Phytosterols and Cardiovascular Disease.

PURPOSE OF REVIEW: Coronary heart disease is the leading cause of mortality worldwide. Elevated blood cholesterol levels are not only the major but also the best modifiable cardiovascular risk factor. Lifestyle modifications which include a healthy diet are the cornerstone of lipid-lowering therapy. So-called functional foods supplemented with plant sterols lower blood cholesterol levels by about 10-15%. RECENT FINDINGS: In the recent revision of the ESC/EAS dyslipidemia guideline 2019, plant sterols are recommended for the first time as an adjunct to lifestyle modification to lower blood cholesterol levels. However, the German Cardiac Society (DGK) is more critical of food supplementation with plant sterols and calls for randomized controlled trials investigating hard cardiovascular outcomes. An increasing body of evidence suggests that plant sterols per se are atherogenic. This review discusses this controversy based on findings from in vitro and in vivo studies, clinical trials, and genetic evidence.

Still a reasonable goal: Targeting cholesterol in dialysis and advanced chronic kidney disease patients.

Chronic kidney disease (CKD) patients have a high burden of cardiovascular disease. In the general population, lipid metabolism disorders, which cause the initiation and progression of atherosclerotic vascular changes, are major targets for preventive and therapeutic strategies in cardiovascular medicine. However, data from large cohort studies and from clinical trials suggest that the treatment guidelines on cardiovascular disease prevention and therapy cannot uncritically be transferred from individuals with intact renal function to CKD patients. Thus, unlike in the general population, neither plasma levels of HDL-cholesterol, nor the key parameter of HDL-cholesterol function-that is, cholesterol efflux capacity-predicts future cardiovascular events. Therefore, HDL-cholesterol should presently not be considered as therapeutic target in CKD patients. In contrast, lowering of LDL-cholesterol has been shown to reduce cardiovascular events at least among nondialysis CKD patients. The cardiovascular benefit of targeting LDL-cholesterol among dialysis CKD patients is less evident. We strongly believe that at least some subgroups of dialysis patients may profit from such treatment, particularly those with highest baseline LDL-cholesterol. Finally, as CKD patients have been characterized to have rather high intestinal cholesterol absorption, and relatively low hepatic cholesterol synthesis, substituting combined statin/ezetimibe treatment for statin monotherapy may be of particular benefit for nephrologic patients.

The Atherogenicity of Plant Sterols: The Evidence from Genetics to Clinical Trials.

The human diet is naturally varied and contains not only essential nutrients, but also contains molecules that the body actively excludes or minimizes exposure. Among these molecules are xenosterols, of which plant sterols comprise the greatest exposure risk. These sterols comprise approximately 50% of the total sterols we eat, yet we retain <0.5% of these in our bodies. The bulk of this exclusion takes place in the intestine and the heterodimeric transporters ABCG5 and ABCG8 are key to keeping these xenosterols out of our bodies. In normal humans, pharmacological supplementation with plant sterols (and stanols) has been used to lower cholesterol as these impair intestinal absorption/ re-absorption of this molecule; lowering plasma cholesterol has cardiovascular risk benefits. This review challenges whether this intervention is beneficial and may even be harmful. We summarize the evidence involving humans who have genetic disruption of ABCG5/ABCG8 function, from clinical trial data examining plant sterols and cardiovascular risk, from genetic data affecting normal humans and ABCG5/ABCG8 variations to data obtained using animal models. Accumulation of xenosterols in any significant amount is clearly associated with increased toxicity, and data suggest that at even low levels there may be effects. Importantly, there is also a paucity of data showing cardiovascular end-point benefits with plant sterol/stanol supplementation. The summary of evidence highlights not only caution in recommending such strategies to lower plasma cholesterol, but also in investigating how these xenosterols can affect processes ranging from cardiovascular, endocrine, and neurological function.

Plant sterols the better cholesterol in Alzheimer's disease? A mechanistical study.

Amyloid-ß (Aß), major constituent of senile plaques in Alzheimer's disease (AD), is generated by proteolytic processing of the amyloid precursor protein (APP) by ß- and γ-secretase. Several lipids, especially cholesterol, are associated with AD. Phytosterols are naturally occurring cholesterol plant equivalents, recently been shown to cross the blood-brain-barrier accumulating in brain. Here, we investigated the effect of the most nutritional prevalent phytosterols and cholesterol on APP processing. In general, phytosterols are less amyloidogenic than cholesterol. However, only one phytosterol, stigmasterol, reduced Aß generation by (1) directly decreasing ß-secretase activity, (2) reducing expression of all γ-secretase components, (3) reducing cholesterol and presenilin distribution in lipid rafts implicated in amyloidogenic APP cleavage, and by (4) decreasing BACE1 internalization to endosomal compartments, involved in APP ß-secretase cleavage. Mice fed with stigmasterol-enriched diets confirmed protective effects in vivo, suggesting that dietary intake of phytosterol blends mainly containing stigmasterol might be beneficial in preventing AD.

Plant sterols in food: no consensus in guidelines.

Plant sterols are supplemented in foods to reduce cardiovascular risk. Randomized controlled trials show 2 g of plant sterols a day reduce serum cholesterol by about 10%. This reduction in serum cholesterol levels is achieved at the expense of increased serum plant sterol levels. Findings in patients with phytosterolemia, in experimental studies and in clinical trials have lead to speculations that plant sterols might be atherogenic. In view of emerging safety issues the role of plant sterols in cardiovascular prevention has become controversial. This review reflects the ongoing controversial scientific debate and points out recent developments in guidelines of national and international societies.

The relationships of phytosterols and oxyphytosterols in plasma and aortic valve cusps in patients with severe aortic stenosis.

Phytosterols such as campesterol and sitosterol are susceptible to oxidation by reactive oxygen species. We hypothesize that the plant sterols (PS) campesterol and sitosterol and their 7-oxygenated metabolites (POPs) correlate within and between human plasma and aortic valve cusps tissues. Plasma and tissue concentrations of PS and POPs were analyzed by gas chromatography-mass spectrometry-selected ion monitoring. Prior to analysis valve cusps tissue was mechanically separated from the calcified parts. PS and POP levels per dry cusps tissue weight were significantly higher compared with the concentrations in the calcified part. Against our hypothesis we found that despite the fact that there is a high correlation between plant sterols in and between plasma and valves cusps tissue, as well as a high correlation between plant sterols and oxyphytosterols and oxyphytosterols themselves within the valve cusps tissue, there was hardly any correlation in the amount of oxyphytosterols in plasma and between plasma and valves. Because plasma samples are easily accessible for large scale population based studies, we have to understand in more detail what the analysis of POPs implies in terms of CVD risk for the future.

Monogenic hypertriglyceridemia and recurrent pancreatitis in a homozygous carrier of a rare APOA5 mutation: a case report.

BACKGROUND: Homozygous mutations in the APOA5 gene constitute a rare cause of monogenic hypertriglyceridemia, or familial chylomicronemia syndrome (FCS). We searched PubMed and identified 16 cases of homozygous mutations in the APOA5 gene. Severe hypertriglyceridemia related to monogenic mutations in triglyceride-regulating genes can cause recurrent acute pancreatitis. Standard therapeutic approaches for managing this condition typically include dietary interventions, fibrates, and omega-3-fatty acids. A novel therapeutic approach, antisense oligonucleotide volanesorsen is approved for use in patients with FCS. CASE PRESENTATION: We report a case of a 25-years old Afghani male presenting with acute pancreatitis due to severe hypertriglyceridemia up to 29.8 mmol/L caused by homozygosity in APOA5 (c.427delC, p.Arg143Alafs*57). A low-fat diet enriched with medium-chain TG (MCT) oil and fibrate therapy did not prevent recurrent relapses, and volanesorsen was initiated. Volanesorsen resulted in almost normalized triglyceride levels. No further relapses of acute pancreatitis occurred. Patient reported an improve life quality due to alleviated chronic abdominal pain and headaches. CONCLUSIONS: Our case reports a rare yet potentially life-threatening condition-monogenic hypertriglyceridemia-induced acute pancreatitis. The implementation of the antisense drug volanesorsen resulted in improved triglyceride levels, alleviated symptoms, and enhanced the quality of life.

[Primary and secondary prevention in hypercholesterolemia: differences relevant to patient care in the PROCYON trial]. / Primär- und Sekundärprävention bei Hypercholesterinämie ­ versorgungsrelevante Unterschiede in der PROCYON-Studie.

BACKGROUND: Cardiovascular disease accounts for one third of deaths in Germany. Elevated levels of low-density lipoprotein cholesterol (LDL-C) are considered a major risk factor. Lowering LDL-C levels is therefore an integral part of the prevention of cardiovascular events. METHODS: The aim of this work is to identify potential differences between primary prevention (PP) and secondary prevention (SP) by means of a post-hoc comparison of cross-sectional data from the PROCYON survey. Medical history, concomitant diseases, adherence, and disease awareness in relation to hypercholesterolemia were queried. RESULTS: 5,494 patients had participated in the survey (PP: 3,798; SP: 1,696). Comparison of the results showed a numerically higher proportion of women (PP 70.7% vs. SP 42.5%) as well as more frequent comorbidities such as hypertension (PP 45.6% vs. SP 61.0%), obesity (PP 20.9% vs. SP 27.4%), and type 2 diabetes mellitus (PP 14.1% vs. SP 23.8%). In primary prevention, hypercholesterolemia was most often diagnosed during screening (PP 74.6%), and in secondary prevention, the diagnosis was most often made during cardiovascular-related hospitalization (SP 58.0%). A cardiologist was consulted by 16.3% (PP) and 54.0% (SP) of patients, respectively. At least semiannual LDL-C checks (PP 46.8% vs. SP 77.9%) and drug intervention (PP 43.0% vs. SP 87.0%) were more frequent in the secondary prevention group. In addition, differences in the implementation of lifestyle changes, improvement of LDL-C levels, adjustment of therapy as well as adherence, treatment satisfaction and patient knowledge were observed. CONCLUSION: The comparison of primary and secondary prevention from the PROCYON survey shows overall better utilization of treatment options and higher intensity of care in the secondary prevention group. However, there is still great potential for improvement in both groups to ensure efficient prevention of cardiovascular events.

Different Perspectives of Patients and Physicians on LDL-C Target Achievement in the Treatment of Hypercholesterolemia: Results on Secondary Prevention from the German PROCYON Survey.

AIMS: Low-density lipoprotein cholesterol (LDL-C) reduction in hypercholesterolemia patients at very high cardiovascular (CV) risk is essential in preventing future CV events. The objective was to assess the perception on hypercholesterolemia management in secondary prevention in Germany. METHODS: PROCYON was a two-part online survey, including a patient questionnaire as well as a physician questionnaire. RESULTS: A total of 109 general practitioners, internists, and cardiologists participated. The current ESC/EAS recommendation for high-risk patients is followed by 19.3% of the physicians. The majority (80.7%) reported an LDL-C target failure rate of at least 30%. More than two thirds (71.6%) have stated treating less than half of their patients with the maximum approved statin dose. The survey included 1696 secondary prevention patients. The majority (86.7%) consult their general practitioner for hypercholesterolemia; 54.0% consult a cardiologist (multiple answers allowed). Most patients (87.0%) were receiving lipid-lowering medication. Among these, 800 (54.2%) reported improved LDL-C levels since diagnosis, 569 (38.6%) reported no improvement, and 106 (7.2%) had no information. Of the treated patients with (N' = 800) and without (N' = 569) improvement, 34.3% vs. 37.3% were on their initial drug and dose, 24.8% vs. 23.7% received multiple drug therapy, 48.9% vs. 48.9% reported a dose change, and 16.1% vs. 14.2% had discontinued at least one drug (multiple answers). Disease knowledge was rated as good or very good by 29.8% of patients. CONCLUSION: PROCYON demonstrated insufficient ESC/EAS guideline implementation regarding target levels and therapeutic escalation strategies. Furthermore, a lack of specialist involvement and patient education was identified.

Phytosterols and Cardiovascular Risk Evaluated against the Background of Phytosterolemia Cases-A German Expert Panel Statement.

Phytosterols (PSs) have been proposed as dietary means to lower plasma LDL-C. However, concerns are raised that PSs may exert atherogenic effects, which would offset this benefit. Phytosterolemia was thought to mimic increased plasma PSs observed after the consumption of PS-enriched foods. This expert statement examines the possibility of specific atherogenicity of PSs based on sterol metabolism, experimental, animal, and human data. Observational studies show no evidence that plasma PS concentrations would be associated with an increased risk of atherosclerosis or cardiovascular (CV) events. Since variants of the ABCG5/8 transporter affect the absorption of cholesterol and non-cholesterol sterols, Mendelian randomization studies examining the effects of ABCG5/8 polymorphisms cannot support or refute the potential atherogenic effects of PSs due to pleiotropy. In homozygous patients with phytosterolemia, total PS concentrations are ~4000% higher than under physiological conditions. The prevalence of atherosclerosis in these individuals is variable and may mainly relate to concomitant elevated LDL-C. Consuming PS-enriched foods increases PS concentrations by ~35%. Hence, PSs, on a molar basis, would need to have 20-40 times higher atherogenicity than cholesterol to offset their cholesterol reduction benefit. Based on their LDL-C lowering and absence of adverse safety signals, PSs offer a dietary approach to cholesterol management. However, their clinical benefits have not been established in long-term CV endpoint studies.

Intensive lipid-lowering therapy for early achievement of guideline-recommended LDL-cholesterol levels in patients with ST-elevation myocardial infarction ("Jena auf Ziel").

BACKGROUND AND AIMS: Currently, less than 20% of patients at very high-risk achieve ESC/EAS dyslipidemia guideline-recommended LDL-C target levels in Europe. "Jena auf Ziel-JaZ" is a prospective cohort study in which early combination therapy with atorvastatin 80 mg and ezetimibe 10 mg was initiated on admission in patients with ST-elevation myocardial infarction (STEMI) and lipid-lowering therapy was escalated during follow-up with bempedoic acid and PCSK9 inhibitors to achieve recommended LDL-C targets in all patients. Moreover, we evaluated side-effects of lipid-lowering therapy. METHODS: Patients admitted with STEMI at Jena University Hospital were started on atorvastatin 80 mg and ezetimibe 10 mg on admission. Patients were followed for EAS/ESC LDL-C target achievement during follow-up. RESULTS: A total of 85 consecutive patients were enrolled in the study. On discharge, 32.9% achieved LDL-C targets on atorvastatin 80 mg and ezetimibe 10 mg. After 4-6 weeks, 80% of all patients on atorvastatin 80 mg and ezetimibe started at the index event were on ESC/EAS LDL-C targets. In 20%, combined lipid-lowering therapy was escalated with either bempedoic acid or PCSK9 inhibitors. All patients achieved LDL-C levels of or below 55 mg/dL during follow-up on triple lipid-lowering therapy. Combined lipid-lowering therapy was well-tolerated with rare side effects. CONCLUSIONS: Early combination therapy with a high-intensity statin and ezetimibe and escalation of lipid-lowering therapy with either bempedoic acid or PCSK9 inhibitors gets potentially all patients with STEMI on recommended ESC/EAS LDL-C targets without significant side effects.

High interindividual variability in LDL-cholesterol reductions after inclisiran administration in a real-world multicenter setting in Germany.

BACKGROUND AND AIMS: Low-density lipoprotein cholesterol (LDL-C) is the main therapeutic target in the treatment of hypercholesterolemia. Small interfering RNA (siRNA) inclisiran is a new drug, which targets PCSK9 mRNA in the liver, reducing concentrations of circulating LDL-C. In randomized trials, inclisiran demonstrated a substantial reduction in LDL-C. The German Inclisiran Network (GIN) aims to evaluate LDL-C reductions in a real-world cohort of patients treated with inclisiran in Germany. METHODS: Patients who received inclisiran in 14 lipid clinics in Germany for elevated LDL-C levels between February 2021 and July 2022 were included in this analysis. We described baseline characteristics, individual LDL-C changes (%) and side effects in 153 patients 3 months (n = 153) and 9 months (n = 79) after inclisiran administration. RESULTS: Since all patients were referred to specialized lipid clinics, only one-third were on statin therapy due to statin intolerance. The median LDL-C reduction was 35.5% at 3 months and 26.5% at 9 months. In patients previously treated with PCSK9 antibody (PCSK9-mAb), LDL-C reductions were less effective than in PCSK9-mAb-naïve patients (23.6% vs. 41.1% at 3 months). Concomitant statin treatment was associated with more effective LDL-C lowering. There was a high interindividual variability in LDL-C changes from baseline. Altogether, inclisiran was well-tolerated, and side effects were rare (5.9%). CONCLUSION: In this real-world patient population referred to German lipid clinics for elevated LDL-C levels, inclisiran demonstrated a high interindividual variability in LDL-C reductions. Further research is warranted to elucidate reasons for the interindividual variability in drug efficacy.

Dietary intake of plant sterols stably increases plant sterol levels in the murine brain.

Plant sterols such as sitosterol and campesterol are frequently administered as cholesterol-lowering supplements in food. Recently, it has been shown in mice that, in contrast to the structurally related cholesterol, circulating plant sterols can enter the brain. We questioned whether the accumulation of plant sterols in murine brain is reversible. After being fed a plant sterol ester-enriched diet for 6 weeks, C57BL/6NCrl mice displayed significantly increased concentrations of plant sterols in serum, liver, and brain by 2- to 3-fold. Blocking intestinal sterol uptake for the next 6 months while feeding the mice with a plant stanol ester-enriched diet resulted in strongly decreased plant sterol levels in serum and liver, without affecting brain plant sterol levels. Relative to plasma concentrations, brain levels of campesterol were higher than sitosterol, suggesting that campesterol traverses the blood-brain barrier more efficiently. In vitro experiments with brain endothelial cell cultures showed that campesterol crossed the blood-brain barrier more efficiently than sitosterol. We conclude that, over a 6-month period, plant sterol accumulation in murine brain is virtually irreversible.

[State of the Art: Statin Therapy]. / State of the Art: Therapie mit Statinen.

This review summarizes the pharmacology and clinical use of HMG-CoA reductase inhibitors, statins. LDL-Cholesterol lowering with statins reduces atherosclerotic cardiovascular risk by approx. one quater per year of treatment. The efficacy and safety of statins are demonstrated by randomized trials irrespective of the patient's age. The synthetic statins, rosuvastatin and atorvastatin, are superior with regard to LDL-C lowering, half-life and drug-interactions compared to the older statins such as simvastatin. Modern lipid lowering therapy uses individualized statin-based combination therapies.

[Therapeutic options to reduce LDL-cholesterol beyond statins]. / Therapieoptionen zur LDL-C-Senkung zusätzlich zu Statinen.

Current dyslipidemia guidelines emphasize statins as the cornerstone of pharmacological lipid-lowering therapy. The cholesterol absorption inhibitor ezetimibe, PCSK9-antibodies, as well as bempedoic acid and inclisiran are newly available options to further reduce LDL-cholesterol. Since modern lipid-lowering therapy is characterized by an individual, "treat-to-target" approach the aim of this review is to provide a better understanding of cholesterol metabolism to guide decision-making and the rational for using early individualized combination therapies.