**6. Environmental agents in cardiovascular risk**

The relationship between air pollution and negative health outcomes has been well established in the literature over the years, first reported with outcomes following the Great London Smog of 1952 when health crises were observed following the event. While the initial correlation was thought to be tied to the pulmonary system, years later the reports were re-examined and showed that cardiac mortality – not pulmonary – was more directly associated with the increase in mortality [98]. In addition, the reexamination has prompted numerous others to delve further into this topic and with technological advancements, research has expanded to include other potential sources of cardiac toxicity such as nanoparticles of various heavy metals. Along with the pulmonary diseases commonly associated with these materials, acute myocardial infarction, atherosclerosis, and increased peripheral resistance have all been implicated with increased exposure [34, 35].

Such findings prompted the WHO to release air pollution guidelines in 2006 in hopes of reducing acute and chronic disease associated with different air pollutants worldwide. Air pollutants can be placed into two broad categories, natural phenomena and human activities [99–101]. Human activities are related to industrial processes and account for pollutants like CO and SO2, which cause most of the harmful adverse health effects. Natural phenomena on the other hand are related to volcanoes, wildfires, and land dust. In addition to this gaseous type of air pollution, particulate

matters (PM) are a major player in negative health outcomes. The two major categories of PM are based on size, which are PM2.5 and PM10 – each having a different symptom profile of which the mechanism of action has not completely been resolved. However, with size, the aerodynamic diameter varies. PM10 have an AD range from 2.5 to 10 μm which allows for deposition into nasal and upper airways while PM2.5 have an AD range of less than 2.5 and less than 0.1 μm, which allows them to penetrate lung alveoli and gain access to the bloodstream [33–35].

Likewise, research into the health effects of nanoparticles is more novel and has been less refined; thus, regulations regarding exposure to these materials are not fully resolved. However, there have been numerous studies highlighting the correlation between exposure to these materials and the resultant impacts on cardiovascular function. Six of the most common metal nanoparticles are titanium oxide, zinc oxide, silver, iron oxide, carbon and silicon oxide nanoparticles. Of this list, iron oxide, carbon, and silicon oxide nanoparticles are not only used commercially, but also are used for cancer therapies, drug delivery, as well as other diagnostics. Most of these nanoparticles are associated with increasing the generation of reactive oxygen species or are pro-inflammatory, thus increasing pro-inflammatory cytokines [102].

#### **6.1 Ambient particulate matter**

While PM10 has adverse associated health effects, acute exposure to PM2.5 resulted in higher death rate related to cardiovascular disease. Short term exposure to particulate matter can result in induction of the systemic oxidation, inflammation, and increased platelet reactivity as result of elevated serum fibrinogen. However, not all people are impacted to the same magnitude by exposure to these pollutants. Those with pre-existing cardiovascular disease, diabetes, smoking status, age, and pulmonary disease like COPD can have increased responses to exposure.

The relationship between ambient particulates has been most heavily studied in the context of impact on blood pressure. According to a study by Gold et al., with every ~5–6 μg/m3 increase in PM2.5, there was a significant increase in cardiovascular disease ranging from 0.5 to 1.5% [103]. In addition, studies have shown that increases in PM2.5 are associated with increases in systolic and diastolic blood pressure. Brook demonstrated that in a period of 5 days in Boston, MA, an increase of 10.5 μg/m3 in PM2.5 resulted in a 2.8 mmHg increase in SBP and 2.7 mmHg increase in DBP [98]. The increased blood pressure would be consistent with impaired endothelial reactivity and enhanced constrictor responses that we demonstrated in experimental animals exposed to ambient particulates [104–106]. While is tempting to consider that the effects are attributable to increased sympathetic autonomic balance, we also have demonstrated that in older, heart-failure prone animals, there was increased risk of heart failure exacerbation, but increased risk of brady arrhythmias, and increased cardiac parasympathetic tone [107].

Even when ambient particulates do not alter the incidence of event, we and others have demonstrated that prior exposure can increase the severity of infarction, reduce the effectiveness of reperfusion, and aggravate progression of heart failure [33–35, 99–101, 104–107]. We also have demonstrated that short, episodic exposure to particulates beginning 4–7 days after an ischemia–reperfusion event was associated with increased adverse remodeling in the ventricle, increased fibrosis and decreased cardiac function 30 days post MI, compared to un-exposed animals (**Figure 2**).

*Predicting Risk of Emerging Cardiotoxicity DOI: http://dx.doi.org/10.5772/intechopen.105040*

#### **Figure 2.**

*Summary select echocardiographic findings on days 7, 14 ad 21 after LAD occlusion in a rat model of infarction in sham animals (blue), those with infarction/vehicle exposure (yellow), and those with MI and subsequent exposure to diesel particle on days 4, 11 and 18 (red) following myocardial infraction) on diesel particle exposure on days 4, 11 and 18. MI produced a dilation of the LV that was stable in the sham group, but progressively increased in the diesel exposure group (panel a). MI produced a thinning of the infarcted myocardial wall that was relatively stable in the sham group but progressed substantially in the diesel exposed group (panel B). Consistent with the structural changes, fractional shortening progressively decreased in the diesel group, while the decrease in the sham group was stable. (\* indicates p < 0.05 for the comparison indicated; previously unpublished data).*

#### **6.2 Engineered nanomaterials (nanoparticles)**

Nanomaterials have wide and varied commercial applications ranging from athletic equipment to clothing, to sunscreens, to drug delivery systems. Studies


#### **Table 1.**

*Summary of active mediators increased in blood or tissue following exposure to various forms of nanomaterials and known to have cardiac effects (assembled from data summarized in 103).*

#### *Predicting Risk of Emerging Cardiotoxicity DOI: http://dx.doi.org/10.5772/intechopen.105040*

regarding the impact of nanoparticles on the cardiovascular system have shown various mechanisms of action. Three, general, well-accepted mechanisms for pulmonary exposure to nanoparticles have been proposed and demonstrated in several studies: 1) nanoparticles trigger lung-mediated systemic inflammatory response or oxidative stress – altering cardiac functioning 2) translocation of the nanoparticles from the lungs to the circulatory system through the alveoli (as seen with PM2.5) 3) alteration through a neurogenic pathway. These studies demonstrate the deleterious effects on the cardiovascular system from the nanoparticles though the exact mechanisms are not completely clear and likely involve a combination of the general proposed mechanisms [108]. The particular effect for any given nanoparticle varies as a function of its composition and is summarized in **Table 1**.

Iron oxide nanoparticles are commonly used in medicinal applications like drug and gene therapy delivery and cancer therapy [102]. The exposure to iron oxides can result in increased vascular permeability and decreased acute heart rate. However, the mechanism of action is not completely resolved though iron oxides are associated with oxidative damage through the generation of ROS.

Carbon nanoparticles are extremely versatile, resulting in them being found in a large range of substances. In medicine, carbon nanoparticles can be found in cancer therapies, drug delivery, gene therapy, sensors, and plastics. Their small particle size, large surface area, and association with catalytic metals are some of the reasons these nanoparticles (SWCNTs) are considered toxic agents which induce ROS generation and oxidative damage via the Fenton reaction. Exposure to these particles is often through the pulmonary route and due to their size, can be transported to secondary organs. Toxic effects can be oxidative damage and recruitment of inflammatory factors as seen in bronchoalveolar lavage fluids. These effects commonly present as decreases in thiol contents, elevation in lipid-peroxidation produces, and increase in liver and heart inflammatory markers like ET-1, ACE, MCP-1, IL-6, IL-10, and IL-12 [102]. Experimental studies of cardiac ischemia and reperfusion validate the increased risk of cardiac injury and the role of induced inflammatory pathways [109–113].

Silicon oxide nanoparticles are a commonly used commercial nanoparticle as well as their use in drug delivery, gene therapy, and diagnosis. These small particles readily mix in air and the common method of exposure is occupational during production. Ironically, silica NPs have recently been used for adenosine delivery for its cardioprotective effects [102]. However, these nanoparticles can also produce ROS which can lead to the release of cytokines and subsequently apoptosis. Study results in mice show an increase of CRP, TNF-alpha, and IL-6. Cardiac markers like ET-1, D-dimer, LDH, CK-MB, and eTNT increased after the silica exposure [102].

Many of the compounds discussed in this chapter have become ubiquitous today with increasing use of nanoparticles in products and ongoing air pollution of the industrialized world. Though strong correlations exist between common pollutants and cardiotoxicity, further research into the exact mechanisms, safe levels of exposure, and chronic effects need to continue.

## **7. Autoimmune mechanisms as an emerging source of cardiovascular risk**

Idiopathic dilated cardiomyopathy (DCM) is a myocardial disease characterized by a progressive depression of myocardial function and ventricular dilation. DCM is the leading cause of severe heart failure, and the most common cause for heart

#### **Figure 3.**

*Cumulative 6 year incidence of a first cardiovascular event in patients with diabetes as a function of pre-existing cardiac autoantibody number at the onset of the study (drawn from data in [117]).*

transplantation. Chronic heart failure remains one of the most important sources of "all cause" morbidity and mortality, with a high frequency of hospital readmission, and a total health care expenditure burden more than twice the cost for all forms of cancer combined. The causes of DCM remain unclear, but research has been directed along three major avenues: genetic factors, viral persistence, and immunological abnormalities, including autoimmunity. Myocarditis is an inflammatory disease and some reports suggest that myocarditis and DCM represent acute and chronic stages of organ-specific autoimmune disease of the myocardium.

General characteristics supporting an autoimmune hypothesis are familial aggregation, a weak association with HLA-DR4, abnormal expression of HLA class II antigens on cardiac endothelium on endomyocardial biopsy, and the presence of organ and disease specific cardiac IgG class autoantibodies in the sera of affected patients and symptom free relatives. Supporting the genetic associations are several parallel lines of evidence. The incidence of cardiac complications is significantly higher in patients with Type I diabetes than it is in with other forms of diabetes. Type 1 diabetes is an autoimmune disease and relationship between Type 1 diabetes and autoimmune myocarditis has been suggested [114]. Similarly, Celiac disease, also with autoimmune components, has been associated with autoimmune myocarditis [115]. Type I diabetes and celiac disease, both autoimmune, have been associated with a high prevalence in Saudi children [116].

The incidence of cardiac complications is significantly higher in patients with Type I diabetes than it is in with other forms of diabetes, and the presence of cardiac autoantibodies in diabetic patients is strongly associated with the probability of subsequent cardiac event (**Figure 3**). Autoantibodies are present in between 30 and 90% of all patients with DCM [118–121]. Maguy has shown recently that there is an autoantibody signature associated with sudden cardiac arrest [36], the presence of autoantibodies against HSP65 is strongly associated with post-operative atrial fibrillation [122] and cardiac autoantibodies have been suggested as significant mediators in COVID related cardiac dysfunction and a possible source of increased cardiovascular risk in COVD survivors [38, 39]. Cardiac autoantibodies are present in at least 10% of post-myocardial infarction patients and may explain disproportionate loss of function in a subset of patients relative to that predicated on the ischemic injury

#### *Predicting Risk of Emerging Cardiotoxicity DOI: http://dx.doi.org/10.5772/intechopen.105040*

per se. Repeated infarctions, stabilized by repeated revascularization may also be repeated episodes for sensitization and expansion of an autoimmune signal leading to increased rates of deteriorating function and heart failure [39].

The possibility that an auto-immune process could complicate post-infraction recovery has been suggested for more than 40 years [123, 124]. High titers of autoantibodies to the beta-1 adrenergic receptor were identified in patients with Chagas disease. The beta-1 adrenergic autoantibody is the most studied so far. It meets Witebsky's postulates for indirect and direct autoimmune etiology. The autoantibody is stimulatory, ultimately leading to increased apoptosis sufficient to cause loss of function. Those results are consistent with models of catecholamine cardiotoxicity and with premature DCM in transgenic mice with cardiac specific overexpression of beta-1 adrenergic receptors. Signaling may be ERK1/2 dependent, but some evidence suggests that the mechanism is independent/different from standard isoproterenol stimulated beta-adrenergic responses [118–120]. Kaya [37] has demonstrated a strong association between cardiac autoantibodies and heart failure, as have others [125, 126], with an emphasis on the myosin molecules as the primary antigenic drive [118–121, 126–128]. Serum levels of troponin are the single best indicator of myocardial injury, but immunizing mice with Troponin I caused T-cell activation and cardiac inflammation with elevated RANTES, MCP-1, MIP1-alpha, MIP1-beta, MIP2, T-cell activation gene 3, CCR1, CCR2 and CCR5. It's clear that the cardiac autoimmune response can be both antibody and T cell mediated [129]. General antiinflammatory effects (carvedilol, prednisone) or macrophage dependent inflammation (Olmesartan) all have shown efficacy is reducing the progression in experimental models of DCM.
