Micro-nanoplastic induced cardiovascular disease and dysfunction: a scoping review

doi:10.21203/rs.3.rs-4906799/v1

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Systematic Review

Micro-nanoplastic induced cardiovascular disease and dysfunction: a scoping review

https://doi.org/10.21203/rs.3.rs-4906799/v1

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Background

The human bioaccumulation of micro- and nano-plastics (MNPs) is increasingly being recognised in the aetiology and pathophysiology of human disease. This systematic scoping review provides a comprehensive investigation of studies examining the impacts of MNPs on the human cardiovascular system.

Methods

Five databases (PubMed, SCOPUS, CINAHL, Web of Science and EMBASE) were systematically searched.

Results

Thirty-four articles were identified, six of which investigated the presence of MNPs within the human cardiovascular system, including atherosclerotic plaques, saphenous vein tissue, and venous blood. The effect of MNPs on cell lines suggest MNPs are cytotoxic, immunotoxic, and genotoxic.

Discussion

The findings of this review, when evaluated together with additional studies utilising animal models, strongly suggest MNPs currently contribute to global cardiovascular morbidity and mortality. In particular, the ability of MNPs to induce endothelial damage, oxy-LDL formation, foam cell development and apoptosis, as well as altering the clotting cascade, has potential implications for vascular diseases. In addition, MNPs may play a role in the aetiology and progression of congenital heart abnormalities, infective pathologies and cardiomyopathies.

Conclusion

Despite an increasing awareness of the ability of MNPs to result in cardiovascular disease and dysfunction, a limited amount of research has been conducted to date characterising the presence of MNPs in the human cardiovascular system. Research is required to understand the extent of this rapidly emerging issue and to develop strategies that will support clinicians to appropriately manage and educate their patients about this issue in the future.

Microplastic

Nanoplastic

Blood

Cardiovascular

Cardiac

Atherosclerosis

Micro-nanoplastics are commonly found within the human cardiovascular system.
Evidence currently suggests micro-nanoplastics are cytotoxic, genotoxic and neurotoxic with potentially significant implications for cardiovascular morbidity, mortality and the global burden of cardiovascular disease.

Cardiovascular disorders and environmental contamination from microplastics are two major challenges within modern society [1, 2]. Currently, our understanding of the interrelationship between these two phenomena is limited [3]. Contemporary evidence points towards an increasing bioaccumulation of microplastics and nanoplastics (MNPs) in humans, leading to increased disease and dysfunction within multiple organ systems, thereby presenting a threat to global public health [3, 4]. However, the lack of research and evidence synthesis to date currently leaves clinicians with a lack of information to inform assessment and management of individuals with MNP-associated disease and dysfunction.

In 2019, the World Health Organisation (WHO) published a report entitled ‘Microplastics in Drinking-Water’, which minimised the significance of MNPs in drinking water in relation to their impact on human health [5]. The assertation that there is “no evidence to indicate a human health concern” [5], is increasingly being challenged by new studies. Once MNPs enter the human body, by means of inhalation, ingestion, or dermal absorption, they can cross biological barriers, leading to systemic exposure and bioaccumulation in vital organs and tissues [4, 6–8]. The ability of MNPs to influence inflammatory [6, 9], metabolic [6, 10], and endocrine pathways [11], in addition to their cytotoxic [12, 13], immunotoxic [6, 14], and genotoxic [12, 13] effects, suggests their implication in a number of disease processes. The discrepancy between the WHO report and current literature emphasises the need for urgent re-evaluation of the health impact of MNPs.

The definition of MNPs is a crucial starting point for this re-evaluation. A lack of consensus in literature elicits conflicts within public policy, legislation, research, and medicine, compounding pre-existing challenges in monitoring and mitigating the impacts of MNPs. Moreover, the characteristics of these MNPs, such as their functionalisation, surface characteristics, shape, additives, pigmentation, and polymer type, are essential in understanding their behaviour and impact on human health. However, these characteristics are yet to be considered in the literature, with most studies focusing only on particle size.

Cardiovascular disease remains a leading cause of morbidity and mortality globally, with data demonstrating that despite advances in recent decades, the mortality rate may be beginning to rise [1]. This concerning trend necessitates urgent research into the mechanisms surrounding the aetiology and progression of diseases relating to vascular pathologies, heart failure, and congenital and electrical abnormalities. This scoping review aims to systematically explore and summarise the literature surrounding MNPs in the human cardiovascular system and their pathological consequences, and explore the methodologies used in their detection and analysis, guided by the following research questions:

RQ 1. What are the characteristics of plastics which have been found within human cardiovascular systems?

RQ 2. What are the pathological considerations which have been raised regarding the presence of plastic in human cardiovascular systems?

RQ 3. What methodology has been utilised to date to characterise plastics within human cardiovascular systems?

RQ 4. How are MNPs defined within the current cardiovascular literature?

For the purposes of this review, a broad definition of the term ‘cardiovascular system’ will be employed, inclusive of the heart, blood vessels, blood, and the components (e.g. immune cells) commonly found within human blood. Whilst other reviews have previously provided broad insights into the potential health implications of microplastics, this scoping review, through a rigorous and systematic interrogation of existing literature, attempts to solidify the field of knowledge surrounding MNPs and the cardiovascular system specifically, raise awareness of the scale of this emerging issue, and lay the foundation for further research which may assist in the development of health policies and clinical practice guidelines.

2.1 Protocol and registration

An a priori protocol was developed, informed by the recommendations of Arksey and O’Malley [15], the Joanna Briggs Institute (JBI) [16], and the PRISMA extension for scoping reviews reporting guidance (PRISMA-ScR). This protocol was published on the Open Science Framework (https://osf.io/w9hr5) on the 08/03/2024. This review was conducted in accordance with the ethical principles set forth in the Declaration of Helsinki.

2.2 Eligibility criteria

A pre-determined eligibility criteria was developed, informed by the population (human), concept (microplastic or nanoplastics and their effects) and context (cardiovascular system). Pre-determined definitions were developed and outlined within the a priori protocol after careful interrogation of the existing literature. For clarity, plastics were defined as a synthetic or semi-synthetic material comprising organic polymers from plant extracts or fossil fuels. The term ‘cardiovascular system’ was defined simply as the heart, blood and associated vessels. To ensure a broad and thorough scope of the literature was undertaken, all research methodologies were included except for abstracts, reviews, pre-prints, conference proceedings, poster presentations, and editorials.

2.3 Search strategy

A search strategy was developed utilising a three-step methodological approach originally proposed by Arksey and O’Malley [15] and further outlined by the JBI. Firstly, a pilot search of PubMed and Google Scholar was undertaken on January 19th 2024. Secondly, results were reviewed to identify additional search terms, with the final search strategy being translated for additional search engines with the assistance of a validated search engine translation software (Systematic Review Accelerator [SRA] Polyglot [17] (Appendix 1). An additional search for grey literature was undertaken utilising Research Rabbit [18], TERA Farmer [19], and Perplexity [20].

2.4 Information sources

Five databases (PubMed, EMBASE, CINAHL, SCOPUS, and Web of Science) were searched on February 26th, 2024. Results from database searches were exported into Endnote X9 [21].

2.5 Selection of sources of evidence

Duplicate results were removed utilising automation software (SRA Deduplicator) [22]. Articles were screened by two authors by title and abstract within SRA Screenatron [22]. Full text screening was undertaken within Covidence [23] by two authors with discrepancies resolved by a third author.

2.6 Charting of data items

A draft extraction table was developed within Microsoft Excel to align with the aims of the scoping review. This was piloted and refined prior to undertaking full data extraction. Where information was not relevant or not reported, this was recorded for clarity.

2.7 Synthesis of results

Data pertaining to definitions was extracted and, where possible, synthesised and visually represented. Similarly, data pertaining to the countries and years of publication was tabulated and visually represented. Studies identifying the presence of plastic in human specimens, and studies evaluating the effects of plastic on cellular viability, uptake, and function, have been tabulated separately.

3.1 Selection of sources of evidence

Database searching led to the retrieval of 700 articles, of which 440 articles were removed via automation within Systematic Review Accelerator and Covidence (Fig. 1). Title and abstract screening of the remaining 260 articles led to the exclusion of a further 210 articles. The full text of 49 articles was successfully retrieved and screened with substantial agreement between authors (Cohen’s Kappa = .760). This process led to the exclusion of a further 16 articles. A final grey literature search led to the retrieval of a single additional article, published following the date of data search execution, resulting in 34 articles being included within the scoping review.

3.2 Synthesis of results

Of the 34 identified articles, 15 countries were represented with China (n = 9), the United States of America (n = 4) and India (n = 4) respresenting half of all identified publications (Fig. 2). Only one article was published prior to the WHO report on microplastics in drinking water [24] being made publicly available. Six articles (Table 1) identified the presence of MNPs in venous blood samples, cardiac tissue, thrombi, saphenous veins, and atherosclerotic plaques, with implications for all-cause mortality (Fig. 3). Sizes of identified particles varied greatly from 1 to 1074 µm (Fig. 4). The remaining 28 articles investigated the effect of MNPs on human cell lines relating to the cardiovascular system.

3.3 Definitions of microplastics and nanoplastics

All articles defined microplastics and nanoplastics primarily based on the size of the particle. Twenty-five (74%) articles provided a description of the term ‘microplastic’, with 14 (41%) of the included articles also defining the term ‘nanoplastic’. Of these articles, 23 (92%) utilised a definition which stipulated an upper size limit of 5 mm. When a lower limit was stipulated it varied significantly from 100 nm [25] to 100 mm [26, 27]. While earlier articles chose to define nanoplastics as particles < 100 nm in size [25, 28–32], a shift occurred in 2022 whereby all articles began to refer to nanoplastics as particles less than 1000 nm in size [33–36] (Table 1).

3.4 Presence of MNPs in atherosclerotic plaques and thrombi and their effects on clotting factors

A single paper was identified analysing the presence of MNPs in atherosclerotic plaques [37] and thrombi [38] respectively (Table 2). Of the 257 patients who completed the 33 month follow up, Marfella et al. identified plastic (polyethylene) in carotid artery atherosclerotic plaques of 150 (58.4%) patients [37]. Additionally, 31 (12.1%) patients had PVC in atherosclerotic plaques [37]. At the 33 month follow up point, the authors noted an increased risk of composite myocardial infarction, stroke, or death from any cause in patient with detectable MNPs compared to MNP-free atherosclerotic plaques [37]. A single article was identified which investigated the presence of MNPs in thrombi in which Wu et al. only observed a single plastic (low density polyethylene) particle [38]. In this case, it is also worth noting that various other foreign particles were also detected including pigments, iron compounds, and metallic oxide particles [38]. Several factors including particle size and whether the particle is non-functional, carboxylated, or aminated have been shown to affect clotting dynamics with smaller, functional particles demonstrating a greater ability to derange clotting dynamics [33, 39], albeit within a low shear environment which may not represent the continuum biomechanics within the vasculature and the subsequent impact on clotting dynamics.

3.5 Vascular tissue, endothelial cells, and smooth muscle cells

A variety of polymer types have been reported within both cardiac tissue obtained during open heart surgery and saphenous vein tissue, with significant variance in quantity per gram, shape, and size [40, 41] (Table 2). When investigating the effect of MNPs on endothelial cells, identified articles commonly utilised human umbilical vein endothelial cells (HUVEC) [30, 31, 42–44] or vascular endothelial cells (EA.hy926) [45] (Table 3). Additionally, a single article by Persiani et al. was identified, investigating the effects of polystyrene and polyethylene (both high and low density) on human coronary artery smooth muscle cells [46]. A significant incongruity currently exists between the polymer types found to date from investigations of human vascular and cardiac tissue, and polymer types utilised within in vitro investigations on the effects of various polymers within cell lines (Table 4). While Lu et al. found little evidence of deleterious effects following exposure of HUVEC cells to 1 µm spheres [42], articles utilising smaller particle sizes found polystyrene MNPs to decrease cell viability and increase autophagy [43]. In particular, functionalised polystyrene particles were found to increase oxidative stress and lactate dehydrogenase, and induce mitochondrial damage resulting in an 82% decrease in ATP production [30]. Similarly, aged MNPs significantly increased IL-6 and TNF, indicating increased inflammatory processes. It is yet to be determined whether the increase in endothelial leakiness [31, 45] increases MNP interaction with vascular smooth muscle.

3.6 Genotoxic and immunotoxic effects

The exposure of polystyrene to peripheral blood mononuclear cells was shown to induce micronucleation and damage [47, 48]. While Ballesteros et al. [48] reported no DNA damage associated with 0.05 to 0.01 µm polystyrene nanoplastic exposure, Sarma et al. [49], utilising a particle size of 50 nm, demonstrated DNA damage and genomic instability. This increased genotoxicity may also, in part, be due to Sarma et al. utilising ultraviolet radiation to sterilise the nanoparticles [49]. Dailianis et al. demonstrated that ultraviolet exposure of low-density polyethylene was associated with higher cytotoxicity and genotoxicity [50].

4.1 Overview

This systematic scoping review demonstrates that research into the presence and effect of MNPs in the human cardiovascular system has rapidly increased since 2019. The majority of this research has utilised in vitro experimental designs with human samples and cell lines. The findings of the six identified articles which investigated MNPs in human tissue are alarming and warrant concern from public health authorities. Of particular note is a lack of research characterising the presence of human MNP contamination from low socioeconomic countries, especially those in the Pacific, which are economically and culturally tied to an ocean facing increasing contamination by MNPs. Taken together, the findings of research to date demonstrating the genotoxic, cytotoxic, immunotoxic, and neurotoxic effects of MNPs, in addition to their deleterious effects on cellular metabolism and inflammatory effects, raise significant concerns for their role in a range of cardiovascular pathologies including atherosclerosis, cardiomyopathies, electrical and congenital abnormalities, and infective pathologies.

Whilst inconsistencies exist in the definition of MNPs in the early literature base, a consistent approach of defining MPs as particles less than 5mm and NPs as less than 1000nm in size has emerged since August 2023 (Table 1). Unfortunately, a lack of research exists to appropriately inform animal and cell line research regarding the characteristics of human environmental exposure, especially as this pertains to varying clinical populations. Despite this, an increasing amount of research investigating the effect of various plastic characteristics (e.g. functionality, size and shape) demonstrates significant variances in levels of toxicity. However, to date, the majority of cell line and animal research has focused on the use of polystyrene NPs. Although commonly found in human specimens relating to the urinary tract (e.g. urine, kidneys), these are not as common as plastic particles such as polyethylene and polypropylene within the human cardiovascular system (Table 4).

4. 2 The role of MNPs in atherosclerosis and coronary artery disease

In 2024, Marfella et al. identified MNPs in 58.4% of atherosclerotic plaques, demonstrating that individuals with MNP-associated atherosclerosis had a higher rate of myocardial infarction, stroke, or death at 34 month follow up [37]. Investigations employing human and animal cell lines have revealed a multitude of biochemical mechanisms, providing evidence for MNPs in the aetiology and pathophysiology of atherosclerosis, and their significant implications for vascular pathologies (Fig. 5). For example, MNPs have been demonstrated to induce endothelial dysfunction, an early stage of atherosclerotic plaque development [65]. Studies utilising 1 µm PS spheres have demonstrated little effect in human umbilical vein endothelial cell lines to date. In contrast, articles utilising smaller and positively charged particles, similar in size to those found within the observational study by Marfella et al. [37], have demonstrated increased reactive oxygen species (ROS) and lactate dehydrogenase (LDH) production. Additionally, studies have described damage to mitochondrial membranes, leading to a > 82% decrease in mitochondrial ATP production [30], decreased cell viability, and impaired angiogenesis, thereby hindering endothelial healing [43, 66]. In addition to endothelial dysfunction, MNPs have deleterious impacts within smooth muscle [67] and lead to decreased levels of high density lipoproteins (HDLs) as well as increased low density lipoproteins (LDLs) [68] and systemic ROS, assisting in the formation of oxy-LDL [69]. Taken together, these results demonstrate the ability of MNPs to lay the foundation for atherosclerotic plaque development.

Following their rapid uptake into the cytoplasm of macrophages, NPs provoke lipid aggregation [70], leading to their differentiation into foam cells [71]. Their continued genotoxic and cytotoxic effect from increased endoplasmic reticulum stress, oxidative stress and disruption to mitochondrial membranes [72] results in apoptosis [73], potentially assisting in the development of a necrotic core, increasing plaque instability [74].

In cases where plaque rupture ensues, MNP contamination deranges the clotting cascade, impacting fibrin polymerisation rates and platelet aggregation. This modulates clot strength and the manner in which the clot adheres to the endothelial wall [75]. Of particular concern clinically, MNPs also impede the production of endothelium-derived nitric oxide [69, 76], impairing vasodilatory responses to clot formation [77]. Importantly, SGLT2 inhibitors within porcine endothelial models treated with NPs have been shown to upregulate endothelial nitric oxide synthase expression, decrease the formation of reactive oxygen species, and ultimately inhibit NP-associated endothelial cell senescence [78]. Together, these two studies demonstrate that the production of nitric oxide is perturbed which may impact the delicate, haemostatic balance between thrombosis and bleeding. The myriad of pathways through which MNPs potentially cause cardiovascular disease provide potential pharmacological targets, requiring further exploration into their pervasive effects. Regardless, the involvement of MNPs in atherosclerotic disease provides significant cause for concern, not only in the context of coronary artery disease, but also in peripheral and cerebrovascular pathologies [37].

4.3 Valvular disorders, cardiomyopathies, and electrical abnormalities

In addition to vascular diseases, MNPs have been implicated in the dysfunction of cardiomyocytes [79] with potential implications for cardiomyopathies and electrical abnormalities [67, 80, 81] (Fig. 6). For example, the exposure of neonatal ventricular myocytes to NPs has been shown to significantly decrease intracellular Ca²⁺ levels, in addition to mitochondrial membrane potentials and cellular metabolism, resulting in a reduction in cardiomyocyte contraction forces [81]. Additionally, MNPs in rat models have been shown to induce cardiac fibrosis through activation of the Wnt/b-catenin pathway and cellular apoptosis [82]. Following polystyrene exposure, in vivo rat models have demonstrated increased troponin I and creatine kinase-MB (CK-MB) levels, as well as disruption of mitochondrial mtDNA and cGAS-STING signalling pathways, leading to cardiomyocyte apoptosis [82–84]. When exposed to MNPs at a concentration equivalent to human exposure, rats demonstrated a marked elevation in cardiac-specific markers and an increase in interventricular septal thickness [69]. This raises considerable concern and highlights a need for urgent research into MNP-associated cardiomyopathies [85].

4.4 Cardiac disorders of infective origins

The rough surface characteristics and size of MNPs found within the human cardiovascular system to date [37] provide an ideal environment to facilitate the adsorption of viruses or bacteria, the development of biofilms, and increased virus survival and infectivity [86–88]. MNPs have been shown to promote the infection of cells through the development of a protein corona facilitating a trojan horse mechanism, whereby NP particles shuttle viruses and bacteria into the cytoplasm [89, 90]. Additionally, the presence of MNPs has been shown to inhibit innate immune functions, in particular the actions of macrophages [91, 92]. Beijer et al. demonstrated a dose-related immune response with the largest secretions of IL-1b, IL-8 and TNF-a elicited by polyethylene terephalate [93], identified within both human blood and cardiac tissue [41, 59]. As a result, MNPs are likely to play an important role in pathologies such as infective endocarditis, rheumatic heart disease and pericarditis.

4.5 Congenital heart abnormalities

Of particular note, research highlighting the presence of MPs in human placentas (including on the foetal side [94]), semen, and the meconium of newborns raises important questions surrounding the potential role of MNPs in the aetiology of congenital cardiovascular abnormalities [95–97]. Research investigating the potential abnormal development of the heart utilising pluripotent stem cells has demonstrated altered atrioventricular valve and cardiomyocyte formation following exposure to polystyrene NPs [28, 80]. In animal models, NPs have been shown to alter umbilical and placenta blood flow [98], with maternal polystyrene NP exposure leading to a 12% reduction in late gestational foetal weight [99]. With more specific reference to the cardiovascular system, maternal MP exposure in rats has also been observed to cause foetal aortic abnormalities [100].

4.6 Current gaps in the literature

Despite significant advances in the field of MNPs and cardiovascular health, research is urgently required in order to assist in the characterisation of MNP contamination within the human cardiovascular system. Researchers moving forward should consider utilising sensitive laboratory-based methodologies which allow for the detection and investigation of the characteristics of MNPs to be elucidated. This will assist in ensuring the dosage and characteristics of MNPs utilised within in vitro studies in future are reflective of in vivo concentrations. In addition, researchers and public health authorities alike are urged to begin investigating the presence of MNPs in low socioeconomic areas, especially those identified as high risk due to exposure to contaminated water, food and living environments. Furthermore, the contamination of various clinical populations requires attention to understand variances in exposure and physiological consequences. In conjunction with laboratory-based analysis, complementary methodologies utilising surveys to characterise behaviour alongside longitudinal studies within both animals and humans, are required to understand how various behaviours and exposures influence MNP contamination and their long-term effects on chronic disease and mortality. Clinical trials using behavioural interventions modifying MNP exposure, for example through dietary modifications, are urgently required in order to inform public health advice and international industry policy development. An interdisciplinary approach which seeks to understand the multiple organ system interactions should be considered to advance our understanding of various individual organ systems.

4.7 Limitations

Due to the rapidly evolving nature of this research field, this scoping review will require updating within the next two years. At this time, further research that may allow for a systematic review and meta-analysis to be conducted on the presence of MNPs in various tissues which is currently precluded by a lack of available data and consistency within methodologies and reporting. Additionally, a lack of research investigating the presence and effect of MNPs on the lymphatic system prohibits a robust discussion on how this complementary organ system affects cardiovascular function. Methodological limitations were noted within some articles which may have affected reported results. For example, reports of haemolytic activity may be overestimated considering Djapovic et al. [35] washed RBCs with hypertonic (0.99%) NaCl. Similarly, Gopinath et al [63] isolation of RBCs by centrifugation without a density gradient medium may have led to the some leucocytes remaining with the RBC concentration resulting in the release of haemolytic enzymes.

This systematic scoping review highlights the notable increase in research interest in this field since 2019, with all currently published studies reporting deleterious effects on the cardiovascular system. Humans, throughout their lives are subject to a plethora of MNPs with varying functionality, surface characteristics, chemical compositions, and sizes daily. To date, research has identified the presence of MNPs within venous blood samples, cardiac tissue, thrombi, saphenous veins and atherosclerotic plaques with implications for all-cause mortality. These findings, in conjunction with in vitro experimental designs, raise significant concerns for the potential contribution of MNPs to cardiovascular pathologies such as atherosclerosis, cardiomyopathies, electrical abnormalities, congenital cardiovascular defects, and infective pathologies. Multiple health authorities, including the WHO and the American College of Physicians, continue to call for research to be rapidly undertaken in this field to shed light on the presence and effect of MNP bioaccumulation in humans, and potential solutions [24, 101, 102]. Without further research, policy makers will be unable to act appropriately, and clinicians will remain in the dark as to the way they should assess, manage, and educate their patients and, more broadly, the general public.

The authors have no relevant financial or non-financial interests to disclose.

Conflicts of Interest:

The authors state explicitly that there are no conflicts of interest financial or otherwise in connection with this article.

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Tables 1 to 4 are available in the Supplementary Files section.

The authors declare no competing interests.

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Micro-nanoplastic induced cardiovascular disease and dysfunction: a scoping review

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Abstract

Background

Methods

Results

Discussion

Conclusion

Figures

Clinical significance

1.0 Introduction

2.0 Methods

2.1 Protocol and registration

2.2 Eligibility criteria

2.3 Search strategy

2.4 Information sources

2.5 Selection of sources of evidence

2.6 Charting of data items

2.7 Synthesis of results

3.0 Results

3.1 Selection of sources of evidence

3.2 Synthesis of results

3.3 Definitions of microplastics and nanoplastics

3.4 Presence of MNPs in atherosclerotic plaques and thrombi and their effects on clotting factors

3.5 Vascular tissue, endothelial cells, and smooth muscle cells

3.6 Genotoxic and immunotoxic effects

4.0 Discussion

4.1 Overview

4. 2 The role of MNPs in atherosclerosis and coronary artery disease

4.3 Valvular disorders, cardiomyopathies, and electrical abnormalities

4.4 Cardiac disorders of infective origins

4.5 Congenital heart abnormalities

4.6 Current gaps in the literature

4.7 Limitations

5.0 Conclusion

Declarations

References

Tables

Additional Declarations

Supplementary Files

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