Atherosclerosis: More Challenging and Complex Than We Thought.

Globally, atherosclerotic cardiovascular disease (ASCVD) accounts for more disability and deaths than any other human condition.1World Health Organization. WHO reveals leading causes of death and disability worldwide: 2000-2019. https://www.who.int/news/item/09-12-2020-who-reveals-leading-causes-of-death-and-disability-worldwide-2000-2019. Accessed September 2023.Google Scholar We now recognize that atherosclerosis is not only a disease characterized by lipid deposition but is a far more complex and challenging condition than we thought.2Libby P. The changing landscape of atherosclerosis.Nature. 2021; 592: 524-533Google Scholar The late Eugene Ormandy3Ormandy Quotes. http://www-control.eng.cam.ac.uk/hu/Ormandy.html. Accessed October 2023.Google Scholar, Hungarian-born conductor of the Philadelphia Orchestra, was famous for his eccentric use of the English language. He described a challenging orchestral piece as “It is not as difficult as I thought it was, but it is harder than it is.” This head-scratching summary could aptly describe the current state of understanding regarding the complexities of atherosclerosis. With the proven benefits of statins and their wide uptake, we thought we may have some degree of control, until we realized that the large residual risk, even with optimal statin therapy,4Ridker PM Genest J Boekholdt SM et al.JUPITER Trial Study Group. HDL cholesterol and residual risk of first cardiovascular events after treatment with potent statin therapy: an analysis from the JUPITER trial.Lancet. 2010; 376 (Epub 2010 Jul 23. PMID: 20655105): 333-339https://doi.org/10.1016/S0140-6736(10)60713-1Google Scholar presented new challenges. The Speciality Update in this issue of the Journal highlights the global challenge of ASCVD and examines how advances in early detection and understanding of the condition are changing the direction of future management. Nedkoff et al5Nedkoff L Briffa T Zemekun D et al.Global trends in atherosclerotic cardiovascular disease.Clin Ther. 2023; (xx:yyy-yyy)Google Scholar provide an overview of global trends in atherosclerotic disease. They offer a sobering perspective on the well-publicized long-term trends in age-standardized rates of CVD mortality and incidence over the past decades. Although these trends are indeed welcome, the combined effects of population growth and aging have contributed to a continued increase in the absolute number of persons living with CVD worldwide. The authors also point out that even declines in age-standardized CVD may have slowed in the most recent decade. Clearly, many challenges remain. Atherosclerosis is the usual cause of coronary artery disease (CAD). Because it is often silent and potentially lethal, early detection is essential. With increasing acceptance of the role of coronary computed tomography angiography in identifying high-risk CAD, attention is turning to how to deliver reliable results to those who stand to benefit. Jaltotage et al6Jaltotage B Sukudom S Ihdayhid A et al.Enhancing risk stratification on CCTA: the role of artificial intelligence.Clin Ther. 2023; (xx:yyy-yyy)Google Scholar discuss how the rapidly evolving field of artificial intelligence (AI) can facilitate the early detection of high-risk CAD. Two papers on the topic of atherosclerotic peripheral artery disease (PAD) discuss how PAD is widespread, frequently overlooked, and undertreated. Jansen et al7Jansen S deBorst GJ Hinchcliffe R et al.PAD: underappreciated impact and residual cardiovascular risk despite revascularization.Clin Ther. 2023; (xx:yyy-yyy)Google Scholar introduce the topic and highlight the burdens associated with reduced mobility, pain, and amputation due to vascular disease. They point out the fact, well known to vascular surgeons but often overlooked by other medical professionals and patients, that revascularization affords symptomatic relief but does not alter the long-term course of the disease. They also summarize their recent proposal to standardize and simplify the definitions of major adverse limb events in clinical and research contexts.8Jansen S Teraa M Chan N et al.Low-dose Colchicine in Patients with Peripheral Artery Disease to Address Residual Vascular Risk (LEADER-PAD) Study Group. Assessing limb outcomes in drug trials in peripheral artery disease: the need for a universal and pragmatic definition.Eur J Vasc Endovasc Surg. 2023; 66: 442-443Google Scholar Golledge9Golledge J. Pathology, progression, and emerging treatments of peripheral artery disease related limb ischemia.Clin Ther. 2023; (xx:yyy-yyy)Google Scholar then discusses the underlying pathology and presents a comprehensive summary of available and emerging therapies for vascular disease. In addition, Kwok et al10Kwok CHR Park JC Joseph SZ et al.Cognition and cerebral blood flow after extracranial carotid revascularization for carotid atherosclerosis: a systematic review.Clin Ther. 2023 Sep 26; Google Scholar contribute a systematic review of the impact of revascularization on cognitive function and its correlation with cerebral blood flow, focusing on cerebral atherosclerosis. Our understanding of the formation of atherosclerotic plaque has progressed substantially beyond the simple concept of lipid accumulation, leading to a re-evaluation of therapeutic targets. Among the fascinating complexities in understanding the formation of atherosclerotic plaques is the remarkable plasticity of cells, in which smooth muscle cells can change from contractile cells to lipid-accumulating foam cells, and how circulating monocytes can adapt both pro-inflammatory and pro-healing phenotypes. Hutton et al11Hutton M Frazer M Lin A et al.New targets in atherosclerosis: vascular smooth muscle cell plasticity and macrophage polarity.Clin Ther. 2023; (xx:yyy-yyy)Google Scholar describe how recent advancements in single-cell transcriptomics are clarifying these changes while also tracking the origins of the cells seen in atherosclerotic plaques and setting up new targets for therapy. Although the “inside-out” concept of atherogenesis originating in the intima is the most widely accepted paradigm, there is substantial evidence that “outside-in” external factors, stemming from the adventitia and perivascular adipose tissue, also play a significant role.12Lin A Dey D Wong DTL Nerlekar N. Perivascular adipose tissue and coronary atherosclerosis: from biology to imaging phenotyping.Curr Atheroscler Rep. 2019; 21: 47Google Scholar Belhoul-Fakir et al13Belhoul-Fakir H Thompson PL Lawrence-Brown M et al.Connecting the dots: how injury in the arterial wall contributes to atherosclerotic disease.Clin Ther. 2023; (xx:yyy-yyy)Google Scholar introduce a novel perspective, suggesting a third potential influence in atherogenesis. They propose that injuries occurring within the medial layer of the arterial wall may represent an overlooked atherogenic factor. This is based on their recent discovery that injuries to the medial layer can initiate localized lipid deposits before lipid accumulation occurs in the intima layer.14Belhoul-Fakir H Wu J Yeow YL et al.Injury to the tunica media initiates atherogenesis in the presence of hyperlipidemia.Front Cardiovasc Med. 2023; 101152124Google Scholar The role of inflammation in atherosclerosis is now well accepted since the landmark paper of Russell Ross 25 years ago.15Ross R. Atherosclerosis—an inflammatory disease.N Engl J Med. 1999; 340: 115-126Google Scholar This understanding has been further developed through the work of Libby et al.16Libby P Loscalzo J Ridker PM et al.Inflammation, immunity, and infection in atherothrombosis: JACC Review Topic of the Week.J Am Coll Cardiol. 2018; 72: 2071-2081Google Scholar Mohammadnia et al17Mohammadnia N Opstals T El Messaoudi S et al.An update on inflammation in atherosclerosis how to effectively treat residual risk.Clin Ther. 2023; (xx:yyy-yyy)Google Scholar present an authoritative update of the status of inflammation in atherosclerosis and options for treatment. They also explore novel biomarkers for assessing inflammation, offering alternatives to the widely used but nonspecific high-sensitivity C-reactive protein. To date, the only anti-inflammatory treatments that have been shown to be effective in reducing cardiovascular events are an expensive injectable monoclonal antibody interleukin-1 inhibitor, canakinumab, and a widely accessible and affordable anti-gout drug, colchicine. Nidorf18Nidorf SM. Seeing colchicine in a new light: repurposing low-dose colchicine for secondary prevention of cardiovascular disease.Clin Ther. 2023; (xx:yyy-yyy)Google Scholar has been a leading researcher in re-purposing colchicine for atherosclerotic cardiovascular disease; he summarizes the clinical trials that have led to its recent approval for this indication by the US Food and Drug Administration. Despite the growing interest in understanding inflammation and evolving concepts of atherosclerosis, effective lowering of LDL-C levels remains central to the treatment of atherosclerosis. This is not always feasible, even with high-intensity statin therapy. Chan and Watts19Chan DC Watts GF. The promise of PCSK9 and lipoprotein(a) as targets for gene silencing therapies.Clin Ther. 2023; (xx:yyy-yyy)Google Scholar summarize recent exciting developments in the long-term inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) through gene silencing. They also introduce readers to recent developments in lowering lipoprotein(a), a lipoprotein garnering a reputation as highly atherogenic but unaffected by statins and PCSK9 inhibition. Cowart et al20Cowart K Singleton J Carris NW. Inclisiran for the treatment of hyperlipidemia and for atherosclerotic cardiovascular disease risk reduction: a narrative review.Clin Ther. 2023; (xx:yyy-yyy)Google Scholar present a comprehensive overview of the recent clinical trials that support the imminent integration of inclisiran into clinical practice. Inclisiran is a frontrunner in PCSK9 silencing. It is administered conveniently through a twice-yearly injection schedule and thus offers the potential for long-term control of LDL levels, especially in cases of statin resistance. Inclisiran is a prime example of a therapeutic formulated using lipid nanoparticles as a delivery system. In an era in which precision medicine is top of mind, safe and precise targeting of new anti-atherosclerotic agents to the plaque is under active investigation. Kirla et al21Kirla H Henry DJ Jansen S et al.Utilizing silica nanoparticles for drug delivery in cardiovascular disease.Clin Ther. 2023; (xx:yyy-yyy)Google Scholar present a detailed overview of the application of silica nanoparticles for this purpose, emphasizing their robust safety profile, tuneable pore size for versatile drug loading, straightforward surface chemistry, and the relative ease of manufacturing. For the practicing clinician, strict risk factor and lipid control remains central to reducing the risk of heart attack, stroke, and amputation, but the recent exciting developments in understanding atherosclerosis summarized in this Specialty Update indicate that new targets are emerging and justify optimism that the global burden of ASCVD can be radically reduced. None declared.