Pharmacological rationale for the very early treatment of acute coronary syndrome with monoclonal antibodies anti-PCSK9

Ferri, Nicola; Ruscica, Massimiliano; Lupo, Maria Giovanna; Vicenzi, Marco; Sirtori, Cesare R.; Corsini, Alberto

doi:10.1016/j.phrs.2022.106439

Cited by 18 publications

(10 citation statements)

References 93 publications

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“…Both evolocumab and alirocumab suppress circulating PCSK9 (97% of the time) within 1 day of injection, indicating a very rapid initiation of effect. At least four confirmed findings in ACS reinforce the rationale for exploring the aggressive and quick pharmacological intervention with PCSK9i: 12 (i) PCSK9 levels in circulation are elevated during ACS; (ii) PCSK9 is related with intra-plaque inflammation, macrophage activation, and endothelial dysfunction; (iii) PCSK9 concentrations relate to inflammation in the acute phase of ACS; (iv) statins boost PCSK9 levels rapidly and, at times, substantially.…”

Section: Early Initiation Of Pcsk9i In Acsmentioning

confidence: 65%

The PACMAN-AMI trial: a revolution in the treatment of acute coronary syndromes

Luca

Halász

2023

European Heart Journal Supplements

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After an acute coronary syndrome (ACS), the risk of major adverse cardiovascular events (MACE) persists despite the reperfusion of the culprit lesion. The addition of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) to standard lipid-lowering therapies has been demonstrated to effectively reduce the levels of low-density lipoprotein cholesterol (LDL-C), with a consistent decrease of MACE in large, randomized clinical trials enrolling patients at high risk of cardiovascular events. There is a strong rationale for an immediate and aggressive LDL-C lowering with the use of PCSK9i in ACS patients. The PACMAN-AMI trial tested this hypothesis demonstrating that in ACS patients, the addition of subcutaneous biweekly alirocumab, compared with placebo, to high-intensity statin therapy resulted in significantly greater coronary plaque regression in non-infarct-related arteries after 52 weeks, as assessed by novel intra-coronary imaging modalities. These findings might provide the mechanistic rationale in favour of early initiation of very intensive LDL-C-lowering therapy in the acute setting of ACS, potentially modifying the actual common pattern of treatment.

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Section: Early Initiation Of Pcsk9i In Acsmentioning

confidence: 65%

The PACMAN-AMI trial: a revolution in the treatment of acute coronary syndromes

Luca

Halász

2023

European Heart Journal Supplements

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“…Another important open question in the field of cardiovascular diseases remains the utility of reducing PCSK9 levels soon after an acute coronary syndrome event [ 60 ]. To answer this question, the aim of the VICTORION-INCEPTION study (NCT04873934) is to evaluate the effectiveness of implementation of a systematic LDL-C management pathway including treatment with inclisiran in participants who have experienced a recent acute coronary syndrome and have an increased LDL-C (≥70 mg/dL) despite being treated with a statin [ 61 ].…”

Section: Inclisiran To Lower Pcsk9mentioning

confidence: 99%

Updates in Small Interfering RNA for the Treatment of Dyslipidemias

Carugo,

Sirtori,

Gelpi

et al. 2023

Curr Atheroscler Rep

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Purpose of Review Atherosclerotic cardiovascular disease (ASCVD) is still the leading cause of death worldwide. Despite excellent pharmacological approaches, clinical registries consistently show that many people with dyslipidemia do not achieve optimal management, and many of them are treated with low-intensity lipid-lowering therapies. Beyond the well-known association between low-density lipoprotein cholesterol (LDL-C) and cardiovascular prevention, the atherogenicity of lipoprotein(a) and the impact of triglyceride (TG)-rich lipoproteins cannot be overlooked. Within this landscape, the use of RNA-based therapies can help the treatment of difficult to target lipid disorders. Recent Findings The safety and efficacy of LDL-C lowering with the siRNA inclisiran has been documented in the open-label ORION-3 trial, with a follow-up of 4 years. While the outcome trial is pending, a pooled analysis of ORION-9, ORION-10, and ORION-11 has shown the potential of inclisiran to reduce composite major adverse cardiovascular events. Concerning lipoprotein(a), data of OCEAN(a)-DOSE trial with olpasiran show a dose-dependent drop in lipoprotein(a) levels with an optimal pharmacodynamic profile when administered every 12 weeks. Concerning TG lowering, although ARO-APOC3 and ARO-ANG3 are effective to lower apolipoprotein(apo)C-III and angiopoietin-like 3 (ANGPTL3) levels, these drugs are still in their infancy. Summary In the era moving toward a personalized risk management, the use of siRNA represents a blossoming armamentarium to tackle dyslipidaemias for ASCVD risk reduction.

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“…Human macrophages do not express PCSK9, but upon PCSK9 uptake, they increase ROS production, reduce cholesterol efflux, and enhance toll‐like receptor 4‐mediated pro‐inflammatory cytokine production (Jaén et al, 2022). PCSK9 is pleiotropic in vascular degeneration pathogenesis, affecting macrophage activation, endothelial dysfunction, platelet reactivity, and intraplaque inflammation (Ferri et al, 2022). Monoclonal PCSK9 antibodies, including evolocumab and alirocumab, are currently under investigation in treating acute coronary syndromes (Ferri et al, 2022), and demonstrate promising therapeutic potential in handling cholesterol and its downstream impacts in cardiovascular events.…”

Section: Potential Future Therapies Based On Cholesterol Transportmentioning

confidence: 99%

Membrane contact sites orchestrate cholesterol homeostasis that is central to vascular aging

Pang

Jin

et al. 2023

WIREs Mechanisms of Disease

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Chronological age causes structural and functional vascular deterioration and is a well‐established risk factor for the development of cardiovascular diseases, leading to more than 40% of all deaths in the elderly. The etiology of vascular aging is complex; a significant impact arises from impaired cholesterol homeostasis. Cholesterol level is balanced through synthesis, uptake, transport, and esterification, the processes executed by multiple organelles. Moreover, organelles responsible for cholesterol homeostasis are spatially and functionally coordinated instead of isolated by forming the membrane contact sites. Membrane contact, mediated by specific protein–protein interaction, pulls opposing organelles together and creates the hybrid place for cholesterol transfer and further signaling. The membrane contact‐dependent cholesterol transfer, together with the vesicular transport, maintains cholesterol homeostasis and has intimate implications in a growing list of diseases, including vascular aging‐related diseases. Here, we summarized the latest advances regarding cholesterol homeostasis by highlighting the membrane contact‐based regulatory mechanism. We also describe the downstream signaling under cholesterol homeostasis perturbations, prominently in cholesterol‐rich conditions, stimulating age‐dependent organelle dysfunction and vascular aging. Finally, we discuss potential cholesterol‐targeting strategies for therapists regarding vascular aging‐related diseases.This article is categorized under: Cardiovascular Diseases > Molecular and Cellular Physiology

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Pharmacological rationale for the very early treatment of acute coronary syndrome with monoclonal antibodies anti-PCSK9

Cited by 18 publications

References 93 publications

The PACMAN-AMI trial: a revolution in the treatment of acute coronary syndromes

The PACMAN-AMI trial: a revolution in the treatment of acute coronary syndromes

Updates in Small Interfering RNA for the Treatment of Dyslipidemias

Membrane contact sites orchestrate cholesterol homeostasis that is central to vascular aging

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