New Approaches for Targeting PCSK9: Small-Interfering Ribonucleic Acid and Genome Editing.

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.

Angiopoietin-like 3 inhibition and the liver: less is more?

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.

Atorvastatin lowers 68Ga-DOTATATE uptake in coronary arteries, bone marrow and spleen in individuals with type 2 diabetes.

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, HbA1c 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.

Molecular Imaging of Aortic Valve Stenosis with Positron Emission Tomography.

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.