There is overwhelming clinical and genetic evidence supporting the concept that low-density-lipoprotein cholesterol should be as low as possible for as long as possible in patients at very high cardiovascular risk. Despite the wide availability of effective lipid-lowering therapies, the majority of patients still fail to reach guideline-based lipid goals. Advances in novel approaches targeting PCSK9 (proprotein convertase subtilisin/kexin type 9) through small-interfering RNA and genome editing hold the potential to bridge this gap, by offering long-acting alternatives, which may overcome adherence and other challenges in the current chronic care model. In this review, we discuss the history of targeting PCSK9 with the use of mRNA and small-interfering ribonucleic acid. We also shed light on targeting PCSK9 with genome editing, including discussion of the VERVE-101 clustered regularly interspaced short palindromic repeats-base editing medicine currently being evaluated in a clinical trial and others in development.

Inflammation is an important driver of disease in the context of atherosclerosis, and several landmark trials have shown that targeting inflammatory pathways can reduce cardiovascular event rates. However, the high cost and potentially serious adverse effects of anti-inflammatory therapies necessitate more precise patient selection. Traditional biomarkers of inflammation, such as high-sensitivity C-reactive protein, show an association with cardiovascular risk on a population level but do not have specificity for local plaque inflammation. Nowadays, advancements in non-invasive imaging of the vasculature enable direct assessment of vascular inflammation. Positron emission tomography (PET) tracers such as 18F-fluorodeoxyglucose enable detection of metabolic activity of inflammatory cells but are limited by low specificity and myocardial spillover effects. 18F-sodium fluoride is a tracer that identifies active micro-calcification in plaques, indicating vulnerable plaques. Gallium-68 DOTATATE targets pro-inflammatory macrophages by binding to somatostatin receptors, which enhances specificity for plaque inflammation. Coronary computed tomography angiography (CCTA) provides high-resolution images of coronary arteries, identifying high-risk plaque features. Measuring pericoronary adipose tissue attenuation on CCTA represents a novel marker of vascular inflammation. This review examines both established and emerging methods for assessing atherosclerosis-related inflammation, emphasizing the role of advanced imaging in refining risk stratification and guiding personalized therapies. Integrating these imaging modalities with measurements of systemic and molecular biomarkers could shift atherosclerotic cardiovascular disease management towards a more personalized approach.

Aims/hypothesis: Inflammation is a core component of residual cardiovascular risk in type 2 diabetes. With new anti-inflammatory therapeutics entering the field, accurate markers to evaluate their effectiveness in reducing cardiovascular disease are paramount. Gallium-68-labelled DOTATATE (⁶⁸Ga-DOTATATE) has recently been proposed as a more specific marker of arterial wall inflammation than ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG). This study set out to investigate whether ⁶⁸Ga-DOTATATE uptake is amenable to therapeutic intervention in individuals with type 2 diabetes. Methods: Individuals aged >50 years with type 2 diabetes underwent ⁶⁸Ga-DOTATATE positron emission tomography (PET)/computed tomography (CT) at baseline and after 3 months treatment with atorvastatin 40 mg once daily. Primary outcome was the difference in coronary ⁶⁸Ga-DOTATATE uptake, expressed as target-to-background ratio (TBR). The secondary outcome was difference in bone marrow and splenic uptake, expressed as the standardised uptake value (SUV). Results: Twenty-two individuals with type 2 diabetes (mean age 63.2±6.4 years, 82% male, LDL-cholesterol 3.42±0.81 mmol/l, HbA_1c 55±12 mmol/mol [7.2%±3.2%]) completed both ⁶⁸Ga-DOTATATE PET/CT scans. The maximum TBR was −31% (95% CI −50, −12) lower in the coronary arteries, and bone marrow and splenic ⁶⁸Ga-DOTATATE uptake was also significantly lower post statin treatment, with a mean percentage reduction of −15% (95% CI −27, −4) and −17% (95% CI −32, −2), respectively. Conclusions/interpretation: ⁶⁸Ga-DOTATATE uptake across the cardio–haematopoietic axis was lower after statin therapy in individuals with type 2 diabetes. Therefore, ⁶⁸Ga-DOTATATE is promising as a metric for vascular and haematopoietic inflammation in intervention studies using anti-inflammatory therapeutics in individuals with type 2 diabetes. Trial registration: ClinicalTrials.gov NCT05730634 Graphical

Purpose of review: The aim of this study was to discuss the potential mechanisms and implications of the opposing liver safety results from recent angiopoietin-like 3 (ANGPTL3) inhibition studies. Recent findings: The clinical development of vupanorsen, a N-acetylgalactosamine (GalNAc) antisense targeting hepatic ANGPTL3, was recently discontinued due to a significant signal of liver transaminase increase. Vupanorsen elicited a dose-dependent increase in hepatic fat fraction up to 75%, whereas the small interfering RNA (siRNA) ARO-ANG3, has reported preliminary evidence of a dose-dependent decrease in hepatic fat fraction up to 30%. Summary: ANGPTL3 inhibition is an attractive therapeutic target to reduce all apoB-containing lipoproteins. The discrepancy in liver signal results between the antisense and siRNA approach may be explained by the level of target inhibition. An alternative explanation may relate to off-target effects of vupanorsen, which have a molecule- and/or platform-specific origin. For intrahepatic strategies, highly potent ANGPTL3 inhibition will for now require special attention for liver safety.

Background: The trans intestinal cholesterol excretion (TICE) pathway is a potential therapeutic target to reduce plasma low‐density lipoprotein (LDL) cholesterol levels. TICE encompasses the direct excretion of cholesterol by enterocytes into feces. In mice, TICE has been shown to be stimulated by a hydrophilic bile acid pool, resulting in increased fecal neutral sterol loss and reduced plasma cholesterol levels. We investigated whether treatment with a hydrophilic bile acid, ursodeoxycholic acid (UDCA), would increase fecal neutral sterols in humans as a proxy for TICE. Methods and Results: We performed a randomized, double‐blind, placebo‐controlled, cross‐over trial in 20 male participants aged >18 years, with plasma LDL cholesterol levels ≥2.6 mmol/L. After a run‐in period of ezetimibe 20 mg once daily for 3 weeks, patients were randomized to UDCA 600 mg or placebo orally once daily for 2 weeks. After a 3 week washout, patients underwent the alternate treatment. At baseline, mean (SD) age, body mass index, and plasma LDL cholesterol were 59±11.3 years, 26.4±3.1 kg/m ² , and 3.9±0.8 mmol/L, respectively. After UDCA treatment, the plasma bile acid hydrophobicity index was reduced compared with placebo (−118.7% versus +2.3%, P <0.001). The fecal neutral sterols did not change (−5.8% versus +18.8%, P =0.51) and treatment with UDCA increased LDL cholesterol with 0.39 mmol/L (+8.1% versus −3.64%, P =0.002) when compared with placebo. Conclusions: UDCA in combination with ezetimibe increased plasma bile acid hydrophilicity in healthy subjects with LDL cholesterol levels >2.6 mmol/L but did not result in increased fecal neutral sterols or decreased LDL cholesterol. This suggests that TICE is not stimulated by an increase in the hydrophilicity of the bile acid pool in humans.

Aortic valve stenosis (AVS) is an increasingly prevalent disease in our aging population. Although multiple risk factors for AVS have been elucidated, medical therapies capable of slowing down disease progression remain unavailable. Molecular imaging technologies are opening up avenues for the non-invasive assessment of disease progression, allowing the assessment of (early) medical interventions. This review will focus on the role of positron emission tomography of the aortic valve with ¹⁸F-fluorodeoxyglucose and ¹⁸F-sodium fluoride but will also shed light on novel tracers which have potential in AVS, ranging from the healthy aortic valve to end-stage valvular disease.