key: cord-0690038-c8bl04lp
authors: Tanwar, Vineeta; Adelstein, Jeremy M; Wold, Loren E
title: Double Trouble: Combined Cardiovascular Effects of Particulate Matter Exposure and COVID-19
date: 2020-10-21
journal: Cardiovasc Res
DOI: 10.1093/cvr/cvaa293
sha: 9a3e05dd529e989306cee5b44fee8938034ba1df
doc_id: 690038
cord_uid: c8bl04lp

The coronavirus disease-2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly grown into a pandemic. According to initial reports, the lungs were thought to be the primary target, but recent case studies have shown its reach can extend to other organs including the heart and blood vessels. The severity of cardiac complications of COVID-19 depends on multiple underlying factors, with air pollutant exposure being one of them as reported by several recent studies. Airborne particulate matter attracts heightened attention due to its implication in various diseases, especially respiratory and cardiovascular diseases. Inhaled particulate matter not only carries microorganisms inside the body but also elicits local and systemic inflammatory responses resulting in altering host’s immunity and increasing susceptibility to infection. Previous as well as recent studies have documented that particulate matter acts as a “carrier” for the virus and aids in spreading viral infections. This review presents the mechanisms and effects of viral entry and how pollution can potentially modulate pathophysiological processes in the heart. We aimed to concisely summarize studies examining cardiovascular (CV) outcomes in COVID-19 patients and postulate on how particulate matter can influence these outcomes. We have also reviewed evidence on the use of rennin-angiotensin system (RAS) inhibitors, namely, ACE inhibitors and angiotensin receptor blockers, in patients with COVID-19. The interplay of pollution and SARS-CoV-2 is essential to understanding the effects of accentuated cardiovascular effects of COVID-19 and deserves in depth experimental investigations.

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first emerged in the Hubei province of China in December 2019 and rapidly spread worldwide to pandemic levels. The World Health Organization (WHO) officially named the novel disease as Coronavirus Disease 2019 and declared the outbreak as a public health emergency of international concern. 1 It has now been over six months since the outbreak and as of August 31 2020, there have been 25,251,334 confirmed cases and 846,841 fatalities reported worldwide. 2 The initial clinical reports of COVID-19 predominantly showed respiratory tract symptoms, characterized by fever, cough, fatigue, pneumonia and acute respiratory distress syndrome. 3 The lungs were initially thought to be the primary target of COVID-19, however other clinical manifestations including cardiac complications, vascular impairment, and stroke are becoming increasingly evident. 4, 5 As the virus affects and damages other vital organs and tissues, COVID-19 is now regarded as a systemic disease.

In the February 2020 issue of Lancet, Huang and coauthors reported that 12% of patients with COVID-19 were diagnosed with acute myocardial injury with elevated levels of troponin I (TnI) 3 , a cardiac-specific biomarker of myocardial injury. 6 In a similar retrospective study, critical COVID-19 patients exhibited 40-fold higher TnI levels and onset of atrial fibrillation. 7 Other markers of cardiac inflammation such as C-reactive protein and NT-proBNP were also found to be elevated 8 and are likely associated with infection-induced myocarditis and ischemia. 9 In addition, COVID-19 infections have been shown to be associated with heart failure and arrhythmias. 10 Table 1 lists several cardiovascular complications of COVID-19 reported in recent clinical studies.

It remains arguable whether COVID-19 infection and cardiac complications are causally linked, directly associated, or if any externally modifiable factor is influencing this correlation. In a recent study by van Doremalen, it was shown that SARS-CoV-2 can remain viable and infectious in aerosols (particulate matter; PM) for hours and on surfaces for days. 11 This could partially explain the reason behind the more severe fatality and transmission rates of COVID-19, unlike those observed with influenza viral infection. 9 Fine particulate matter may damage the respiratory system by inducing oxidative stress, leading to serious health problems including decreased resistance to respiratory viral infections. 12 Recent literature clearly indicated that more polluted places are likely to have increased COVID-19 mortality. 13, 14 These are not the first studies to highlight a substantial link between air pollution levels and deaths from viral diseases. A study published in 2003 found that severe acute respiratory syndrome (SARS) patients were 84% more likely to die if they lived in areas with high levels of pollution, although these results were not adjusted for important confounders, such as age, gender and other comorbid conditions. 15 A key determinant of the spread of COVID-19 has been identified as population density. 16 As denser population catalyzes the spread of the virus 17 , the possibility of the outbreak and transmission of the disease is higher in the urban areas. However, there may be an effect from ambient air pollution as increased population density is associated with increased pollution. 18 The direct or indirect correlation between COVID-19 infection, cardiovascular injury, and PM pollution is the main focus of this review as

we attempt to answer the question: Does PM pollution act as a co-factor for viral entry into the heart and exacerbate the susceptibility and severity of cardiovascular disease (CVD) and deaths due to COVID-19?

The novel coronavirus SARS-CoV-2 , which is closely related to SARS-CoV, has been found to infect cardiac tissue via a similar mechanism involving ACE2. 19 ACE2 is found to be expressed in a wide variety of tissues, with some of the highest levels in the lungs and heart. 20,21 ACE2 converts angiotensin I and angiotensin II into potent vasodilators angiotensin 1-9 and angiotensin 1-7, respectively. 22 By counteracting the vasoconstrictive actions of angiotensin II, ACE2 negatively regulates the reninangiotensin system and plays a role in blood pressure homeostasis. 22 The key player for viral entry into the host cells is the spike (S) protein, which is responsible for ACE2 binding and fusion to the host cell ( Figure 1 ). 19 Before the S protein can fuse, it must first be cleaved by a host cell protease known as transmembrane protease serine type 2 (TMPRSS2). This priming by TMPRSS2 is believed to be essential for cell entry by SARS-CoV-2, just as it was for SARS-CoV. In the absence of TMPRSS2, SARS-CoV was found to alternatively be primed by other host cell proteases, such as Cathepsin B/L, which is also thought to be the case for SARS-CoV-2. 19 Inhibition of Cathepsin B/L significantly reduced SARS-CoV-2 entry, suggesting Cathepsin B/L dependence.

However, based on investigations of both previous viral disease outbreak SARS and middle eastern respiratory syndrome (MERS), Cathepsin B/L is not believed to be essential for the viral spread and pathogenesis, unlike the priming by TMPRSS2. 19 

ACE2 Regulation: Once SARS-CoV-2 binds to ACE2 and gains entry into the host cell, there is a subsequent downregulation of ACE2 that results in reduced degradation of angiotensin II, a potent vasoconstrictor and culprit of endothelial damage and myocardial dysfunction. 23 The resulting increased levels of circulating angiotensin II binds angiotensin II type 1 (AT1) receptors, along with sympathetic nervous system activation, are believed to contribute to the vasoconstriction and pulmonary damage that results in acute respiratory distress syndrome (ARDS). 23 ACE2 can counteract the untoward effects of angiotensin II (by converting it to angiotensin 1-7) by exerting vasodilatory, anti-inflammatory, antioxidant and antifibrotic effects. 24, 25 An important role of ACE2 in contributing to the cardioprotective effect was demonstrated by Loot et. al.. 26 Their findings showed reversal of cardiac dysfunction and restoration of vascular endothelial response post myocardial infarction after angiotensin 1-7 infusion. ACE2 gain-of-function studies revealed that it mediates favorable post-MI remodeling and recovery 27 , and improved left ventricular diastolic function through reduction in oxidative stress, fibrosis, and myocardial hypertrophy. 28, 29 Alternatively, mice lacking ACE2 (lossof-function) were more likely to develop left ventricular systolic dysfunction and HF with reduced ejection fraction. 20 Previous experimental and clinical studies demonstrated that SARS-CoV mediates myocardial inflammation associated with ACE2 downregulation and is likely responsible for the adverse cardiac outcomes in SARS patients. 20 Based on previous evidence, we speculate that binding of SARS-CoV-2 is likely to alter ACE2 function, resulting in adverse cardio-respiratory effects.

Exaggerated Immune & Inflammatory Response: The overwhelming inflammatory response leading to production of large quantities of cytokines, known as the "cytokine storm", is an indirect mechanism by which SARS-CoV-2 damages the myocardium. 10 This "cytokine storm" is usually seen in more critically ill patients, such as those with ARDS and multiple organ failure. 30 It has been shown that severely ill COVID-19 patients had decreased expression of IFN-γ in CD4+ cells, along with an exaggerated release of cytokines and chemokines, resulting in damage to the host cells and tissues. 31 The magnitude of the "cytokine storm" strongly correlates with infection severity, as severe COVID-19 cases were found to have significantly higher levels of IL-6, IL-10, and TNF-α, along with more severe lymphopenia compared to moderate cases. 31 IL-6 not only stimulates production of other cytokines, but also contributes to vascular leakage, interstitial edema and has been shown to cause myocardial dysfunction. 32 Indeed, inflammation has been considered as an important risk factor for long QT-syndrome (LQTS) and TdP, primarily via direct electrophysiological effects of cytokines on the myocardium. 33 A recent study revealed an association between increased levels of IL-6 and high TnI levels, indicating "cytokine storm" as a contributor to myocardial injury. 34 Systemic Effects -Myocardial Oxygen Supply/Demand Mismatch: SARS-CoV-2 primarily causes pulmonary manifestations such as pneumonia and acute respiratory distress syndrome. The association between pneumonia and cardiac complications has been documented previously 35 and various studies also confirmed that extrapulmonary complications of acute respiratory infections serve as triggers of CVDs . 36 Hypoxemia and hypotension due to pulmonary dysfunction leads to insufficient oxygen supply to the myocardium. As a result of ongoing hypoxia, the cardiometabolic demand is increased in the wake of inadequate supply further causing the imbalance between myocardial oxygen supply and demand. 37 As the disease progresses, the oxygen supply/demand ratio becomes increasingly aggravated ultimately leading to myocardial damage.

Respiratory and metabolic acidosis and electrolyte and acid base abnormalities are other systemic contributors leading to myocardial damage. 38 Consequently, (less cardiac output and ineffective circulating volume) the sympathetic nervous system is activated to maintain circulatory homeostasis and perfusion to vital organs by increasing inotropy and chronotropy of the failing myocardium. 39 In the long term, these mechanisms turn maladaptive by further compromising coronary perfusion 40 and are responsible for disease progression leading to myocardial stunning, arrhythmias and sudden death. 41 COVID-19 associated extra-pulmonary complications may manifest as cardiomegaly and pericardial effusion on chest CT imaging. 42 

Air pollution represents a serious public health issue as it ranks 9 th in overall mortality worldwide 43 , and hence is recognized as one of the top ten global health burdens 44 .

Particularly through its impact on cardiovascular diseases, it causes as many as 8.9 million premature deaths per year worldwide. 45 Besides nitrogen dioxide (NO2) and ozone (O3), the current focus of research is mainly on particulate matter (PM2.5 and PM10) as these occur frequently at elevated concentrations in large metropolitan areas.

Particulate matter is comprised of solid particles and liquid droplets from various sources and are classified according to their aerodynamic diameters: coarse (PM10), fine (PM2.5), and ultrafine (PM0.1). The size, surface area and chemical composition determines the toxicity of PM. 46 According to various particle size deposition models 47, 48 , particles with aerodynamic diameter >10 μm deposit in the nose or extrathoracic airway, while inhaled particles of the size range 3-6 μm reaches and deposit in the lower respiratory tract. Particles between 2.5-0.1 μm can penetrate deep into the alveolar region. In particular, PM2.5 and PM10 have been shown to act as carriers for viral spread and facilitates the prolonged survival of microorganisms 49 , including viruses 50 , which could partly explain the association of air pollution with the increased spread of respiratory viral infections. 50 Ye et al. (2016) demonstrated a positive correlation between the infection rate due to respiratory syncytial virus and PM fractions (PM2.5; r = 0.446, p < 0.001 and PM10; r = 0.397, p < 0.001). 51 Other similar studies provided evidence on the interaction between PM and viruses 52 and highlighted that an increase in PM2.5 concentration by 10µg/m 3 was associated with higher incidence of viral infection. 53 With recent studies specifically exploring the PM-SARS-CoV-2 interaction, data is now available confirming this lethal association. Experiments conducted by Van Doremalen et al. indicated that the transmission of SARS-CoV-2 by aerosols is plausible, since it remains viable and infectious for hours and on surfaces for up to days. 11 The first preliminary evidence showed the presence of SARS-COV-2 RNA on PM particles in Bergamo, Italy, suggesting that the virus can create clusters with the particles which can be carried and detected on PM10. 54, 55 The authors inferred that by creating clusters with PM, SARS-CoV-2 reduces their diffusion coefficient, which enhances the persistence of the virus in the atmosphere and could serve as an index for COVID-19 diffusion. Few other laboratory experiments on aerosol sampling have investigated the presence of SARS-CoV-2. In a recent study, Liu and colleagues analyzed the presence of SARS-CoV-2 RNA in particle samples collected inside two designated hospitals in Wuhan, and quantified the copy counts of the virus using a droplet-digital-PCR-based detection method. 56 Their data showed the presence of SARS-CoV-2 on two different size ranged particles, one in the range of 0.25 and 1.0 μm (submicrometer) and the other > 2.5 μm (supermicrometer). The authors indicated that the airborne route could be a possible pathway for contamination. Similar findings are confirmed from air samples collected at the Nebraska University Hospital. 57 The authors pointed out that SARS-CoV-2 may spread through both direct (droplet and person-to-person) as well as indirect mechanisms (contaminated objects and airborne transmission). A more recent data from air samples collected from ICU and general wards of COVID-19 patients at the National Centre for Infectious Diseases, Singapore also revealed the presence of SARS-CoV-2 RNA on aerosol particles of 1-4 μm in size. 58 On the contrary, Ong et al.

did not confirm the presence of airborne SARS-CoV-2 RNA swab 59 , but the negative results are likely due to small sample size, inconsistent methodology, and dilution of the air sample because of continuous air exchanges. Based on these observations, it might be conceivable that the higher the levels of atmospheric PM, the more binding of SARS-CoV-2 and thus more chances of an individuals' exposure to the virus. These studies also underscore the need for future studies designed to detect virus RNA survivability on PM samples especially in highly polluted countries like India as this vital information could serve as a biomarker for COVID-19 transmission.

Several recent studies have now documented that PM acts as a medium for the aerial transport of SARS-CoV-2 60 Italy can be considered as an additional co-factor of the high level of lethality recorded in that area. 13 Spain) and found positive correlations between PM2.5 and infection frequency. 67 Similar potential correlation between air pollution and COVID-19 mortality has also been described in several other studies. 68, 69 These initial data clearly indicated that PM favors not only the virus pathogenicity but is also increased the effectiveness of virus spread (by creating a suitable microenvironment for its persistence) and mortality rates due to COVID-19. These observations also corroborate with previous studies demonstrating that PM may act as a "carrier" for the viral droplet nuclei, eventually leading to the spreading of viral infections. 12,51

The majority of reports have focused on the pulmonary effects of PM compared to cardiovascular effects, leading to some doubt about the causal association between pollution and CV mortality. There is now convincing evidence from animal as well as human studies that PM has direct interactions on sites remote from the lungs. A study conducted in hamsters demonstrated that a substantial fraction of intratracheally-instilled ultrafine particles (radiolabeled denatured albumin with diameter <100 nm) diffuses from the lungs into the systemic circulation. 70 Another study in rats showed that ultrafine silver particles entered the systemic pathways after inhalation. 71 Similarly, PM can pass directly into the circulation in human studies. 72 75, 76 In addition, positive associations between short-term air pollution and viral infections has also been reported. 77 The severity of viral infections is influenced by the number of extra-pulmonary manifestations, including cardiovascular complications 78 such as myocarditis, ischemic heart disease, and idiopathic diabetic cardiomyopathy (iDCM). 78 Furthermore, due to an imbalance between increased metabolic demand and reduced cardiac reserve in the wake of viral infection, chronic cardiovascular disease may become unstable.

The combined impact of 1) the PM-SARS-CoV-2 interaction, 2) pre-existing heart conditions, and the 3) lone effects of PM on an individual's cardiovascular system is not yet fully elucidated. Thus, the question remains how PM aided SARS-CoV-2 entry into the heart affects cardiovascular outcomes in COVID-19 patients (with or without preexisting conditions)?

Evidence from previous viral disease outbreaks such as SARS and MERS point out that coronaviruses affect the cardiovascular system. 79 98 Further, special consideration has been suggested for those with inherited arrhythmia syndromes due to the arrhythmogenic potential of COVID-19. 85 It is becoming more apparent that SARS-CoV-2 can lead to both novel cardiovascular effects and exacerbation of existing CV comorbidities resulting in a higher rate of mortality.

On both a physiological and pathological basis, a strong heart-lung connection exists. In the setting of severe pulmonary infections, the exaggerated inflammatory response induced by cytokines is thought to affect other organs, such as the heart, by "spilling over" into the systemic circulation. 99 This "spill over" has been proposed as an indirect mechanism for myocardial injury. 100 Moreover, it has also been suggested that the potential for myocardial damage seen in infected patients can be indirect due to reduced oxygen supply, severe lung failure, and/or the previously discussed cytokine storm. 101 The severe hypoxia and ARDS that accompanies severe respiratory infections like COVID-19 has been suggested as a key contributor to development of this myocardial injury 83 , mainly due to oxidative stress and increased cardiometabolic demand. 96 Conversely, it is proposed that the myocardial damage may be directly due to ACE2 downregulation in the cardiac tissue 101 , as discussed previously. The presence of this vigorous inflammatory response in the myocardium can also lead to myocarditis, heart failure, cardiac arrhythmias, and even sudden cardiac death. 89 Despite the majority of available clinical analyses being preliminary with small sample sizes, great consideration and further investigation is warranted regarding the potential for cardiovascular complications, both direct and indirect, in COVID-19 patients.

Firstly, SARS-CoV-2 infects cardiac tissue using ACE2 as 'entry gates' present on cardiomyocytes, pericytes, and endothelial cells 97 and causes direct damage to the myocardium. It has been shown previously that chronic exposure to PM2.5 increases both pulmonary 102, 103 and circulatory ACE2 expression. 104 The massive viral binding to ACE2 reduces its availability resulting in decreased production of angiotensin 1-7

(vasodilator) and an excess of angiotensin II (vasoconstrictor). Virus-mediated depletion of ACE2 appears to be crucial in mediating cardiac injury. 20, 101 In an attempt to We speculate that patients who were exposed to high levels of PM2.5 overexpress ACE2, which in turn facilitates more viral binding and consequent ACE2 depletion leading to exaggerated disease response. Thus, it can be hypothesized that in areas where PM levels are high such as northern Italy, COVID-19 patients present with exaggerated cardiac complications.

Secondly, smaller PM particles (particles with an aerodynamic diameter ≤ 2.5 micrometers) are known to enter the heart directly via translocating into the blood stream resulting in inflammation. 74 Recent reports indicated that SARS-CoV-2 absorbs and can remain viable on the surface of PM (PM-SARS-CoV-2 interaction). The PM-SARS-CoV-2 interaction might be responsible for giving additional access to the virus in reaching distal airway/alveoli and travelling indirectly to the heart. Where exposure to PM is associated with cytokine/chemokine production and inflammation 112 , SARS-CoV-2 also elicits an exaggerated host immune response. 113 It is thus conceivable that both PM and SARS-CoV-2 together elicits high grade systemic inflammatory state ('cytokine storm') characteristic of COVID-19. 83 In this regard, the presence of myocardial inflammation and viral particles have been reported recently in the endomyocardial biopsy of a COVID-19 patient. 114 Other reports in COVID-19 patients have found high viral load-induced fulminant myocarditis with inflammatory cell infiltration. 32, 115 Interestingly, studies have shown that inflammatory signals are capable of increasing the expression of ACE2 in the respiratory epithelium 102, 116, 117 and that increased ACE2 exerts anti-inflammatory action. [118] [119] [120] The crucial role of ACE2 in defending lung epithelial cells from the inflammatory action of PM2.5 has also been shown previously by Lin et al. 102 However, in the current context, we speculate that the upregulation of anti-inflammatory ACE2 (in response to pro-inflammatory stimuli), is unable to counteract augmented inflammation because the virus, by binding to ACE2, blocks its activity and likely contributes to severe SARS-CoV-2 infection. respectively), an exceptionally high number of COVID-19 positive cases were present and 50-75% of the positive cases were asymptomatic. 128 It has also been demonstrated that serious COVID-19 patients have 60 times higher viral loads compared to mild cases, suggesting that higher viral loads might be associated with more severe clinical outcomes. 129 Thus, it can be postulated that less exposure to PM2.5 could lead to lower expression of ACE2 and subsequently less viral load and mild symptoms. 128

Angiotensin I converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers 146 Another study using data from Danish national administrative registries concluded that prior use of ACEI/ARBs was not significantly associated with COVID-19 diagnosis in patients with hypertension or with severe disease. 147 In addition, ACEIs/ARBs were not found to be associated with COVID-19 severity in a study conducted in the USA. 148 Furthermore, few observational studies also found that ACEIs/ARB use was not associated with increased severity of COVID-19 illness. 144, [149] [150] [151] [152] [153] [154] [155] 156 The results from these retrospective and observational studies suggest that treatment with ACEIs or ARBs is not associated with worse outcomes in infected patients.

All of the studies systemically reviewed and included in this manuscript indicate that 

Taken together, a compelling association between PM and SARS-CoV-2 appears to exist, and this association facilitates the longevity of virus particles in atmosphere, increases transmission and pathogenicity, and influence the incidence and severity of COVID-19 CV outcomes. In such a context, it would be valuable to carry out additional experimental studies to 1) screen PM for virus contamination, 2) determine the particle size to which the virus binds, 3) confirm the presence of the SARS-CoV-2 RNA on PM, and to 4) investigate the duration for which the virus remains active and infectious in association with PM. Further investigations to study the effect of the virus within the myocardium will likely facilitate future diagnostic and therapeutic modalities that may improve treatment and management of this novel disease.

COVID-19 exerts severe pathophysiological impacts on the CV system, under this scenario, discontinuing RAS inhibitors in COVID-19 patients is unwarranted. In fact, serious complications due to discontinuation of these drugs have far more adverse consequences than the surmised adverse effects. It is likely that due to pneumonia, COVID-19 patients will experience adverse CVD outcomes in the future. Thus, followup studies are essential amongst survivors. Future studies also warrant detailed randomized-controlled epidemiological studies in multiple geographic regions affected by COVID-19.

This work was supported in part by the OSU College of Medicine Roessler Research Scholarship (JA) and National Institutes of Health R01 grants AG057046, HL139348, and ES019923 to LEW. 

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Effects of spironolactone and eprosartan on cardiac remodeling and angiotensin-converting enzyme isoforms in rats with experimental heart failure

Myocardial infarction increases ACE2 expression in rat and humans

ACE2 deficiency modifies renoprotection afforded by ACE inhibition in experimental diabetes

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Association of Renin-Angiotensin System Inhibitors With Severity or Risk of Death in Patients With Hypertension Hospitalized for Coronavirus Disease 2019 (COVID-19) Infection in Wuhan, China

Renin-Angiotensin-Aldosterone System Blockers and the Risk of Covid-19

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Renin-Angiotensin-Aldosterone System Inhibitors and Risk of Covid-19

COVID-19 with Different Severities: A Multicenter Study of Clinical Features

Association of Inpatient Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Mortality Among Patients With Hypertension Hospitalized With COVID-19

Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension

Angiotensin II Receptor Blockers and Angiotensin-Converting Enzyme Inhibitors Usage is Associated with Improved Inflammatory Status and Clinical Outcomes in COVID-19 Patients With Hypertension

Hypertension in patients hospitalized with COVID-19 in Wuhan, China: A singlecenter retrospective observational study

Anti-hypertensive Angiotensin II receptor blockers associated to mitigation of disease severity in elderly COVID-19 patients

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