Atherosclerosis. Supplements最新文献

Based on an early suggestion by Winkler et al. 2003 and a subsequent successful study by Wang et al. 2006 using lipid apheresis (LA) in 9 patients with preeclampsia to prolong pregnancies, the use of apheresis as therapeutic option in severe early onset preeclampsia has received increasing attention. Further studies using different LA systems also prolonged pregnancy and have been published in the last few years. Albeit using different LA systems and relying on different working hypothesis, all studies demonstrated a promising stabilisation against the disease's progression. Overall time from hospitalisation to the need for mandatory delivery was longer for those patients receiving apheresis compared to historical or matched control patients not receiving apheresis. These data will be reviewed and different hypotheses about the beneficial mechanism of action of apheresis will be discussed. Since up to now there is no curative treatment for preeclampsia other than observation and delivery, future work shall be encouraged.

Background and aims

Muscle-related symptoms with or without creatine kinase (CK) elevation are common adverse effects associated with statin use. Symptoms are ranging from benign myalgia to myositis and in rare cases to rhabdomyolysis. The aim was to characterize and describe muscular side effects and create an anatomical frequency mapping.

Methods

The prospective observational study was performed at a large lipidology outpatient unit in Vienna. 1111 consecutively admitted patients with muscular side effects on statin monotherapy were included during a 4-year period. Anatomical mapping of the affected muscles, signs and symptoms, the onset of symptoms after starting statin therapy and disappearance after cessation of treatment was assessed.

Results

In 96.5% of the patients with muscle symptoms, there was no elevation of CK. The anatomical mapping revealed exercised muscles as being mainly affected in 84%. In the upper extremity, symptoms were mainly described at the dominating side. Mostly affected muscles were the pectoral (61.4%), followed by the quadriceps femoris (59.8%), the biceps brachii (54.3%) and the deltoid (22.5%) muscles. The majority of symptoms (76.9%, n = 854) appeared within 29 days. Symptoms disappeared after discontinuation of statin therapy at a mean of 5.4 days.

Conclusions

Physical activity seems to be a key trigger for onset of statin-induced muscular side effects. The appearance of symptoms can be symmetrical, asymmetrical, generalized or in isolated muscle groups only. Different statins usually produce similar symptoms, but often some patients tolerate one statin better than another.

Background

Left ventricular ejection fraction (LVEF) is a valuable measure to assess left ventricular systolic function. Lipid lowering therapy by statins has been shown to have an impact on LVEF already after a 6 months treatment. Higher doses of statins have been claimed to be more effective as compared to a conventional one and even a difference between lipophilic and hydrophilic compounds has been reported. The effect of regular lipoprotein-apheresis (LP-apheresis) on LVEF was previously poorly examined.

Patients involved in a regular LP-apheresis program are supposed to undergo a number of follow-up investigations among them myocardial scintigraphy and LVEF, measured by radionuclide ventriculography.

Methods

We examined 18 patients before initiation and after one year of ongoing LP-apheresis. 13 patients (11 males, 2 females, mean age 58.3 ± 5.3 years, groups A) were since more than a year on stable, unchanged statin treatment (atorvastatin 40 mg, simvastatin 40 mg, rosuvastatin 20 mg±ezetimibe), the other 5 patients (3 males, 2 females, mean age 57.1 ± 4.6 years, group B) were intolerant to statins being on micronized fenofibrate±resorption inhibitors (cholestyramine). All patients had a Lp(a) < 30 mg/dl. As part of the usual follow-up monitoring, LVEF was determined by means of radionuclide ventriculography after application of 550 MBq ^99m Tc-pertechnetate.

Results

The follow-up LVEF was checked at a mean of 48.7 weeks in group A and 51.2 weeks in group B. Except in 1 patient (LVEF 46.8% before vs. 45.2% after LP-apheresis initiation) in group A we noted a significant increase in LVEF in 12 patients of group A (92%) and in all patients of group B. Mean LVEF increased significantly in both groups (A: 42.7±8.1 → 46.5±7.5% (p < 0.001) and B: 41.9±8.4 → 46.5±6.3 %; p < 0.001). The relative rise was nearly identical (group A 9.6%, in group B 9.7%).

Conclusions

Our findings indicate that regular long-term LP-apheresis treatment apparently increases LVEF, independently on current statin treatment. This implies a role of lowering of atherogenic lipoproteins as underlying mechanism. A prospective study should clarify the relative extent of LVEF improvement induced by LP-apheresis.

Background and aims

Acute hyperlipidaemic pancreatitis (HP) may develop in pregnancy in patients with genetic predisposition. There are no accepted guidelines for the management of this rare but life-threatening condition in pregnancy. Plasma exchange (PEX) was suggested as a suitable option to treat HP in pregnancy; however, further evidence from case reports/case series are needed.

Methods

Three PEX procedures (2000 ml of plasma replaced with 5% albumin) were performed in one week in a pregnant patient at 25 weeks of gestational age with severe HP. Triglyceride related genes (LPL, APOA5, APOE, GPIHBP1, GPD1, LMF1, CREB3L3) were screened by DNA sequencing. Medline and Embase databases were searched electronically in January 2018 using different combinations of the relevant medical subject headings for “pancreatitis in pregnancy” and “therapeutic apheresis”.

Results

Gene profiling assessed a combined heterozygous state for the variants pSer19Trp of the APOA5 gene and pCys130Arg of the APOE (allele E4) gene.

PEX led to significant and progressive reduction of triglyceride plasma levels along with cholesterol and C-reactive protein. Meanwhile a fast improvement of pregnant clinical condition was observed. This allowed the delivery at term of a healthy newborn without gestational complications. An outcome hardly achievable in patients managed exclusively by a pharmacological approach.

Conclusions

PEX led to a positive maternal outcome in absence of foetal and gestational complications in a case of severe HP in pregnancy. As clinical trials are lacking, case reports still represent the best way to reasonably implement clinical management of this rare but life-threatening disease.

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.