Abstract Reverse cholesterol transport, although not well understood, is an important mechanism in the pathophysiology of atherosclerosis. Macrophages can eliminate some cholesterol from ...atherosclerotic lesions by an oxidative mechanism involving sterol 27-hydroxylase. Patients with inherited “cerebrotendinous xanthomatosis” lack sterol 27-hydroxylase (CYP27A1) and develop severe premature atherosclerosis despite normal serum cholesterol concentrations. Thus, it has been speculated that sterol 27-hydroxylase is an anti-atherosclerotic enzyme. Here, we report the case of a 25-year-old patient who presented to our emergency room with an acute non-ST elevation myocardial infarction due to severe coronary heart disease. Lipid analysis revealed dramatically increased 27-hydroxycholesterol and low high-density lipoprotein (HDL)-cholesterol levels. Previous reports suggest that 27-hydroxylase is upregulated to protect peripheral cells from severe cholesterol accumulation, especially in cases of ineffective reverse cholesterol transport due to low HDL-cholesterol levels. Our findings indicate that oxysterols could play an important and so far underestimated role in reverse cholesterol transport.
Advances in genomics, understanding of the effects of cumulative exposure and various environmental risk factors have moved us closer to better models of care focused at early risk assessment and ...treatment to prevent cardiovascular (CV) disease. We review relevant contributions in 2019 to the field of CV disease prevention, with a focus on epidemiology, lipids, diabetes, and hypertension.
The last decades of research in cardiovascular prevention have been characterized by successful bench-to-bedside developments for the treatment of low-density lipoprotein (LDL) hypercholesterolemia. ...Recent examples include the inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) with monoclonal antibodies, small interfering RNA and antisense RNA drugs. The cumulative effects of LDL cholesterol on atherosclerosis make early, potent, and long-term reductions in LDL cholesterol desirable—ideally without the need of regular intake or application of medication and importantly, without side effects. Current reports show durable LDL cholesterol reductions in primates following one single treatment with PCSK9 gene or base editors. Use of the CRISPR/Cas system enables precise genome editing down to single-nucleotide changes. Provided safety and documentation of a reduction in cardiovascular events, this novel technique has the potential to fundamentally change our current concepts of cardiovascular prevention. In this review, the application of the CRISPR/Cas system is explained and the current state of in vivo approaches of PCSK9 editing is presented.
Decreasing low-density lipoprotein cholesterol (LDL-C) is one of the few established and proven principles for the prevention and treatment of atherosclerosis. The higher the individual ...cardiovascular risk, the higher the benefit of lipid-lowering pharmacotherapy. Therefore, treatment options are chosen based on a patient's total cardiovascular risk. The latter depends not only on the levels of LDL-C but also on the presence of cardiovascular disease (CVD) and on the number and severity of other risk factors. Current guidelines recommend the lowering of LDL-C to 115 mg/dl (3 mmol/l) in patients with low and moderate risk. The LDL-C treatment target is <100 mg/dl (2.6 mmol/l) for patients at high risk and <70 mg/dl (1.8 mmol/l) for patients at very high risk. Although lifestyle measures remain a fundamental part of treatment, many patients require drug therapy to achieve their LDL-C targets. Statins are the drugs of choice, with other options including ezetimibe and the newly available monoclonal antibodies against PCSK9 (proprotein convertase subtilisin/kexin type 9). In some cases, bile acid-binding sequestrants and fibrates can also be considered. Nicotinic acid is no longer available in Germany. PCSK9 antibodies decrease LDL-C about 50-60 % and are well tolerated. Their effects on clinical endpoints are being investigated in large randomized trials. The aim of the present review is to summarize the current guidelines and treatment options for hypercholesterolemia. Moreover, we provide an appraisal of PCSK9 antibodies and propose their use in selected patient populations, particularly in those at very high cardiovascular risk whose LDL-C levels under maximally tolerated lipid-lowering therapy are significantly over their treatment target.
Background: European data pre-2019 suggest statin monotherapy is the most common approach to lipid management for preventing cardiovascular (CV) events, resulting in only one-fifth of high- and very ...high-risk patients achieving the 2019 ESC/EAS recommended low-density lipoprotein cholesterol (LDL-C) goals. Whether the treatment landscape has evolved, or gaps persist remains of interest. Methods: Baseline data are presented from SANTORINI, an observational, prospective study that documents the use of lipid-lowering therapies (LLTs) in patients ≥18 years at high or very high CV risk between 2020 and 2021 across primary and secondary care settings in 14 European countries. Findings: Of 9602 enrolled patients, 9044 with complete data were included (mean age: 65.3 ± 10.9 years; 72.6% male). Physicians reported using 2019 ESC/EAS guidelines as a basis for CV risk classification in 52.0% (4706/9044) of patients (overall: high risk 29.2%; very high risk 70.8%). However, centrally re-assessed CV risk based on 2019 ESC/EAS guidelines suggested 6.5% (308/4706) and 91.0% (4284/4706) were high- and very high-risk patients, respectively. Overall, 21.8% of patients had no documented LLTs, 54.2% were receiving monotherapy and 24.0% combination LLT. Median (interquartile range IQR) LDL-C was 2.1 (1.6, 3.0) mmol/L (82 60, 117 mg/dL), with 20.1% of patients achieving risk-based LDL-C goals as per the 2019 ESC/EAS guidelines. Interpretation: At the time of study enrolment, 80% of high- and very high-risk patients failed to achieve 2019 ESC/EAS guidelines LDL-C goals. Contributory factors may include CV risk underestimation and underutilization of combination therapies. Further efforts are needed to achieve current guideline-recommended LDL-C goals. Trial registration: ClinicalTrials.gov Identifier: NCT04271280. Funding: This study is funded by Daiichi Sankyo Europe GmbH, Munich, Germany.
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