**5. Non-infectious systemic inflammatory diseases**

Systemic Lupus Erythematosus (SLE) also commonly known as lupus, is a chronic autoimmune disease that can affect the joints, skin, brain, lungs, kidneys, and blood vessels. Widespread inflammation and tissue damage occur in these affected organs. Patients with SLE have been reported to have a higher risk of cardiovascular events compared to the general population. Common risk factors known to increase cardiovascular disease are smoking, hypertension, hyperlipidemia, and diabetes, which are also frequent comorbidities in individuals with lupus [24]. Adding to these traditional risk factors, the systemic and vascular inflammation that occurs in individuals with lupus cause the atherosclerotic process to accelerate.

**Figure 1** summarizes data indicating that Individuals diagnosed with lupus experience cardiovascular events more frequently. Patients recently diagnosed with lupus had a 3-fold increased risk of myocardial infarction and a 2-fold increased risk of ischemic stroke in the next 5 years [22]. It was also noted that the relative risk for MI and Stroke both were significantly increased within the first year of the diagnosis with lupus. The hazard ratio in the first year for cardiovascular diseases was 5.63 (95% CI 4.02–7.87), for myocardial infarction was 6.47 (95% CI 4.42–9.47), and for stroke was 6.28 (95% CI 4.83–8.17) [22].

When assessing heart failure and its relationship with SLE, patients with lupus are found to have increased short-term and long-term risk of heart failure compared to those without SLE [25]. Due to an increased risk of heart failure within a year of a lupus diagnosis, there is a need for earlier cardiac monitoring in this population.

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

#### **Figure 1.**

*Summary of cumulative incidence of cardiovascular disease (top panel), myocardial infarction (middle panel), or stroke (bottom panel) in individuals with systemic lupus Erythmatosis (SLE) compared to control (drawn from data in 22).*

The median age for patients with SLE diagnosed with heart failure was 65 years old. When comparing this population of patients to those without lupus in any age group, the rate of heart failure still remained higher in those with lupus. Patients younger than the median age of 65 years had a higher rate of heart failure than older patients without lupus. This finding correlates with other research which suggests increased cardiovascular risk in younger patients who have lupus. Although there are no definite conclusions regarding the direct relationship between heart failure and lupus, there are several possible theories that extend beyond the common cardiovascular risk factors. For example, those with lupus who are also taking medications such as

glucocorticoids, NSAID's and hydroxychloroquine may enhance their chances of developing heart failure due to specific cardiotoxic drug interactions [25].

Interestingly, SLE affects women more often than men. The association between lupus and cardiovascular disease in women has been shown to be a major cause of premature mortality and morbidity. In a retrospective study looking at women who were diagnosed with lupus within the age range of 35–44 years old, the likelihood of myocardial infarction was increased 52 fold compared to the control group. Comparatively, women diagnosed with lupus who were 45–54 years old, showed a slight decline in the incidence rate for a myocardial infarction. Some plausible explanations include a prothrombic effects of estrogen in combination with hypertension, renal disease, and antiphospholipid antibodies in premenopausal women aged 35–44 years.

In contrast, women of menopausal age (45–54) have declining estrogen levels, which may play a role in providing a cardioprotective effect. While there was a decline in incidence rates for myocardial infarction in the 45–54-year-old women age group, the incidence rates rose again in women 55 and older. Women with SLE display an increase in the estrogen-to-androgen ratio which could explain the increased risk of the SLE during pregnancy and menses. Multivariate analysis of women diagnosed with SLE and having a cardiac event demonstrated that diagnosis of SLE at an older age (39 vs. 34), longer SLE duration (13 vs. 10 years), prolonged use of corticosteroids (11 vs. 7 years), diagnosis of hypercholesterolemia (18 vs. 4%), and postmenopausal status (48 vs. 29%) all contributed significantly to the increased risk of a cardiovascular event in women with SLE [23].

Asthma is a chronic inflammatory airway disease causing around 500,000 hospitalizations per year in America. Because there is a risk of overlapping effects in therapies, individuals with cardiovascular disease often are excluded from asthma studies, and individuals with asthma often are excluded from cardiovascular studies, making a relationship between asthma and cardiovascular disease more difficult to identify.

It is increasingly appreciated that the localized inflammatory airway process is supported by a more generalized systemic inflammatory state and inflammatory processes are major contributors to the evolution and severity of myocardial infarction and their associated reperfusion injuries [29–32]. As such, asthma may be considered as a potential risk factor for enhanced cardiac injury either with an acute myocardial infarction directly, or with reperfusion injury following revascularization therapy. The airway inflammatory response in asthma is driven by T Helper cells type 2 (Th2) and then followed by a systemic inflammatory response characterized by increases in pro-inflammatory biomarkers such as high sensitivity C-reactive protein (hsCRP) and Interleukin 6 (IL-6). Individuals with asthma have higher circulating levels of myeloperoxidase, consistent with higher potential for ROS generation. Asthmatriggered inflammation triggers endothelial release of Platelet-Activating Factor (PAF), which contributes significantly to the airway hyper-responsiveness in asthma, but also may play a role in the increased risk for an acute myocardial infarction in asthmatic patients [26].

Patients with asthma were found to have increased risk of myocardial infarction. Furthermore, the increased MI risk appears to "scale" with the severity of the underlying asthmatic disease. Those with active asthma (individuals on an asthmatic medication) had a risk that was 29% above the increased MI risk seen in patients classified as having non-active asthma (individuals not on asthma medication), but the

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

data are a bit more challenging since those with active asthma also were more likely to be older, diabetic and with increased BMI [26]. In a separate study, it was found that child-onset asthma did not increase the risk of a myocardial infarction, but adultonset asthma was more likely associated with this elevated risk [27].

The elevated risk that is linked between active asthma and an acute myocardial infarction is primarily increased in the first week after an asthma exacerbation. During this study's reference period, the incident rate of MI was 25/100 personyears, but increased to 120.1/100 person-years in the 1–7 day risk period following an asthma exacerbation. In the 8–14 day risk period after an asthma exacerbation, the incident rate dropped to 50.1/100 person-years and further dropped to 38/100 person-years in the 15–28 days post asthma exacerbation [28].

There are many theories linking asthma exacerbation to increased risk of acute myocardial infarction. Acute respiratory infections are the most common cause of asthma exacerbation. Asthma propagates inflammatory pathways and cytokines leading to systemic vascular inflammation and platelet activation, fibrinolysis inhibition, and elevated CRP. Markers such as hsCRP will cause other inflammatory regulators to be upregulated resulting in leukocyte adhesion to the arterial endothelium. Arterial thrombosis results from platelet activation and endothelial dysfunction. The release of inflammatory cells resulting in the accumulation of neutrophils, platelets, fibrin, and red blood cells are characteristic of a Type 1 myocardial infarction [28]. Experimental studies in our lab, using a rag-weed sensitization to produce a hyperresponsive allergic airway model, demonstrated clearly that myocardial ischemia and reperfusion induced larger infarctions, that were associated with higher inflammatory infiltrates, and increased inducible expression of pro-inflammatory adhesion molecules in the contrary vascular that was present only on reperfusion, but was not expressed under basal sensitized conditions [95–97].
