Silencing Myeloid Netrin-1 Induces Inflammation Resolution and Plaque Regression

Rationale: Therapeutic efforts to decrease atherosclerotic cardiovascular disease risk have focused largely on reducing atherogenic lipoproteins, yet lipid lowering therapies alone are insufficient to fully regress plaque burden. We postulate that arterial repair requires resolution of a maladaptive immune response, and that targeting factors that hinder inflammation resolution will facilitate plaque regression. Objective: The guidance molecule netrin-1 is secreted by macrophages in atherosclerotic plaques, where it sustains inflammation by enhancing macrophage survival and blocking macrophage emigration. We tested whether silencing netrin-1 in advanced atherosclerosis could resolve arterial inflammation and regress plaques. Methods and Results: To temporally silence netrin-1 in myeloid cells, we generated genetically modified mice in which Ntn1 could be selectively deleted in monocytes and macrophages using a tamoxifen-induced CX3CR1-driven cre-recombinase ( Ntn1 fl/fl Cx3cr1 creERT2+ ) and littermate control mice ( Ntn1 fl/fl Cx3cr1 WT ). Mice were fed western diet in the setting of hepatic PCSK9 overexpression to render them atherosclerotic, and then treated with tamoxifen to initiate deletion of myeloid netrin-1 (Mø ΔNtn1 ) or not in controls (Mø WT ). Morphometric analyses performed 4 weeks later showed that myeloid Ntn1 silencing reduced plaque burden in the aorta (-50%) and plaque complexity in the aortic root. Monocyte-macrophage tracing experiments revealed lower monocyte recruitment, macrophage retention, and proliferation in Mø ΔNtn1 compared to Mø WT plaques, indicating a restructuring of monocyte-macrophage dynamics in the artery wall upon netrin-1 silencing. Single cell RNA-sequencing of aortic immune cells prior to and after netrin-1 silencing revealed upregulation of gene pathways involved in macrophage phagocytosis and migration, including the Ccr7 chemokine receptor signaling pathway required for macrophage emigration from plaques and atherosclerosis regression. Additionally, plaques from Mø ΔNtn1 mice showed hallmarks of inflammation resolution, including higher levels of pro-resolving macrophages, interleukin-10, and efferocytosis, as compared to plaques from Mø WT mice. Conclusions: Our data show that targeting netrin-1 in advanced atherosclerosis ameliorates atherosclerotic inflammation and promotes plaque regression.

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Assessing Atherosclerotic Cardiovascular Disease Risk with Advanced Lipid Testing: State of the Science

European Cardiology Review ◽

10.15420/ecr.2019.18 ◽

2020 ◽

Vol 15 ◽

Author(s):

Charles Amir German ◽

Michael David Shapiro

Keyword(s):

Cardiovascular Disease ◽

Clinical Medicine ◽

Plasma Lipids ◽

Disease Risk ◽

Cardiovascular Disease Risk ◽

Lipid Lowering ◽

Atherosclerotic Cardiovascular Disease ◽

Lipid Lowering Therapy ◽

Obesity And Diabetes ◽

Lipid Panel

Cardiovascular disease is the number one cause of death and disability worldwide. While substantial gains have been made in reducing cardiovascular mortality, future projections suggest that we have reached a nadir and may be at an inflection point, given the rising tide of obesity and diabetes. Evaluation and management of plasma lipids is central to the prevention of atherosclerotic cardiovascular disease. Although the standard lipid panel represents a well-established platform to assess risk, this test alone can be insufficient and/or misleading. Advances in our understanding of atherosclerosis have led to the development of lipid-based biomarkers that help to discriminate the risk of cardiovascular disease when it is unclear. While these biomarkers provide novel information, their implementation into clinical medicine remains difficult given discrepancies in the literature, lack of assay standardisation, poor accessibility and high cost. However, additional measures of atherogenic lipoproteins or their surrogates may offer insight beyond the standard lipid panel, providing a more precise assessment of risk and more accurate assessment of lipid-lowering therapy.

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Non-statin lipid-lowering therapy over time in very-high-risk patients: effectiveness of fixed-dose statin/ezetimibe compared to separate pill combination on LDL-C

Clinical Research in Cardiology ◽

10.1007/s00392-020-01740-8 ◽

2020 ◽

Author(s):

Julius L. Katzmann ◽

Francesc Sorio-Vilela ◽

Eugen Dornstauder ◽

Uwe Fraas ◽

Timo Smieszek ◽

...

Keyword(s):

Disease Risk ◽

Cardiovascular Disease Risk ◽

Lipid Lowering ◽

Fixed Dose ◽

Atherosclerotic Cardiovascular Disease ◽

Lipid Lowering Therapy ◽

High Potency ◽

Atherosclerotic Cardiovascular Disease Risk ◽

Very High ◽

Over Time

Abstract Background Many patients at very-high atherosclerotic cardiovascular disease risk do not reach guideline-recommended targets for LDL-C. There is a lack of data on real-world use of non-statin lipid-lowering therapies (LLT) and little is known on the effectiveness of fixed-dose combinations (FDC). We therefore studied prescription trends in oral non-statin LLT and their effects on LDL-C. Methods A retrospective analysis was conducted of electronic medical records of outpatients at very-high cardiovascular risk treated by general practitioners (GPs) and cardiologists, and prescribed LLT in Germany between 2013 and 2018. Results Data from 311,242 patients were analysed. Prescriptions for high-potency statins (atorvastatin and rosuvastatin) increased from 10.4% and 25.8% of patients treated by GPs and cardiologists, respectively, in 2013, to 34.7% and 58.3% in 2018. Prescription for non-statin LLT remained stable throughout the period and low especially for GPs. Ezetimibe was the most prescribed non-statin LLT in 2018 (GPs, 76.1%; cardiologists, 92.8%). Addition of ezetimibe in patients already prescribed a statin reduced LDL-C by an additional 23.8% (32.3 ± 38.4 mg/dL), with a greater reduction with FDC [reduction 28.4% (40.0 ± 39.1 mg/dL)] as compared to separate pills [19.4% (27.5 ± 33.8 mg/dL)]; p < 0.0001. However, only a small proportion of patients reached the recommended LDL-C level of < 70 mg/dL (31.5% with FDC and 21.0% with separate pills). Conclusions Prescription for high-potency statins increased over time. Non-statin LLT were infrequently prescribed by GPs. The reduction in LDL-C when statin and ezetimibe were prescribed in combination was considerably larger for FDC; however, a large proportion of patients still remained with uncontrolled LDL-C levels. Graphic abstract

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The Expected 30-Year Benefits of Early Versus Delayed Primary Prevention of Cardiovascular Disease by Lipid Lowering

Circulation ◽

10.1161/circulationaha.120.045851 ◽

2020 ◽

Vol 142 (9) ◽

pp. 827-837 ◽

Cited By ~ 4

Author(s):

Michael J. Pencina ◽

Karol M. Pencina ◽

Donald Lloyd-Jones ◽

Alberico L. Catapano ◽

George Thanassoulis ◽

...

Keyword(s):

Cardiovascular Disease ◽

Disease Risk ◽

Cardiovascular Disease Risk ◽

Substantial Reduction ◽

Older Age ◽

Lipid Lowering ◽

Treatment Recommendation ◽

Atherosclerotic Cardiovascular Disease ◽

Old Patients ◽

Atherosclerotic Cardiovascular Disease Risk

Background: Lipid-lowering recommendations for prevention of atherosclerotic cardiovascular disease rely principally on estimated 10-year risk. We sought to determine the optimal time for initiation of lipid lowering in younger adults as a function of expected 30-year benefit. Methods: Data from 3148 National Health and Nutrition Examination Survey (2009–2016) participants, age 30 to 59 years, not eligible for lipid-lowering treatment recommendation under the most recent US guidelines, were analyzed. We estimated the absolute and relative impact of lipid lowering as a function of age, age at initiation, and non–high-density lipoprotein cholesterol (HDL-C) level on the expected rates of atherosclerotic cardiovascular disease over the succeeding 30 years. We modeled expected risk reductions based on shorter-term effects observed in statin trials (model A) and longer-term benefits based on Mendelian randomization studies (model B). Results: In both models, potential reductions in predicted 30-year atherosclerotic cardiovascular disease risk were greater with older age and higher non–HDL-C level. Immediate initiation of lipid lowering (ie, treatment for 30 years) in 40- to 49-year-old patients with non–HDL-C ≥160 mg/dL would be expected to reduce their average predicted 30-year risk of 17.1% to 11.6% (model A; absolute risk reduction [ARR], 5.5%) or 6.5% (model B; ARR 10.6%). Delaying lipid lowering by 10 years (treatment for 20 years) would result in residual 30-year risk of 12.7% (A; ARR 4.4) or 9.9% (B; ARR 7.2%) and delaying by 20 years (treatment for 10 years) would lead to expected mean residual risk of 14.6% (A; ARR 2.6%) or 13.9% (B; ARR 3.2%). The slope of the achieved ARR as a function of delay in treatment was also higher with older age and higher non–HDL-C level. Conclusions: Substantial reduction in expected atherosclerotic cardiovascular disease risk in the next 30 years is achievable by intensive lipid lowering in individuals in their 40s and 50s with non–HDL-C ≥160 mg/dL. For many, the question of when to start lipid lowering might be more relevant than whether to start lipid lowering.

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Personalized Statin Therapy and Coronary Atherosclerotic Plaque Burden in Asymptomatic Low/Intermediate-Risk Individuals

Cardiorenal Medicine ◽

10.1159/000487205 ◽

2018 ◽

Vol 8 (2) ◽

pp. 140-150 ◽

Cited By ~ 1

Author(s):

Ranganath Muniyappa ◽

Radwa A. Noureldin ◽

Khaled Z. Abd-Elmoniem ◽

Riham H. El Khouli ◽

Jatin Raj Matta ◽

...

Keyword(s):

Cardiovascular Disease ◽

Statin Therapy ◽

Risk Reduction ◽

Disease Risk ◽

Cardiovascular Disease Risk ◽

Coronary Plaque ◽

Plaque Burden ◽

Number Needed To Treat ◽

Atherosclerotic Cardiovascular Disease ◽

Asymptomatic Individuals

Background: Current guidelines for the primary prevention of atherosclerotic cardiovascular disease are based on the estimation of a predicted 10-year cardiovascular disease risk and the average relative risk reduction estimates from statin trials. In the clinical setting, however, decision-making is better informed by the expected benefit for the individual patient, which is typically lacking. Consequently, a personalized statin benefit approach based on absolute risk reduction over 10 years (ARR10 benefit threshold ≥2.3%) has been proposed as a novel approach. However, how this benefit threshold relates with coronary plaque burden in asymptomatic individuals with low/intermediate cardiovascular disease risk is unknown. Aims: In this study, we compared the predicted ARR10 obtained in each individual with plaque burden detected by coronary computed tomography angiography. Methods and Results: Plaque burden (segment volume score, segment stenosis score, and segment involvement score) was assessed in prospectively recruited asymptomatic subjects (n = 70; 52% male; median age 56 years [interquartile range 51–64 years]) with low/intermediate Framingham risk score (< 20%). The expected ARR10 with statin in the entire cohort was 2.7% (1.5–4.6%) with a corresponding number needed to treat over 10 years of 36 (22–63). In subjects with an ARR10 benefit threshold ≥2.3% (vs. < 2.3%), plaque burden was significantly higher (p = 0.02). Conclusion: These findings suggest that individuals with higher coronary plaque burden are more likely to get greater benefit from statin therapy even among asymptomatic individuals with low cardiovascular risk.

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