Lipoprotein apheresis - Shortening of treatment intervals reduces cardiovascular events: Case reports.

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.

One year follow-up of patients with reduced left ventricular ejection fraction (LVEF) on lipoprotein apheresis.

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 ±â€¯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 ±â€¯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.

Lipoprotein apheresis in Austria - Reduction of cardiovascular events by regular lipoprotein apheresis treatment.

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.

Statin-induced muscular side effects at rest and exercise - An anatomical mapping.

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.

Tc-99m-PSMA imaging allows successful radioguided surgery in recurrent prostate cancer.

OBJECTIVE: The introduction of the prostate specific membrane antigen (PSMA) offers the possibility to discover prostate cancer recurrences being frequently so small that they cannot be detected by conventional imaging modalities, such as magnetic resonance or computed tomography. SUBJECTS AND METHODS: A 78 years old patient after radical prostatectomy and lymphadenectomy suffered from recurrence of the disease and galium-68-PSMA (68Ga-PSMA) showed a single hot spot. Therefore, the first time in this indication in Austria radioguided surgery was performed after application of technetium-99m (99mTc)-PSMA, which confirmed the single lesion already shown by 68Ga-PSMA. RESULTS: The lymph node was located dorsal to the urinary bladder dome in the presacral area, where normally no lymphadenectomy is performed, he was identified by the probe and removed. Postoperatively PSA-monitoring showed a decline from 13,1ng/mL (preoperatively) to <0,1ng/mL within 1 month. CONCLUSION: The use of radiolabeled PSMA (primary diagnosis with 68Ga, radioguided surgery with 99mTc and finally treatment with 177Lu) seems to be a major breakthrough in diagnosis and treatment of prostate cancer.

[Therapeutic options in hyperlipidemia]. / Therapieoptionen von Fettstoffwechselstörungen.

Treatment of lipid disorders (dyslipidemia) is the cornerstone of atherosclerosis prevention and reduction of progression. Lifestyle modification is the first step to improve the plasma lipid profile. Statins play a central role in the reduction of LDL cholesterol. Whether and to what extent other lipids such as triglycerides or lipoprotein(a) should also be treated depends on the extent of atherosclerotic disease and its progression over time. Especially in residential cardiac rehabilitation we have the opportunity to encourage adherence and adapt medication as necessary due to a face to face contact over 4 weeks. Moreover, the prescription for a PCSK9-inhibitor could be resolved or the indication for a lipoprotein apheresis could be considered.

Pleiotropic effects of regular lipoprotein-apheresis.

BACKGROUND: Lipoprotein(LP)-apheresis is the treatment of choice in patients suffering from severe familial hypercholesterolemia. A wide range of mechanisms has been claimed to be responsible for the known clinical benefit. METHODS: Patients suffering from heterozygous familial hypercholesterolemia undergoing LP-apheresis either with direct adsorption of lipoproteins (DALI) or dextran sulfate (DS) were examined. A total volume of 10 l blood was exchanged. Non-lipid effects, mainly concerning endothelial function (circulating endothelial cells, circulating endothelial progenitor cells, flow-mediated vasodilation, microalbuminuria) as well as left ventricular ejection fraction and homocysteine were assessed. RESULTS: A single LP-apheresis session improves paradox contractile response in statin intolerant patients, but not in those on regular statin therapy. In contrast, over a 6-months follow-up after treatment initiation, all the examined parameters (circulating endothelial cells, circulating endothelial progenitor cells, flow mediated vasodilatation, homocysteine, microalbuminuria and left ventricular ejection fraction) improved. When available, a comparison between DS vs. DALI was performed. In none of the subgroups a significant difference was noted. DISCUSSION: These findings indicate that beyond the well known lipid/lipoprotein lowering action the broad spectrum of functional tests examined reflecting mainly endothelial function is significantly improved by LP-apheresis treatment on the long-term and seems to be a key underlying reason for the clinical improvement seen in these patients.

A retrospective analysis of the accuracy of radioactively labeled autologous leukocytes in patients with infected prosthetic joints.

BACKGROUND: Labeled leukocyte scintigraphy (LS) is considered a valuable tool in preoperative diagnosis of prosthetic joint infections (PJI). The aim of this study was to determine the accuracy of LS combined with bone marrow scintigraphy (BMS), as well as inflammation markers CRP and WBC, in detecting infection in patients with prosthetic joints. MATERIAL AND METHODS: This study included patients suspected of having PJI between January and September 2013 at the Vienna General Hospital who underwent imaging with 99mTc-HMPAO labeled autologous leukocytes and subsequent BMS. Diagnostic accuracy was assessed in terms of sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). RESULTS: A total of 48 patients were included. The most common joint investigated was knee (25), followed by hip (9), shoulder (2), and elbow (1). Other parts of the body investigated included the femur (6), tibia (2), leg (2), and foot (1). The pathogens most frequently isolated included Staphylococcus epidermidis and Candida albicans. The sensitivity of LS was 60%, specificity 97%, PPV 86% and NPV 90%. Overall accuracy was calculated to be 90%. CONCLUSIONS: This study was able to demonstrate that 99mTc-HMPAO labeled autologous leukocytes in patients presenting with symptoms of PJI is accurate. In contrast, however, inflammation markers CRP and WBC are not accurate pre-diagnostic markers for PJI.

Role of Artificial Intelligence Techniques (Automatic Classifiers) in Molecular Imaging Modalities in Neurodegenerative Diseases.

Artificial Intelligence (AI) is a very active Computer Science research field aiming to develop systems that mimic human intelligence and is helpful in many human activities, including Medicine. In this review we presented some examples of the exploiting of AI techniques, in particular automatic classifiers such as Artificial Neural Network (ANN), Support Vector Machine (SVM), Classification Tree (ClT) and ensemble methods like Random Forest (RF), able to analyze findings obtained by positron emission tomography (PET) or single-photon emission tomography (SPECT) scans of patients with Neurodegenerative Diseases, in particular Alzheimer's Disease. We also focused our attention on techniques applied in order to preprocess data and reduce their dimensionality via feature selection or projection in a more representative domain (Principal Component Analysis - PCA - or Partial Least Squares - PLS - are examples of such methods); this is a crucial step while dealing with medical data, since it is necessary to compress patient information and retain only the most useful in order to discriminate subjects into normal and pathological classes. Main literature papers on the application of these techniques to classify patients with neurodegenerative disease extracting data from molecular imaging modalities are reported, showing that the increasing development of computer aided diagnosis systems is very promising to contribute to the diagnostic process.

Individual kidney depth determination is mandatory to assess split renal function in nephrography irrespective of age.

Nephrography having been introduced more than 60 years ago still now is one of the most frequently used and informative procedures in Nuclear Medicine. Although being considered a well standardized method, a worldwide study in 34 centers in 21 countries revealed that determination of split kidney function shows unacceptable high variation, particularly in patients with a relative kidney function below 30%. Furthermore, kidney depth usually is not considered. The calculation of kidney depth by various formulas available, each claiming to be more predictive, is different in races and does not allow individual information, which particularly in patients with a diseased kidney may become unreliable. We investigated 331 patients (167m, 164f) aged 1 to 76 years (84 of them being less than 20 years old), where kidney depth has been estimated by means of sonography as well as by a lateral view gamma camera image obtained immediately after the investigation. At the age of 10 years the kidney depth may vary already by 20%, in some patients increasing to 30% at the age of 20 and showing further increase with increasing age. In adults, >50% show a depth difference between right and left kidney of >1cm. There is an excellent correlation between sonographic and nephrographic kidney depth determination, at mean there was no difference between the kidney depth of the right hand and left hand side. Furthermore, we demonstrate that the incorporation of waist circumference instead of body mass index into the formulas is more precise. These findings indicate that the assessment of split kidney function particularly in patients with kidney disease, transplant donors and atypical localization irrespective of age should be mandatory in clinical routine.

The effect of elevated lipoprotein(a) on autologous platelets function: a retrospective analysis.

OBJECTIVE: Platelet labeling is used to study platelets in vivo in terms of diagnosing intravascular thrombosis, as well as studying their role and biological activity in atherosclerosis. A low labeling efficiency (LE) can negatively impair testing results. Labeling efficiency depends on various factors, including low-density-lipoprotein (LDL)-cholesterol levels in the blood. Lipoprotein(a) (Lp(a)) is a lipoprotein subclass that when elevated, is frequently associated with the premature development of cardiovascular disease through activation of different signaling pathways and cell surface receptors. SUBJECTS AND METHODS: We retrospectively studied 51 patients with isolated elevated Lp(a) (>50 mg/dL, ranging up to 440 mg/dL) compared to patients with normal lipid profiles who underwent autologous radioactive platelet labeling during the time period of January 2001-September 2013 at the Vienna General Hospital. Platelets were radiolabeled according to ISORBE consensus. RESULTS: LE was decreased in patients with elevated Lp(a). Cross-incubation of hyper-Lp(a) patients with normal Lp(a) plasma and vice versa demonstrated that platelets themselves and not the plasmatic environment are accountable for the decline in LE. Furthermore, LE positively correlated with an increase in platelet incubation time, the highest LE being seen after 30 minutes. CONCLUSION: This study determined that extremely elevated Lp(a) profiles, especially values greater than 150 mg/dL, may significantly impair platelets function such as labeling results. Platelets are responsible for the decrease in LE in hyper-Lp(a) patients. Non-HDL-Lp is the most informative parameter of impaired LE. We thus recommend to include Lp(a) in the list of parameters that need to be taken into consideration in studying autologous radiolabeled platelets.

Systematic screening for cardiovascular risk at pharmacies.

BACKGROUND: Early identification and treatment of cardiovascular risk factors (CVRFs) is essential to prevent excess morbidity, mortality and healthcare-related costs. We sought to investigate whether an active screening programme at pharmacies could identify a significant proportion of patients with previously undetected CVRFs. METHODS AND RESULTS: Between April and July 2013, 184 pharmacies in Lower Austria enrolled a total of 6800 participants, in whom body mass index (BMI), blood pressure (BP), total cholesterol and blood glucose were measured. Mean age was 58±17 years and 67.8% were women. 21% of men and 16% of women had a BMI≥30 kg/m2. The crude prevalence of diabetes mellitus (DM) was 7%, hypercholesterolaemia was identified in 57%, and 44% had elevated BP. Among fasting individuals (n=1814), DM was found in 18%. In total, 30% were confronted with a CVRF they were previously unaware of, and pharmacists recommended 45% of all participants to actively consult a physician. A first-time diagnosis of a CVRF was most frequent in the age groups between 25 and 64 (32% of participants). CONCLUSIONS: This pharmacy-based approach for cardiovascular risk screening found similar overall prevalences of CVRFs as reported by national surveys, but revealed underdiagnoses, particularly in lower age groups. A previously unknown CVRF was identified in every third individual, frequently prompting the pharmacists to recommend the consultation of a physician. An active screening approach at pharmacies might therefore serve as an effective alternative to the public preventive medical examination, particularly in younger age groups.

Molecular imaging of atherosclerotic lesions by positron emission tomography - can it meet the expectations?

Early non-invasive imaging of atherosclerosis and in particular the detection of lesions at risk with high specificity could significantly affect cardiovascular morbidity and mortality. Conventional nuclear medicine approaches, in particular using autologous radiolabeled lipoproteins, can be related to histopathological findings; however, they fail to identify lesions at risk. Positron emission tomography (PET) tracers with much better physical properties have been examined, the most detailed information being available for F-18-deoxyglucose (FDG) and F-18-sodium fluoride (NaF). These two approaches are sensitive to different biochemical mechanisms, i.e. inflammation and microcalcification. Initial enthusiasm, in particular for F-18-FDG, has disappeared, although for F-18-NaF there is some hope, but this is not a breakthrough. No tracer is available so far that is able to identify a specific characteristic of a lesion prone to rupture. Other PET tracers in the pipeline have been examined, mainly in experimental models and only a few in patients, but they failed to contribute significantly to early lesion discovery and do not support great expectations. The key question is: Do we understand what we see? Moreover, methodological problems, a lack of standardization of imaging protocols and aspects of quantification provide a wide range for potential future improvements. While monitoring a therapeutic intervention seems to be possible for both F-18-FDG and F-18-NaF, highly specific early identification of lesions at risk by PET imaging is still far away. As of today, PET is not ready for routine clinical judgment of atherosclerotic lesions at risk to rupture. Even if all these problems can be solved, radiation exposure will still remain a concern, in particular for repeated studies.

Muscle- and skeletal-related side-effects of statins: tip of the iceberg?

The clinical spectrum of muscle- and skeletal-related side-effects of statins includes varied myalgias and weakness, an asymptomatic increase in the concentration of creatine kinase and other biochemical parameters, myositis and rhabdomyolysis. Currently, there is no consensus on the definition of 'statin myopathy'. Evidence suggests that deleterious effects may also be associated with the volume or dosage of structured exercise and/or the intensity of physical activity. Moreover, non-muscle adverse effects on the joints and tendons are often overlooked and underemphasized. The incidence of myopathy associated with statin treatment typically ranges between 1.5% and 10%. Few data are available regarding the prevalence of muscle- related symptoms associated with different statins and the distribution of affected muscles. Furthermore, discrepancies between clinical trials and daily practice may emanate, in part, because of inconsistent definitions or exclusion criteria.The pathophysiology of statin-related myopathy is incompletely understood. A dose-dependent and proapoptotic effect, direct effects on mitochondria, drug interactions and genetic factors, or combinations thereof, may be involved. Recently, a rare immune-mediated myopathy triggered by statin use has been described. With the increasing number of patients treated with statins and with more patients being prescribed high doses of potent statins to achieve low-density lipoprotein targets, muscle-related side-effects will become more prevalent. Currently, the only effective treatment is the discontinuation of statin use. Further research is needed to develop alternative LDL-lowering drugs when statins are not well tolerated and to establish additional effective strategies to manage lipids and lipoproteins.