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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.

In 2003, clinical observations led to the discovery of the involvement of proprotein convertase subtilisin/kexin type 9 (PCSK9) in lipid metabolism. Functional studies demonstrated that PCSK9 binds to the low-density lipoprotein (LDL) receptor directing it to its lysosomal degradation. Therefore, carriers of gain-of-function mutations in PCSK9 exhibit decreased expression of LDL receptors on the hepatocyte surface and have higher LDL cholesterol (LDL-C) levels. On the contrary, loss-of-function mutations in PCSK9 are associated with low LDL-C concentrations and significantly reduced lifetime risk of cardiovascular disease. These insights motivated the search for strategies to pharmacologically inhibit PCSK9. In an exemplary rapid development, fully human monoclonal antibodies against PCSK9 were developed and found to effectively reduce LDL-C. Administered subcutaneously every 2-4 weeks, the PCSK9 antibodies evolocumab and alirocumab reduce LDL-C by up to 60% in a broad range of populations either as monotherapy or in addition to statins. Two large cardiovascular outcome trials involving a total of similar to 46,000 cardiovascular high-risk patients on guideline-recommended lipid-lowering therapy showed that treatment with evolocumab and alirocumab led to a relative reduction of cardiovascular risk by 15% after 2.2 and 2.8 years of treatment, respectively. These findings expanded the armamentarium of pharmacological approaches to address residual cardiovascular risk associated with LDL-C. Furthermore, the unprecedented low LDL-C concentrations achieved (e.g., 30 mg/dL in the FOURIER study) suggest that the relationship between LDL-C and cardiovascular risk is without a lower threshold, and without associated adverse events during the timeframe of the studies. The side effect profile of PCSK9 antibodies is favorable with few patients exhibiting injection-site reactions. Currently, the access to PCSK9 antibodies is limited by high treatment costs. The development of no

Julius L Katzmann,1 Felix Mahfoud,2 Michael Böhm,2 Martin Schulz,3,4 Ulrich Laufs1 1Department of Cardiology, Universitätsklinikum Leipzig, Leipzig, Germany; 2Medical Clinic III, Cardiology, Angiology, Intensive Care, Universitätsklinikum des Saarlandes, Homburg, Germany; 3Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universität Berlin, Berlin, Germany; 4Department of Medicine, ABDA – Federal Union of German Associations of Pharmacists, Berlin, Germany Background: Many patients at high cardiovascular risk do not reach targets for low-density lipoprotein cholesterol (LDL-C) and blood pressure (BP). Depression is a frequent comorbidity in these patients and contributes to poor medication adherence.Objective: The aim of this study was to elucidate the associations between adherence to lipid- and BP-lowering drugs, the diagnosis of depression, and the control of LDL-C and BP.Patients and methods: This study was conducted as multicenter, single-visit cross-sectional study in Germany. Adherence was assessed by the Morisky Medication Adherence Scale-8 (MMAS-8), and depression was assessed as documented in the patient chart.Results: A total of 3,188 ambulatory patients with hypercholesterolemia (39.8%), stable coronary artery disease (CAD; 7.4%), or both (52.9%) were included. Patients had a history of myocardial infarction (30.8%), diabetes (42.0%), were smokers (19.7%), and 16.1% had the investigator-reported diagnosis of depression. High or moderate adherence to lipid-lowering medication compared to low adherence was associated with lower LDL-C levels (105.5±38.3 vs 120.8±42.4 mg/dL) and lower BP (systolic BP 133.4±14.5 vs 137.9±13.9 mmHg, diastolic BP 78.3±9.6 vs 81.8±9.6 mmHg) and with a higher proportion of patients achieving the guideline-recommended LDL-C (16.9% vs 10.1%) and BP target (52.2% vs 40.8%, all comparisons P&am