**2. Pathophysiology of MACE related to PAD and atherosclerotic risk factors**

In patients with diagnosed PAD, the risk of MACE appears to be greater than patients without PAD [3, 14]. The major atherosclerotic risk factors including DM, hypertension, dyslipidemia, and smoking are increased the MACE due to the atherosclerotic involvement of arterial system in vascular beds that affect blood supply to the target organs (**Figure 2**).

#### **Figure 2.**

*The relationship between atherosclerotic risk factors and major adverse cardiovascular events with overlap in multisite atherosclerotic vascular disease. HTN, hypertension; DM, diabetes mellitus; DLD, dyslipidemia; CKD, chronic kidney disease; CRP, C-reactive protein; CAD, coronary artery disease; LEAD, lower extremity arterial disease; CVD, cerebrovascular disease; MACE, major cardiovascular events; MI, myocardial infarction.*

The metabolic abnormality in patients with DM lead to hyperglycemia, insulin resistance, and increasing of free fatty acid. Three fundamental dysmetabolism process led to endothelial dysfunction and atherosclerosis [34]. Hyperglycemia increases the oxidative stress by increasing of reactive oxygen species (ROS). In addition, the cellular mitogenic pathway activation through the mitochondrial generation of the superoxide anion including advanced glycation end products (AGEs), protein kinase C (PKC) activation, and nuclear factor kappa B (NF-κB) are induced by high blood glucose level. In patients with long duration DM, insulin resistance cause endothelial dysfunction, decreasing of nitric oxide (NO) synthase, expression of adhesion molecules, and atherosclerotic lesions [34]. In addition, a thrombosis risk in DM is increasing though the hypercoagulation and platelet aggregation. The elevation of plasminogen activator inhibitor 1 (PAI-1), tissue factors and decreasing of NO are promoting coagulation cascade and platelet activation. Finally, insulin resistance is also promoted atherosclerotic process due to lipid metabolism disturbance such as high triglycerides (TG), high apolipoprotein B (ApoB), small and dense low-density lipoprotein (LDL), low high-density lipoprotein (HDL) cholesterol [35–37].

In early atherosclerotic process, the endothelial dysfunction is associate with hypertensive patients. A reduction in NO result in a reduced vasodilatory response, and result in an inflammation, thrombosis, and activate coagulation cascade [34, 38, 39]. The repetitive blood pressure alterations in patients with hypertension cause ongoing renin-angiotensin system activation. Angiotensin II, the product of renin-angiotensin system is a potent vasoconstrictor has an impact on the atherosclerotic lesions [35–37]. In the setting of dyslipidemia, a foam cell which is an intracellular droplets of cholesterol ester are occurred under the high LDL and low HDL in peripheral blood. The damaged endothelial of vessel wall cause the foam cells adhere and migrate into the intima layer and developed macrophages. The ongoing thickening of the intima by foam cell is developed after the vascular smooth muscle cell (VSMC) proliferates above the endothelial damaged area until the fibrous cap formation to create the atherosclerotic plaque [40].

*Cardiovascular Complications Related to Lower Limb Revascularization and Drug-Delivering… DOI: http://dx.doi.org/10.5772/intechopen.107973*

Smoking causes an inflammation of vessel wall which related to atherosclerotic plaque formation through interleukin-6, tissue necrosis factor-α, interleukin-1-β, leukocyte, C-reactive protein (CRP), and other inflammatory markers [34, 38, 39]. The endothelial dysfunction by the increasing of ROS productions through the reduction of NO, and activation of enzymes are present in smoker patients. In addition, the prothrombotic state of platelet activation and aggregation are create by increasing of thromboxane A2 (TXA2), von Willebrand factor (vWF), thrombin, fibrin and decreasing of prostacyclin, antithrombotic, and fibrinolytic substances (PAI-1) [35–37].

The atherosclerosis of lower extremity artery is systemic disease which involved other vascular beds that affect blood supply to the cardiac and brain (**Figure 2**). So, it is usually that the LEAD, CAD, and CVD commonly occur together (**Figure 2**). So, the presence of lower extremity stenosis/occlusion is associated with an increased risk of stenosis/occlusion of coronary artery, carotid and vertebrobasilar arterial system which is clinically presented by MI and stroke [3, 14]. 25–70% and 14–19% of patients who present with LEAD often coexists with CAD and CVD, respectively. Conversely, only 7–16% and 18–22% of patients with CAD and severe carotid stenosis are coexists with LEAD, respectively [35]. Patients with severe LEAD which indicate by ankle brachial index (ABI) <0.4 or severe atherosclerosis on anatomic distribution by Trans-Atlantic Inter-Society Consensus for the management of PAD (TASC II) exhibit more extensive calcified and progressive coronary atherosclerosis [14, 35]. Therefore, the MACE is categorized into two fundamental parts including CAD and CVD based on vascular bed involvement which focus on the morbidity (stroke, MI, HF) and mortality (fatal stroke and fatal MI) (**Figure 2**). Currently, updated MACE is expanded to five-point including acute MI, stroke, hospitalization for unstable angina or revascularization procedures, HF, and cardiovascular mortality [3, 4, 14, 35, 36].

The risk of ongoing development to CLTI appears to be greater in patients who have a pre-existing CAD and CVD such as history of stroke, MI or HF. Comparing with PAD, patients with CLTI have a higher risk of MACE and premature death due to cardiovascular disease. In patients with developed CLTI, the risk of amputation and mortality rate is extremely increased to 30% and 25%, respectively [3, 14, 35]. For this reason, treatment of patients with CLTI is not only revascularization to salvage a functional limb but also aggressive best medical treatment to reduce MACE. The medical management of patients with PAD including atherosclerotic risk factors modification, statin therapy and antiplatelet therapy for symptomatic PAD can decreased risk of development of CLTI and overall prognosis for patients with PAD [3, 13].
