dosages reduced Lp(a) by 72 and 80%; in about 81 and 98% Lp(a) levels <50 mg/dl were achieved. Tolerability and safety were confirmed, whereby injection site reactions were the most common side effects. This raises hope that the planned phase 3 trial will reproduce these findings and show a reduction of cardiovascular events.

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.

Lipoprotein(a) (Lp(a)) is a genetic risk factor for cardiovascular disease (CVD) and is associated with the induction and sustaining of atherosclerotic cardiovascular diseases (ASCVD). Since 2008 Lp(a) along with progressive CVD has been approved as an indication for regular lipoprotein apheresis (LA) in Germany. The German Lipoprotein Apheresis Registry (GLAR) has been initiated to provide statistical evidence for the assessment of extracorporeal procedures to treat dyslipidemia for both LDL-cholesterol (LDL-C) and Lp(a). The GLAR now allows prospective investigations over a 5-year period about annual incidence rates of cardiovascular events. Here Lp(a) patients (LDL-C < 100 mg/dl; Lp(a) > 60 mg/dl or >120 nmol/l) showed the same reduction of major coronary (83%) and non-coronary events (63%) as had been formerly shown in the Pro(a)LiFe study. However, Lp(a) is not only an apolipoprotein(a) (apo(a)) and LDL-C containing particle, which is covalently bound to a LDL-C core by a disulphide bridge. The composition of this particle, inter alia containing oxidized phospholipids, gives pro-atherosclerotic, pro-inflammatory, and pro-thrombotic properties, inducing atherosclerotic processes mainly in the arterial wall. However, recent investigations have shown that a reduction of inflammatory settings without LDL-C or Lp(a) reduction may reduce ASCVD events. Lipoprotein apheresis (LA) could not only reduce LDL-C and Lp(a) in parallel, but also different inflammatory and coagulation parameters. In summary lipoprotein apheresis is not only anti-atherosclerotic, but also anti-inflammatory and anti-thrombotic and therefore an ideal treatment option with respect to the shown reduction of major adverse coronary events (MACE) and major adverse non-coronary events (MANCE) by reducing Lp(a) levels.

The structural similarity with plasminogen as well as thrombogenic and atherogenic in vitro functions raise the question if lipoprotein(a) (Lp(a)) is a risk factor for venous thromboembolism (VTE) and ischemic stroke. Numerous case–control and prospective studies using different cut-off values to define high Lp(a) generated conflicting evidence for both VTE and ischemic stroke. Several meta-analyses demonstrated independent associations of elevated Lp(a) with a history of VTE or ischemic stroke. However, the evidence of prospective studies for associations of Lp(a) with incident stroke or recurrent VTE remains inconclusive. For ischemic stroke, data suggest that Lp(a) increases the risk of large-artery atherosclerosis stroke, but not cardioembolic or lacunar stroke. Lp(a) may increase the risk of VTE in the presence of additional thrombophilic risk factors. Larger cohort studies are needed to elaborate the importance of higher Lp(a) cut-offs and interactions with other risk factors and subgroups of stroke or VTE. The value of Lp(a) to estimate residual vascular risk after the first thromboembolic event remains to be adequately explored.

Lipoprotein(a) (Lp(a)) is an internationally recognized atherogenic risk factor which is inherited and not changed by nutrition or physical activity. At present, only proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors may modestly decrease its concentration (but not in all patients)—leading to a certain decrease in cardiovascular events (CVE) in controlled studies. However, at present an elevation of Lp(a) is not a generally accepted indication for their use. More effective is lipoprotein apheresis (LA) therapy with respect to both lowering Lp(a) levels and reduction of CVE. In the future, an antisense oligonucleotide against apolipoprotein(a) will probably be available. Atherosclerosis in patients with an elevation of Lp(a) may affect several vessel regions (carotids, aorta, coronaries, leg arteries). Thus, Lp(a) should be measured in high-risk patients. These patients are usually cared for by their family doctors and by other specialists who should closely cooperate. Lipidologists should decide whether costly therapies like PCSK9 inhibitors or LA should be started. The main aim of current therapy is to optimize all other risk factors (LDL cholesterol, hypertension, diabetes mellitus, body weight, renal insufficiency). Patients should be regularly monitored (lab data, heart, arteries). This paper describes the duties of physicians of different specialties when caring for patients with high Lp(a) concentrations.

Lipoprotein(a) (Lp(a)) is an internationally accepted independent atherogenic risk factor. Details about its synthesis, many aspects of composition and clearance from the bloodstream are still unknown. LDL receptor (LDLR) (and probably other receptors) play a role in the elimination of Lp(a) particles. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors increase the number of available LDLRs and in this way very effectively reduce the LDL cholesterol (LDL-C) concentrations. As shown in controlled studies using PCSK9 inhibitors, Lp(a) levels are decreased by 20 to 30%, though in some patients no effect was observed. So far, it has not been clarified whether this decrease is associated with an effect on the incidence of cardiovascular events (CVEs). In two recently published well-performed secondary prevention studies (FOURIER with evolocumab, ODYSSEY OUTCOMES with alirocumab) baseline Lp(a) levels were shown to have an impact on CVEs independently of baseline LDL-C concentrations. The rather modest PCSK9 inhibitor-induced decrease of Lp(a) was associated with a reduction of CVEs in both studies, even after adjusting (ODYSSEY OUTCOMES) for demographic variables (age, sex, race, region), baseline Lp(a), baseline LDL-C, change in LDL-C, and clinical variables (time from acute coronary syndrome, body mass index, diabetes, smoking history). The largest decrease of CVEs was seen in patients with relatively low concentrations of both LDL-C and Lp(a) (FOURIER). These findings will probably have an influence on the use of PCSK9 inhibitors in patients with high Lp(a) concentrations.

General lipoprotein (Lp) (a) screening can help to identify patients at high risk for cardiovascular disease. Non-invasive methods allow early detection of clinically asymptomatic incipient atherosclerotic disease. Medical treatment options are still unsatisfactory. Lp(a) apheresis is an established treatment in Germany for secondary prevention of progressive cardiovascular disease. Statin-based lowering of LDL cholesterol and thrombocyte aggregation inhibitors still represent the basis of medical treatment. Target levels for LDL-cholesterol should be modified in patients with hyperlipoproteinemia (a).

Lipoprotein (a) (Lp (a)) is one risk factor for the development of cardiovascular diseases. Several studies have shown that Lp (a) hyperlipoproteinaemia has a particular influence on the development of coronary heart disease (CHD). A retrospective single-centre observation study was performed to evaluate the effectiveness of lipid apheresis on the basis of consecutively performed percutaneous coronary interventions (PCI) in patients with high Lp (a) values and angiographically documented CHD. In 23 pts (male 18, age 60.04 ± 0.58 years) with angiographically documented CHD (first manifestation 48.00 ± 9.41 years), elevated LDL cholesterol (144.39 ± 92.01 mg/dl) and Lp (a) (133.04 ± 39.68 mg/dl), 49 PCI and 3 coronary artery bypass grafting (CABG) procedures had been performed prior to the initiation of lipid apheresis. Following the initiation of weekly lipid apheresis, LDL cholesterol was 99.43 ± 36.53 mg/dl and Lp (a) 91.13 ± 33.02 mg/dl. In a time interval of 59.87 ± 49.49 months (median 51.00, range 1–153 months) 15 pts did not require an additional PCI. In 8 pts (7 pts 3‑vessel disease, 1 pt 2‑vessel disease) 14 PCI – no CABG – were performed after 69.38 ± 71.67 months (median: 32.50, range 17–232 months). The incidence of PCI could thus be reduced by 71.43%.

Since 2005 an interdisciplinary German apheresis working group has been established by members of both German Societies of Nephrology and of Lipidologists and completed the data set for the registry according to the current guidelines and the German indication guideline for apheresis in 2009. In 2011 the German Lipoprotein Apheresis Registry (GLAR) was launched and data are available over nearly 5 years now. During the time period 2012–2016, 71 German apheresis centers collected retrospective and prospective observational data of 1435 patients undergoing lipoprotein apheresis (LA) treatment of high LDL-C levels and/or high Lp (a) levels suffering from cardiovascular disease (CVD) or progressive CVD. A total of 15,527 completely documented LA treatments were entered into the database. All patients treated by LA showed a median LDL-C reduction rate of 67.5%, and a median Lp (a) reduction rate of 71.1%. Analog to the Pro(a)LiFe pattern, patient data were analyzed to the incidence rate of coronary events (MACE) 1 and 2 years before the beginning of LA treatment (y-2 and y‑1) and prospectively two years on LA treatment (y + 1 and y + 2). During two years of LA treatment a MACE reduction of 78% was observed. In the years considered, side effects of LA treatment were low (5.9%) and mainly comprised puncture problems. The data generated by the GLAR shows that LA lowers the incidence rate of cardiovascular events in patients with high LDL-C and/or high Lp (a) levels, progressive CVD, and maximally tolerated lipid lowering medication. In addition, LA treatments were found to be safe with a low rate of side effects.

Recently it has been demonstrated that elevated lipoprotein (a) (LPA) levels are associated with an increased risk of cardiovascular disease across multiple ethnic groups. However, there is only scanty data about the incidence of elevated LPA levels in different patient cohorts. As a consequence, we aimed to examine whether patients with elevated LPA levels might be seen more often in a cardiovascular center in comparison to the general population. We reviewed LPA concentrations of 52,898 consecutive patients who were admitted to our hospital between January 2004 and December 2014. We subdivided them into different groups according to their LPA levels. Data was compared to available information in medical literature. 26.4% of the patients had LPA levels >30 mg/dl which is in line with the data from literature. Mean level of LPA concentration in our study was twice as high in comparison to the general population (25.8% vs. 13.3%). 4.6% had LPA levels >98 mg/dl (general population <0.3%). In patients admitted to a cardiovascular center the proportion of LPA >30 mg/dl is comparable to the general population but mean levels over all are twice as high and the proportion of patients with LPA levels of >98 mg/dl is extremely higher.

Lipoprotein (a) (Lp(a)) is a modified low-density lipoprotein (LDL) particle with an additional specific apolipoprotein (a), covalently attached to apolipoprotein B‑100 of LDL by a single thioester bond. Increased plasma Lp(a) level is a genetically determined, independent, causal risk factor for cardiovascular disease. The precise quantification of Lp(a) in plasma is still hampered by mass-sensitive assays, large particle variation, poor standardization and lack of assay comparability. The physiological functions of Lp(a) include wound healing, promoting tissue repair and vascular remodeling. Similarly to other lipoproteins, Lp(a) is also susceptible for oxidative modifications, leading to extensive formation of pro-inflammatory and pro-atherogenic oxidized phospholipids, oxysterols, oxidized lipid-protein adducts in Lp(a) particles, that perpetuate atherosclerotic lesion progression and intima-media thickening through induction of M1-macrophages, inflammation, autoimmunity and apoptosis. The oxidation-specific epitopes of modified lipoproteins are major targets of pre-immune, natural IgM antibodies, that may attenuate the pro-inflammatory and pro-atherogenic effects of Lp(a). Although the data are still insufficient, recent studies suggest a potential anti-neoplastic role of Lp(a).

Lipoprotein(a) (Lp(a)) is an independent cardiovascular risk factor playing a causal role for atherosclerotic cardiovascular disease (CVD). Lipoprotein apheresis (LA) is a safe well-tolerated outpatient treatment to lower LDL-C and Lp(a) by 60–70%, and is the ultimate escalating therapeutic option in patients with hyperlipoproteinemias (HLP) involving LDL particles. Major therapeutic effect of LA is preventing cardiovascular events. Lp(a)-HLP associated with progressive CVD has been approved as indication for regular LA in Germany since 2008. The Pro(a)LiFe-study investigated with a prospective multicenter design the long-term preventive effect of LA on incidence rates of cardiovascular events prospectively over a period of 5 years in 170 consecutive patients who commenced regular LA. During a median period of 4.7 years of the pre-LA period, Lp(a) associated progressive CVD became apparent. Apolipoprotein(a) (apo(a)) isoforms and polymorphisms at the apo(a) gene (LPA) were analyzed to assess hypothetical clinical correlations. 154 patients (90.6%) completed 5‑years follow-up. Significant decline of the mean annual major adverse cardiac event (MACE) rate was observed from 0.41 ± 0.45 two years prior to regular LA to 0.06 ± 0.11 during 5 years with regular LA (p < 0.0001). 95.3% of patients expressed at least one small apo(a) isoform. Calculation of isoform specific concentrations allowed to confirm the equivalence of 60 mg/dl or 120 nmol/l as Lp(a) thresholds of the German LA guideline. Results of 5 years prospective follow-up confirmed that LA has a lasting effect on prevention of cardiovascular events in patients with Lp(a)-HLP and afore progressive CVD.

A high level of lipoprotein(a) (Lp(a)) is recognized as an independent and additional cardiovascular risk factor contributing to the risk of early onset and progressive course of cardiovascular disease (CVD). All lipid lowering medications in use mainly lower low density lipoprotein-cholesterol (LDL-c) with no or limited effect on levels of Lp(a). Niacin, the only component lowering Lp(a), is firstly often poorly tolerated and secondly not available anymore in many countries. A level of <50 mg/dl was recommended recently as the cut off level for clinical use and decision making. Since lipoprotein apheresis (LA) lowers not only LDL-c but also Lp(a) significantly, its use is recommended in some countries in very high-risk patients with early or progressive CVD. Retrospective analyses show that regular LA improves the course of CVD. This is supported by a recent prospective observational trial and data of the German Lipoprotein Apheresis Registry. Despite many treatment options, all too often it is not possible to reduce LDL-c levels to target and to reduce Lp(a) levels sustainably at all. Therefore, new drug therapies are awaited. Some of the lipid modifying drugs in development lower Lp(a) to some extent in addition to LDL-c; the only specific approach is the apoprotein(a) antisense oligonucleotide. Currently LA is the standard of care as a last resort treatment in high-risk patients with elevated Lp(a) and severe CVD despite optimal control of all other cardiovascular risk factors.

In contrast to existing EAS/ESC guidelines on the management of lipid disorders, current recommendations from nephrological societies are very conservative and restrictive with respect to any escalation of lipid lowering/statin therapy. Furthermore, lipoprotein(a) (Lp(a)) – an established cardiovascular risk factor – has not even been mentioned. While a number of retrospective and prospective studies suggested that Lp(a) has relevant predictive value and might have – at least in stage-3 chronic kidney disease (CKD) – the same negative effects if draged along in non-CKD patients, there is no guidance on diagnostic or therapeutic procedures. The persistent lack of recognition automatically leads to therapeutic nihilism, which might pose a number of relatively young patients to a significantly increased risk for adverse cardiovascular events. Further evaluation of Lp(a) in CKD is very important to provide appropriate treatment to patients with high Lp(a) levels, even in the presence of CKD.

Ischemic heart disease is the main cause of death worldwide and it is accelerated by increased low-density lipoprotein (LDL) cholesterol (LDL-C) and/or lipoprotein (a) (Lp(a)) concentrations. Proprotein convertase subtilisin/kexin type 9 (PCSK9) alters both LDL-C and in part Lp(a) concentrations through its ability to induce degradation of the LDL receptor (LDLR). PCSK9, however, has additional targets which are potentially involved in lipid metabolism regulation such as the very low density lipoprotein receptor (VLDL), CD36 (cluster of differentiation 36) and the epithelial cholesterol transporter (NPC1L1) and it affects expression of apolipoprotein B48. The PCSK9 activity is tightly regulated at several levels by factors influencing its transcription, secretion, or by extracellular inactivation and clearance. Many comorbidities (kidney insufficiency, hypothyreoidism, hyperinsulinemia, inflammation) modify PCSK9 expression and release. Two humanized antibodies directed against extracellular PCSK9 received approval by the European and US authorities and additional PCSK9 directed therapeutics (such as silencing RNA) are already in clinical trials. Their results demonstrate a significant reduction in both LDL-C and Lp(a) concentrations – independent of the concomitant medication – and one of them reduced plaque size in high risk cardiovascular patients; results of two ongoing large clinical endpoints studies are awaited. In this review, we summarize and discuss the recent biological data on PCSK9, the regulation of PCSK9, and finally briefly summarize the data of recent clinical studies in the context of lipid metabolism.

High concentrations of lipoprotein(a) (Lp(a)) represent an important independent and causal risk factor associated with adverse outcome in atherosclerotic cardiovascular disease (CVD). Effective Lp(a) lowering drug treatment is not available. Lipoprotein apheresis (LA) has been proven to prevent cardiovascular events in patients with Lp(a)-hyperlipoproteinemia (Lp(a)-HLP) and progressive CVD. Here we present the course of a male patient with established peripheral arterial occlusive disease (PAOD) at the early age of 41 and coronary artery disease (CAD), who during follow-up developed over 2 years a progressive syndrome of cerebellar and spinal cord deficits against the background of multifactorial cardiovascular risk including positive family history of CVD. Spastic tetraplegia and dependency on wheel chair and nursing care represented the nadir of neurological deficits. All conventional risk factors including LDL-cholesterol had already been treated and after exclusion of other causes, genetically determined Lp(a)-HLP was considered as the major underlying etiologic factor of ischemic vascular disease in this patient including spinal cord ischemia with vascular myelopathy. Treatment with an intensive regimen of chronic LA over 4.5 years now was successful to stabilize PAOD and CAD and led to very impressive neurologic and overall physical rehabilitation and improvement of quality of life. Measurement of Lp(a) concentration must be recommended to assess individual cardiovascular risk. Extracorporeal clearance of Lp(a) by LA should be considered as treatment option for select patients with progressive Lp(a)-associated ischemic syndromes.

The increasing use of ventricular assist devices (VADs) in terminal heart failure patients provides new challenges to cardiac rehabilitation physicians. Structured cardiac rehabilitation strategies are still poorly implemented for this special patient group. Clear guidance and more evidence for optimal modalities are needed. Thereby, attention has to be paid to specific aspects, such as psychological and social support and education (e.g., device management, INR self-management, drive-line care, and medication). In Germany, the post-implant treatment and rehabilitation of VAD Patients working group was founded in 2012. This working group has developed clear recommendations for the rehabilitation of VAD patients according to the available literature. All facets of VAD patients’ rehabilitation are covered. The present paper is unique in Europe and represents a milestone to overcome the heterogeneity of VAD patient rehabilitation.

Lipoprotein(a) (Lp(a)) was first described by K. Berg and is known for more than 50 years. It is an interesting particle and combines the atherogenic properties of low-density lipoprotein (LDL)-cholesterol as well as the thrombogenic properties of plasminogen inactivation. However, due to technical problems and publication of negative trials the potential role of Lp(a) in atherosclerosis was severely underestimated. In recent years our understanding of the function and importance of Lp(a) improved. Interventional trials with niacin failed to demonstrate any benefit of lowering Lp(a); however, several studies confirmed the residual cardiovascular disease (CVD) risk of elevated Lp(a). LDL/Lp(a) apheresis is able to lower Lp(a) and some new drugs under development should help us to lower Lp(a) in the near future. It will be important to follow this with hard endpoint trials. Until then most clinicians recommend the use of an aggressive LDL-lowering approach in patients with high Lp(a). Since most of these patients with high Lp(a) might have manifested atherosclerosis anyway, we would also consider the use of acetylsalicylic acid.

Lipoprotein (a) [Lp(a)] is a modified LDL particle with an additional apolipoprotein [apo(a)] protein covalently attached by a thioester bond. Multiple isoforms of apo(a) exist that are genetically determined by differences in the number of Kringle-IV type-2 repeats encoded by the LPA gene. Elevated plasma Lp(a) is an independent risk factor for cardiovascular disease. The phenotypic diversity of familial Lp(a) hyperlipidemia [Lp(a)-HLP] and familial hypercholesterolemia [FH], as defined risks with genetic background, and their frequent co-incidence with additional cardiovascular risk factors require a critical revision of the current diagnostic and therapeutic recommendations established for isolated familial Lp(a)-HLP or FH in combination with elevated Lp(a) levels. Lp(a) assays still suffer from poor standardization, comparability and particle variation. Further evaluation of the current biomarkers and establishment of novel comorbidity biomarkers are necessary for extended risk assessment of cardiovascular disease in FH or Lp(a)-HLP and to better understand the pathophysiology and to improve patient stratification of the Lp(a) syndrome complex. Lp(a) promotes vascular remodeling, increased lesion progression and intima media thickening through induction of M1-macrophages, antiangiogenic effects (e.g. vasa vasorum) with secretion of the antiangiogenic chemokine CXCL10 (IP10) and CXCR3 mediated activation of Th1- and NK-cells. In addition inhibition of serine proteases causing disturbances of thrombosis/ hemostasis/ fibrinolysis, TGFb-activation and acute phase response (e.g. CRP, anti-PL antibodies) are major features of Lp(a) pathology. Anti-PL antibodies (EO6 epitope) also bind to oxidized Lp(a). Lipoprotein apheresis is used to reduce circulating lipoproteins in patients with severe FH and/or Lp(a)-HLP, particularly with multiple cardiovascular risks who are intolerant or insufficiently responsive to lipid-lowering drugs.