**3. Diabetes and macrovasculopthy: double trouble!**

The alterations in vascular homeostasis that include anatomic, structural, and functional changes in blood vessels lead to multi-organ dysfunction and increase CV risk burden [18]. Diabetic microvascular and macrovascular complications have similar pathogenetic mechanisms and characteristics. The microvascular complications include retinopathy, neuropathy and nephropathy and the macrovascular complications include ischemic heart disease, cerebrovascular disease and peripheral vascular diseases [19–21].

The relationship between diabetes and CVD is complex and multifactorial [22]. Studies demonstrated the following macrovascular complications in T2DM patients:


### **4. Pathophysiology of diabetic macrovasculopathy**

Atherosclerotic vascular disease mainly occurs due to endothelial dysfunction [35, 36], which is the failure of the vascular endothelium to subserve its normal role in vasodilatation and/or vascular homeostasis. The physiological impairment that causes diabetic vasculopathy includes endothelial dysfunction, platelet hyper-reactivity, smooth muscle cell (SMC) dysfunction, impaired fibrinolysis coupled with a tendency for thrombosis and coagulation, and increased inflammation [37, 38]. Endothelial dysfunction links each of these pathological manifestations to develop macrovasculopathy [39]. The main regulatory function of endothelium stimulation includes vasodilatation; other mechanisms include vasoconstriction, and antiplatelet and anticoagulant effects [40]. Endothelial dysfunction lead to morphologic and structural vascular changes [41]. Capillary endothelium rapidly disappears [42], intercellular junctions weaken causing increased vascular permeability [43], protein synthesis is dysregulated and expression of adhesion glycoproteins on endothelial cells is altered [42–45], thereby triggering adherence of monocytes and leucocytes and their increased transendothelial migration [43].

The characteristic feature of diabetic complications includes the progression of atherosclerotic lesion or alteration of vasculature, which is a major cause of CVD development [46]. It was shown that diabetes accelerates these processes by stimulating the atherogenic activity of vascular SMC and these considered as the integral part in the development of atherosclerosis [35]. The process begins as a response to chronic minimal injury to the endothelium leading to it being dysfunctional. Fewer vascular SMCs are also found in patients with diabetes with advanced atherosclerotic lesions [47]. Diabetes alters vascular smooth muscle function in ways that promote atherosclerotic lesion formation, plaque instability and clinical events. Platelet aggregation and adhesion are seen in diabetic patients [48–51]. The process involves an increase in intrinsic platelet activation and decrease endogenous inhibitors of platelet activity [35]. Platelets exhibit enhanced platelet aggregation activity in the early disease state that may precede the development of CVD [48–54]. T2DM also brings about some changes in coagulation of blood. A procoagulant state has been shown in people having diabetes [55–57]. It was demonstrated that there is an increase in plasminogen activator inhibitor-1 (PAI-1), von Willebrand factor (vWF), fibrinogen, factor VII and thrombin–antithrombin complexes in macrovascular diseases and poor glycemic control [55–61].

### **5. Pathogenesis of vasculopathy**

• It was also demonstrated that 18% of diabetic patients have evidence of coronary heart disease at diagnosis, and the risk of a fatal myocardial infarction is increased 2–4 times in

• Fatal cardiovascular events were 70 times more common than deaths from microvascular

• Peripheral vascular disease (PVD) is estimated to be the most costly complication of diabe-

• PVD greatly increases the risk of intermittent claudication, foot ulcers, gangrene, infection

• Lower extremity amputations are at least 10 times more common in people with diabetes than in non-diabetic individuals in developed countries and more than half of all non-

Atherosclerotic vascular disease mainly occurs due to endothelial dysfunction [35, 36], which is the failure of the vascular endothelium to subserve its normal role in vasodilatation and/or vascular homeostasis. The physiological impairment that causes diabetic vasculopathy includes endothelial dysfunction, platelet hyper-reactivity, smooth muscle cell (SMC) dysfunction, impaired fibrinolysis coupled with a tendency for thrombosis and coagulation, and increased inflammation [37, 38]. Endothelial dysfunction links each of these pathological manifestations to develop macrovasculopathy [39]. The main regulatory function of endothelium stimulation includes vasodilatation; other mechanisms include vasoconstriction, and antiplatelet and anticoagulant effects [40]. Endothelial dysfunction lead to morphologic and structural vascular changes [41]. Capillary endothelium rapidly disappears [42], intercellular junctions weaken causing increased vascular permeability [43], protein synthesis is dysregulated and expression of adhesion glycoproteins on endothelial cells is altered [42–45], thereby triggering adherence

of monocytes and leucocytes and their increased transendothelial migration [43].

The characteristic feature of diabetic complications includes the progression of atherosclerotic lesion or alteration of vasculature, which is a major cause of CVD development [46]. It was shown that diabetes accelerates these processes by stimulating the atherogenic activity of vascular SMC and these considered as the integral part in the development of atherosclerosis [35]. The process begins as a response to chronic minimal injury to the endothelium leading to it being dysfunctional. Fewer vascular SMCs are also found in patients with diabetes with advanced atherosclerotic lesions [47]. Diabetes alters vascular smooth muscle function in ways that promote atherosclerotic lesion formation, plaque instability and clinical events. Platelet aggregation and adhesion are seen in diabetic patients [48–51]. The process involves an increase in intrinsic platelet activation and decrease endogenous inhibitors of platelet activity [35]. Platelets exhibit enhanced platelet aggregation activity in the early disease state that may precede the development of CVD [48–54]. T2DM also brings about some changes in

people with T2DM [29].

74 Recent Trends in Cardiovascular Risks

tes in relation to inpatient care.

traumatic lower limb amputations are due to T2DM [34].

**4. Pathophysiology of diabetic macrovasculopathy**

complications [33].

and amputation [32].

It is now well-established that metabolic, humoral and hemodynamic factors contribute to the characteristic dysfunction in diabetic vasculopathy. Prolonged hyperglycemia is considered as a major factor in the pathogenesis of diabetic vasculopathy [62–64]. Hyperglycemia together with several other factors accelerates the progression of atherosclerosis. In particular, hypoglycemia increases oxidative stress [65]; enhances leucocyte–endothelial interaction [66], and glycation of protein, lipoproteins, apolipoproteins and clotting factors, which cumulatively enhance vasomotor tone, vascular permeability, growth and remodeling [42–45]. Moreover, hyperglycemia delays endothelial cell replication, increases cell death [42, 45, 67– 70] and potentially accelerates the atherosclerotic process. Glucose-induced damage occurs through advanced glycation, activation of protein kinase C (PKC), and sorbitol accumulation [71, 72]. Early glycated products on collagen, intestinal tissues and blood vessels undergo a series of chemical rearrangement to form irreversible AGE. AGE product promotes atherosclerotic effect by receptor-mediated biological activities e.g. monocyte emigration, release of cytokines and growth factors from macrophages and increase in endothelial permeability and procoagulant activity [73].

Dysregulation of Lipid metabolism underlies pathogenesis of macrovascular diseases of diabetes origin [74]. Diabetic dyslipidemia causes increase in total cholesterol and low-density lipoprotein (LDL) and -decrease in high-density lipoprotein (HDL) and high triglyceride levels [74, 75]. LDL and other lipoproteins enter the endothelial cells by vascular transport and may get modified by oxidation, glycation, aggregation, association with proteoglycans or incorporation to immune-complexes [76–78].

Insulin resistance is a common feature associated with T2DM and development of CVDs. Insulin resistance precedes the development of overt T2DM and leads to endothelial dysfunction and increases blood plasma levels of endothelin and vWF [79]. Furthermore, insulin resistance may cause increase in arterial blood pressure by triggering several mechanisms, such as, activation of sympathetic nervous system, increase in renal sodium retention, alteration in transmembrane cation transport, augmentation of growth-promoting actions of SMCs and vascular hyperactivity [80–82].

Increased expression and action of various cytokines and growth factors in T2DM may induce macrovascular injury via activation of proliferative cytokines epidermal growth factor [83] and platelet-derived growth factor (PDGF) [84]. Metabolic and hemodynamic factors interact to stimulate the expression of cytokines and growth factors in the various vascular trees, which contribute to the characteristic dysfunction observed in diabetic vasculopathy [20].

Intracellular hyperglycemia has been implicated in the pathogenesis of diabetic complications through the activation of PKC, an intracellular second messenger system [85, 86]. PKC appears to be activated in a range of diabetic tissues including heart and aorta [20]. The beta isoform of PKC is involved in abnormalities of endothelial-dependent vasodilatation in diabetes by promoting superoxide ions (O2 − ) to react with nitric oxide to produce peroxynitrate (ONOO<sup>−</sup> ), which damages tissues and activates monocyte macrophages [87]. Diabetic vasculopathy is characterized by early migration of monocytes into the arterial wall [88]. Monocytes differentiate into macrophages to form foam cells which secrete growth factors and metalloproteinases. The growth factors stimulate cell proliferation and matrix production, and the metalloproteinases cause matrix degeneration [78].

Another major factor involved in the pathogenesis of vasculopathy is oxidative stress [89–91]. Increased oxidative stress in T2DM induces generation of free radicals that cause vascular tissue damage. In the pathogenesis of diabetic vasculopathy, white blood cells (WBCs) play a potential role. High WBC count predicts a decrease in insulin action and development of T2DM [92]. Inflammation is a primary risk factor for CVD [93], and proinflammatory cytokines and C-reactive protein are found to be linked to the development of diabetes. Increased WBC count, in particular, increase in activated neutrophils is a major contributing factor in development of CVD [94]. Activation of neutrophils leads to altered rheological properties of blood, increases blood corpuscular adhesion, and damages endothelium with cytotoxic reactive oxygen species and proteolytic enzymes [95]. These changes trigger activity of granulocytes and monocytes in endothelial injury site and result in atherogenesis. Besides, leucocyte adhesiveness/aggregation is found to be slightly increased in those who have had concomitant diabetes [96].
