Microplastics and nanoplastics: tiny threats for cardiovascular diseases?

The widespread presence of plastic in modern society has led to an environmental crisis with profound implications for human health. Initially hailed as revolutionary materials for their versatility and durability, they have become a pervasive pollutant, fragmenting into microplastics (MPs) and nanoplastics (NPs) that infiltrate ecosystems, the food chain, and ultimately the human body. Recent studies have evidenced the pervasive presence of MPs and NPs in various human tissues, including the blood, placenta, brain, lungs, liver and atheroma.1–4 Seminal findings suggest that the cardiovascular system might suffer the noxious effects of MPs or NPs toxicity.2 Indeed, our data provided the first clinical evidence that MPs and NPs accumulate in atherosclerotic plaques, an effect associated with an increased cardiovascular risk. Specifically, in a cohort of patients undergoing carotid endarterectomy, those with detectable MPs and NPs in their plaques exhibited a 4.5-fold higher risk of major adverse cardiovascular events (MACE) than those without.2 These findings, coupled by the existing experimental evidence derived from preclinical models and suggesting that MPs promote inflammation, endothelial dysfunction, oxidative stress, apoptosis, and pyroptosis in the vasculature, might imply that MPs and NPs play an active role in atherogenesis or in the promotion of MACE.5 Beyond their suggested, intrinsic toxicity, MPs and NPs might also act as carriers of other toxic substances such as heavy metals, pesticides and herbicides that can damage the cardiovascular system.6 These discoveries open new and urgent clinical and basic cardiovascular research questions. They challenge the traditional view of atherosclerosis by introducing a novel environmental risk factor and raise fundamental prevention, diagnosis, and treatment issues. Nevertheless, large studies with different populations are needed to corroborate and extend these findings. Unfortunately, the complexity of dosing MPs and NPs is a severe limitation for this kind of studies, possibly limiting also the comparability between different results. However, available evidence is sufficient to consider the possible role of MPs and NPs as a new cardiovascular risk a matter of research interest and a public health priority (Figure 1). Mechanisms operating for micronanoplastics (MNPs) entry in our body and their possible involvement in atherosclerotic processes. From a clinical perspective, the presence of MPs and NPs in atherosclerotic plaques represents an emerging risk factor that may require integration into cardiovascular prevention strategies. While common cardiovascular risk factors such as hyperlipidaemia, hypertension, obesity, and smoking are well established, the role of environmental pollutants in cardiovascular disease is gaining increasing attention in the last years. Air pollution toxic effects, including particulate matter (PM2.5), have long been associated with increased cardiovascular mortality.7 The discovery that MPs and NPs may exert similar effects suggests that cardiovascular medicine must expand its focus to include also an ‘environmental cardiology’.6,7 A critical issue is whether MPs and NPs contribute directly to plaque formation and/or destabilization, or their presence is simply a marker of a broad environmental exposure. MPs and NPs induce vascular inflammation, endothelial dysfunction, and oxidative stress in preclinical models, possibly suggesting that they are not mere bystanders.2 However, proving causality in humans remains challenging since longitudinal studies are lacking. Another fundamental question is how MPs and NPs enter the vascular system and accumulate in plaques. Potential routes include ingestion via contaminated food and water, inhalation of airborne particles, and direct absorption through the skin,5–7 suggesting that their systemic distribution is likely widespread.5–7 However, which sources and routes are more relevant is unknown, an aspect that could hamper the development of strategies minimizing the exposure to plastics. For the essential science community, discovering MPs and NPs in atherosclerotic plaques raises critical mechanistic questions. First, a key point is how these particles interact with vascular cells and whether realistic amounts of MPs and NPs effectively promote the abovementioned pathways in humans. In turn, a key point is to explore whether these mechanisms directly contribute to plaque progression or exacerbate pre-existing vascular pathology.2,5,7 Alternatively, indirect mechanisms such as the deregulation of the micriobiota might be also conceived.5 Secondly, do size and MPs types are relevant for their cardiovascular effects? It has been2 suggested that NPs preferentially accumulate in plaques due to the nanometre range allowing them to penetrate biological barriers more than larger particles. Understanding whether certain polymers are more pathogenic than others could guide future regulatory efforts. Given the ubiquity of plastics, tackling their cardiovascular impact requires a dual approach: primary and secondary prevention. Primary prevention should aim at reducing plastic contamination in the environment and, as a corollary, in the human body. This is essentially a political and economic challenge, requiring global action to curb plastic production and pollution. Current geopolitical and economic trends do not offer much optimism, as regulatory measures remain weak and obviously influenced by industrial and social interests.8 In addition, even if plastic production ceased today, the effects of environmental contamination would persist for at least a century, highlighting the need for long-term strategies. Secondary prevention strategies might focus on mitigating the effects of MPs and NPs in the human body. This is where cardiovascular medicine can play a role. If a role for MPs and NPs in promoting inflammation, endothelial dysfunction, and apoptosis in humans is substantiated, then existing anti-atherosclerotic therapies may offer partial protection. Drugs that target vascular inflammation and endothelial function, including statins, PCSK9 inhibitors, SGLT2 inhibitors, and GLP-1RA, may counteract vascular inflammation, even though they do not eliminate the root cause. A more radical approach would involve removing MPs and NPs from the body. The immediate strategy could be to enhance their excretion via the gastrointestinal tract. Research into dietary fibres, probiotics, and bile acid sequestrants could explore their potential to trap and eliminate MPs from the intestine before they enter circulation. MPs and NPs in cardiovascular disease represent an unprecedented scientific and clinical challenge. If their role in atherogenesis and/or cardiovascular diseases development is confirmed, then they could emerge as a novel cardiovascular risk factor, similarly to what is emerging with fine particulate matter. Addressing this issue requires a multidisciplinary approach integrating multiple technologies, epidemiology, molecular biology, pharmacology, and public health. While reducing plastic exposure remains the ultimate goal, we anticipate that developing therapeutic strategies to counteract plastic-induced vascular damage might be necessary. Cardiovascular medicine should adapt to the new challenges posed by these novel, tiny environmental threats. This work was supported by: European Union – Next Generation EU, under the National Recovery and Resilience Plan (PNRR), Mission 4 –Component 1 CUP: B53D23030780001. Project Code: P2022RHFSS; PNRR Project ANTHEM (AdvaNced Technologies for Human-cEntredMedicine) Project Code PNC0000003, CUP: B53C22006540001; PRIN2022 - CUP: B53D23020210006, Arketipo: ARtificial Intelligencefor Early RisK PrEdicTIon of Heart Failure by Combining Circulating EPiSignature to Clinical Features Project Code F/310107/05/X56, CUP:B29J23000310005. No data availability due to the fact that it is a review article. Biography: Raffaele Marfella, MD, PhD, is Full Professor of Internal Medicine and Director of the Department of Advanced Medical and Surgical Sciences at the University of Campania “Luigi Vanvitelli,” Naples. He has authored over 300 peer-reviewed publications and 20 books, with an H-index of 75 and more than 24 000 citations. Professor Marfella has co-ordinated numerous national and international research projects on diabetes, oxidative stress, and cardiovascular disease. He serves on the editorial boards of several scientific journals and as a reviewer for The Lancet, Circulation, Diabetologia, and The New England Journal of Medicine. His pioneering study in NEJM demonstrated the association between microplastics and nanoplastics in atherosclerotic plaques and cardiovascular events. He has been an invited speaker at over 370 congresses and has received multiple awards recognizing his contributions to cardiovascular research and leadership in translational medicine. Biography: Francesco Prattichizzo, PhD, is a principal investigator employed at IRCCS MultiMedica, a hospital located in Milan (Italy) with a specific research activity on cardiovascular diseases. He previously covered different positions at Università Politecnica delle Marche, Ancona (Italy) and IDIBAPS, Barcelona (Spain), studying the role of diabetes and aging as cardiovascular risk factors. Among other areas, a key focus of his ongoing research activity is the study of the effects of pollution, and in particular of micronanoplastics, on the development of cardiovascular diseases. Currently, he has published more than 100 papers and has an H-index of 48. Biography: Prof. Paolisso is Full Professor of Internal Medicine at University of Campania “Luigi Vanvitelli” and has been Research Fellow at Catholic University in Brussels (Belgium), University of Liege (Belgium) and National Institute of Health (Phoenix, AZ, USA). Prof. Paolisso is strongly committed to enhancing the results of scientific research carried out at the University in the fields of Social and Human Sciences, Life Sciences and Natural and Technological Sciences. He has contributed with strategic intense activities to the following studies: (i) role of micro-nanoplastic in the development of cardio and cerebrovascular diseases; (ii) study of the molecular and metabolic aspects of aging and longevity including the relationships between aging, glucose metabolism, and cardiovascular diseases; (iii) study of the role of the different genetic polymorphisms in metabolic diseases linked to aging and determinism of longevity; and (iv) study of epigenetic modifications (methylation, miRNA, etc., histone modifications) and aging disease.