Atherosclerosis. Supplements最新文献

Homozygous familial hypercholesterolaemia (HoFH) is the rare, severe, but treatable disease characterised by exceedingly high levels of low-density lipoprotein cholesterol (LDL-C) and subsequent premature coronary heart disease. Of note, HoFH detection rate and patient access to healthcare and treatment modalities still differ considerably across EU countries. To our current knowledge, there are still no published reports describing HoFH in the paediatric population of Southeastern Europe.

In this case report, a few important topics on obstacles in getting adequate health care service and management of HoFH children from Southeastern Europe are tackled.

Idiopathic nephrotic syndrome (INS) is characterized by three different entities, namely minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS) and membranous nephropathy (MN). While there is an increasing understanding of primary MN with the discovery of antibodies directed against phospholipase A2 receptor (PLA2R Ab) and thrombospondin type 1 domain-containing 7A, circulatory factors causative of inducing MCD and FSGS remain in part elusive. Extracorporeal treatment forms (mostly plasma exchange) have been reserved for patients with either a disease course refractory to commonly prescribed immunosuppressive drugs or to patients with recurrence after kidney transplantation. There is a paucity of data supporting the use of immunoadsorption (IAS) in the management of MCD and MN and evidence to perform LDL-apheresis in the former is limited to reports from Japan. Treatment with IAS in primary FSGS has shown mixed responses, possibly biased by including treatment-resistant cases in the absence of genetic testing. In those with recurrence of the disease following kidney transplantation, IAS has shown high remission rates with an acceptable safety profile. There is a need to compare IAS to plasma exchange (PLEX) in this indication and due to a higher amount of plasma processed during one session, IAS may have advantages over PLEX. Removal of PLA2R Ab by IAS is currently being tested in a phase II clinical trial. More clinical trials in a prospective and randomized fashion need to be designed to prove the concept that IAS may be a treatment option for INS. While PLEX is still the leading extracorporeal treatment form in these indications, this review aims to highlight the efficacy and safety of IAS in the management of INS.

Background

Lipoprotein (Lp-) apheresis is a life-long therapy, usually performed in weekly intervals. In some cases, however, atherosclerotic disease progresses despite adequate therapy with weekly Lp-apheresis and maximal lipid lowering medication. In an attempt to improve the effectiveness of therapy, we temporarily shortened treatment intervals of Lp-apheresis in patients with elevated lipoprotein(a) (Lp(a)) and further progression of coronary atherosclerosis despite weekly Lp-apheresis and maximal lipid lowering medication.

Methods

We illustrate three case reports of patients with elevated Lp(a), who underwent regular weekly Lp-apheresis treatment for secondary prevention. The intensified treatment protocol contained three therapies in two weeks (alternating 2 per week and 1 per week).

Results

The shortening of treatment intervals achieved a stabilization of atherosclerotic disease in case 1. After a total of 68 therapies in 52 weeks (1.31 sessions/week) the elective coronary angiography revealed excellent long-term results. In case 2, the intensified treatment protocol is still ongoing. The patient reported a decrease in angina pectoris and an increase in exercise capacity since the beginning of more frequent therapy sessions. In some cases, as it is shown in case 3, a fast decision for shortening the treatment intervals is necessary.

Conclusions

The intensified treatment regimen resulted in an improvement in clinical symptoms and no further progression of atherosclerosis. In conclusion, shorter therapeutic Lp-apheresis intervals, at least temporarily, should be considered in patients who suffer from clinical and/or angiographic progression of atherosclerosis, despite maximal lipid lowering medication and weekly Lp-apheresis.

Background

Relative importance of traditional and non-traditional components of metabolic syndrome (MetSy) as risk factors for subclinical target organ damage in obese children is still under investigation. Recent studies highlight the role of serum uric acid (SUA) as an emerging non-traditional independent risk factor which correlates with obesity, MetSy, type 2 diabetes, preclinical cardiac and extracardiac organ damage, as well as cardiovascular events.

Aims

To study the relationship between SUA and left ventricular geometry pattern in obese children with or without MetSy.

Patients and methods

In this cross-sectional study, a total of 73 obese children, 64.4% male, and 35.6% female, with median age of 15 years (IQR = 12–16) were examined. Body mass index, glycaemia, standard lipid profile, fasting insulin level, HOMA index, serum uric acid level, 24-h average systolic blood pressure, left ventricular mass index (LVMI) and relative wall thickness (RWT) were evaluated in all children.

Results

LVMI in our study group was 46 g/m^2.7 (IQR = 42–55) while the RWT was 37% (IQR = 31–41). Median SUA level was 341 μmol/L (IQR = 283–387). In the entire sample of children, SUA was independently associated with the RWT (coeff = 0.02, p < 0.01). In a sub-group of metabolically unhealthy children, we found no statistically significant association between SUA and LVMI nor between SUA and RWT (coeff. = 0.002, p = 0.92; coeff. = 0.01, p = 0.20, respectively).

Conclusion

Serum uric acid is an important independent non-traditional risk factor for the development of concentric left ventricular geometry in obese children. These findings deserve further investigation to determine whether high SUA in obese children may be a therapeutic target.

Background

Lipoprotein apheresis (LA) is a well-established therapy for lowering lipid levels in serious cases of dyslipidaemia, including high levels of lipoprotein(a) [Lp(a)]. This method lowers both LDL cholesterol and Lp(a) by more than 60% in most of patients; however, because randomized clinical studies could be extremely difficult, also other markers of the effect of this procedures on vascular health are of importance. Therefore, in addition to changes in plasma lipids and Lp(a) during LA, we also analysed the response of biomarkers associated with vascular integrity: small non-coding microRNAs (miRNAs).

Materials and methods

We analysed the changes in miRNAs in two women (age 70 and 72 years) with clinically manifest extensive and progressive atherosclerotic disease and high levels of Lp(a) and with different clinical course who were treated by LA. In both women we analysed changes of 175 circulating plasma miRNAs using pre-defined serum/plasma focus panels at the beginning of and one year after the therapy.

Results

In addition to reduced levels of plasma lipids and Lp(a), circulating plasma levels of miR-193a-5p; -215-5p; -328-3p; -130a-3p; -362-3p; -92b-3p decreased, and levels of miR-125a-5p; -185-5p; -106a-5p; -320b; -19a increased (all P < 0.05) in both women. Moderate differences were found between both women with regard to the different course of atherosclerotic disease.

Conclusions

Long-term LA substantially changes circulating plasma miRNAs associated with vascular integrity reflected different clinical course in both women. If confirmed, this approach could improve the assessment of the effectiveness of this therapy on an individual basis.

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

Purpose

We analyzed efficacy and safety of PCSK9i in patients undergoing lipoprotein apheresis (LA) and in patients treated at our outpatient department for metabolic disorders.

Methods

The medical records of 40 LA patients, taking PCSK9i were reviewed with respect to LDL-cholesterol (LDL-C) and lipoprotein(a) (Lp(a)) lowering as well as occurrence of adverse events. Furthermore, we analyzed the data of 152 patients of our outpatient department, undergoing PCSK9i therapy.

Results

Mean pre-apheresis LDL-C value was reduced by PCSK9i from 3.71 ± 1.19 to 1.78 ± 0.84 mmol/l (53 ± 12%). The relative lowering of the pre-apheresis Lp(a) was 20 ± 12% (from 191 ± 63.5 to 152 ± 51.9 nmol/l). 25% of LA patients could stop LA after reaching LDL-C target after initiation of PCSK9i. 75% of the patients are continuing the regular LA therapy, showing an insufficient LDL-C lowering following PCSK9i injections or/and additionally elevated Lp(a) or/and adverse effects of PCSK9i, leading to the discontinuation of injections. The number of LA patients has grown from 112 in 2016 to 128 nowadays due to an increasing percentage of patients with elevated Lp(a) (79% and 89% respectively). The mean reduction rate of LDL-C under PCSK9i therapy in outpatients was 53.03%. In 34% of patients the target value could not be reached. 43% of persons suffered from adverse effects.

Conclusions

3/4 of LA patients could not stop extracorporeal treatment after PCSK9i administration. In hypercholesterolemic patients with coexisting elevated Lp(a) and progressive cardiovascular disease the combination of LA and PCSK9i could be beneficial. The total patients’ number in LA units increases due to persons with Lp(a)-hyperlipoproteinemia.

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.

Background and aims

Lipoprotein apheresis (LA) is a highly effective method to improve the clinical and metabolic situation in patients with therapy-resistant disorders of lipid metabolism. Cholesterol is the substrate for the synthesis of all steroid hormones. If repeated massive reduction of LDL-cholesterol may interfere with human adrenal steroidogenesis, and could become clinically relevant is unknown, so far. Thus, the aim of this study was to determine possible short- and long-term effects of LA on blood plasma levels of ACTH, cortisol, aldosterone, DHEAS, renin and testosterone.

Methods

In total, 39 patients, treated with one of four LA techniques were studied: 1. Lipid Filtration (LF; n = 7), 2. Dextran Sulfate Adsorption (DSA; n = 7), 3. Membrane Filtration Optimised Novel Extracorporeal Treatment (MONET; n = 8), and 4. Direct Absorption of Lipoproteins (DALI; n = 15). Hormone levels were analyzed before and after five LA sessions with an interval of 20 weeks covering a total observation time of two years. In addition patients were comprehensively characterized by clinical and laboratory data.

Results

Patients treated with LA revealed an acute reduction of steroid hormones and ACTH, independent of apheresis technology but no long-term insufficiency in steroidogenesis was observed. Plasma renin levels were stable in LF patients and were highly elevated in patients under DSA, MONET and DALI apheresis throughout the observation period.

Conclusions

In summary, these data suggest that although different LA techniques considerably differ in their acute effects on hormone levels during LA, they did not alter long-term hormone levels sustainably.

Background

In Austria, about 12 patients per 1 million inhabitants are treated currently with lipoprotein (LP-) apheresis. In 2016 it has been suggested, that about 5000 patients were treated worldwide with LP-apheresis, more than half of them in Germany. Regular LP-apheresis aims to decrease apolipoprotein B-rich lipoproteins and to reduce cardiovascular events. In this analysis we present the current situation of LP-apheresis in Austria and we evaluated the cardiovascular event rate 2 years before versus 2 years after starting LP-apheresis.

Methods

A retrospective analysis of 30 patients (19 men and 11 women) was performed at Athos Institute, Vienna, Austria. The study period included two years prior versus two years after the beginning of LP-apheresis. Cardiovascular events and interventions were defined as regarding the coronary (MACE) or the non-coronary (peripheral, cerebral or renal) vascular system.

Results

The first cardiovascular event before treatment initiation occurred at a mean age of 48.4 years (range 34–73), treatment was started at a mean age of 55.6 years (range 34–73). The mean rate of incidence of cardiovascular events per patient per 2 years before beginning of LP-apheresis (y-2 and y-1) versus 2 years during treatment (y+1 and y+2) was reduced by 77.78% (1.50 versus 0.33 events/patient/2 years, p = 0.003).

Conclusions

The significant reduction in MACE and vascular disease during regular LP-apheresis at weekly intervals is consistent with data from the literature. Difficulties arise in comparing such studies due to different definition of events or interventions and different study durations. However, LP-apheresis is an efficient treatment option and causes significantly prolonged event-free survival for patients at risk.