**6. Diagnosis of vasculopathy**

Increased arterial stiffness is a dysfunctional property of the arterial circulation that leads to CVD. The stiffening of aorta and other central arteries is a potential risk factor for increased CV morbidity and mortality [97]. Arterial stiffness can be measured by a number of methods. Some of these are more widely used in the clinical settings as these are simple, accurate and, reproducible and thus can easily be applied for the evaluation of CV risk. [98]. Most of them are complex or need sophisticated technical equipment, which limits their application in clinical practice. Among the non-invasive and simple methods of evaluating arteries, pulse wave velocity (PWV) [99] and augmentation index (AI) [100–103] measurement are widely used as indexes of large artery elasticity and stiffness.

*Pulse wave velocity* (PWV) is the oldest and probably the best clinical measure of stiffness over an arterial segment [104]. The technique of PWV is valid and reproducible, and has been widely applied in clinical and research setting [105]. PWV is determined by measurement of the time taken for the pulse wave to traverse the distance between two fixed measuring points [99]. PWV may be measured in various segments of the arterial circulation [106] and is therefore derived as (distance [m]/time [s]), in m/s, ranging from 5–20 m/s [104]. It is assessed either between carotid and femoral arteries (aortic PWV) or carotid and radial arteries known as brachial PWV [99].

*The pulse wave analysis* (PWA) is the generation of ascending aortic pressure wave [107]. The system is used to assess central aortic pressure which depends on accurate recording of the radial pulse wave [108, 109]. The radial pressure pulse contains all the basic information from which the ascending aortic pulse is generated [107]. It is calibrated against the brachial pressure, then generation of ascending aortic pressure waveform through the use of generalized transfer function in a computerized process [107]. It gives information to ventricular/vascular interaction from both pressure and time values, as calculated from the synthesized aortic waveform. Therefore, PWA used for deriving central arterial pressure waveforms, from which *augmentation index* (AI) and the timing of the reflected pressure wave can be determined as indices of arterial stiffness. Aortic AI is defined as the increment in pressure after the first systolic shoulder to the peak of the aortic pressure expressed as a percentage of aortic pulse pressure [110]. It is a surrogate measure of systemic arterial stiffness [111–113] which is calculated from the derived aortic waveforms using PWA and expressed as a percentage (%).

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 dia-

lopathy 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

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/aggrega-

tion is found to be slightly increased in those who have had concomitant diabetes [96].

Increased arterial stiffness is a dysfunctional property of the arterial circulation that leads to CVD. The stiffening of aorta and other central arteries is a potential risk factor for increased CV morbidity and mortality [97]. Arterial stiffness can be measured by a number of methods. Some of these are more widely used in the clinical settings as these are simple, accurate and, reproducible and thus can easily be applied for the evaluation of CV risk. [98]. Most of them are complex or need sophisticated technical equipment, which limits their application in clinical practice. Among the non-invasive and simple methods of evaluating arteries, pulse wave velocity (PWV) [99] and augmentation index (AI) [100–103] measurement are widely used as indexes

*Pulse wave velocity* (PWV) is the oldest and probably the best clinical measure of stiffness over an arterial segment [104]. The technique of PWV is valid and reproducible, and has been widely applied in clinical and research setting [105]. PWV is determined by measurement of the time taken for the pulse wave to traverse the distance between two fixed measuring points [99]. PWV may be measured in various segments of the arterial circulation [106] and is therefore derived as (distance [m]/time [s]), in m/s, ranging from 5–20 m/s [104]. It is assessed either between carotid and femoral arteries (aortic PWV) or carotid and radial arteries known as brachial PWV [99].

), which damages tissues and activates monocyte macrophages [87]. Diabetic vascu-

) to react with nitric oxide to produce peroxynitrate

−

betes by promoting superoxide ions (O2

76 Recent Trends in Cardiovascular Risks

**6. Diagnosis of vasculopathy**

of large artery elasticity and stiffness.

metalloproteinases cause matrix degeneration [78].

(ONOO<sup>−</sup>

*Pulse pressure* is one of the simplest measures of arterial stiffness, varies with the rigidity of the arterial wall and easily practicable in the clinical setting. Pulse pressure is the difference between systolic and diastolic BP, depends on cardiac output, large artery stiffness and wave reflection. It can be easily measured by sphygmomanometer. However, pulse pressure alone is inadequate to assess arterial stiffness accurately. Brachial pulse pressure may not change despite increasing arterial stiffness when induced by circulating angiotensin II [114].

*Pulse contour analysis* estimates arterial stiffness non-invasively and measures both capacitive (storage) and cushioning (oscillatory) arterial functions. In this technique arterial pulse contour is used to assess large artery capacitance and the capacitance of smaller arteries that are the primary source of reflected waves or oscillations in the arterial system. This technique involves tonometry at the radial artery, but the compliance is derived differently, using a model of the circulation and an assessment of diastolic pressure decay. Pressure pulse contour analysis requires estimation of cardiac output from an algorithm.

*Photoplethysmography* records the digital volume pulse [115]. This technique records the transmission of infrared light passing through the finger to measure the alteration in flow and produces a volume waveform. A stiffness index and a reflexion index that reflect systemic arterial stiffness are developed using this technique. The technique is relatively simple and easily portable [105]. However, problems include the damping of peripheral pulse, and temperature-dependant changes in the peripheral circulation.

*Ultrasound and Doppler techniques* are used to visualize wall thickness and vascular diameter on a monitor screen. Using an ultrasound transducer to perpendicularly project ultrasound beams to the artery, the optimal sound reflections from the wall are obtained and the reflected echoes from the wall and lumen are monitored. Simultaneously, blood pressure is also measured to adjust the change in arterial diameter to estimate arterial stiffness.

*Magnetic resonance imaging* (*MRI*) *technique* is used to measure vascular compliance and distensibility. The technique demonstrates the inverse relationship between aortic distensibility and age, i.e. aortic distensibility is reduced in hypertensive patients [116], and that arterial compliance is reduced in patients with CAD but increased in athletes [117].

*Oscillometric BP measurement* can be used to estimate the arterial stiffness. The pattern of oscillations depends on arterial stiffness. As the cuff is deflated, oscillations are increased, reaching a peak at mean arterial pressure. By coupling this to a computer algorithm, an index of arterial stiffness can be calculated.

### **7. Treatment modalities of diabetic vasculopathy**

CVD is a major complication and the leading cause of early death among people with T2DM [118]. Much of the diabetes-associated morbidity and mortality predominantly reflects its deleterious effect on macrovascular and microvascular diseases [119, 120]. As T2DM is a complex metabolic disorder characterized by hyperglycemia, hypertension, hypercoagulability, and dyslipidemia, the diabetic patients with CVD require therapy for each of these metabolic abnormalities to reduce atherogenesis and prevent CV complications [121]. The main strategies for an effective therapy are to reverse insulin resistance, restore beta cell function, and control hepatic glucose output. The key treatment modalities include lifestyle modification and pharmacological interventions.

### **7.1. Lifestyle management**

Lifestyle management is an essential part of management of T2DM and CVD in diabetic patients. Dietary restriction is recommended to achieve weight loss and reduce the risk factors for CVD in T2DM. Calorie restriction and weight loss bring down the blood pressure to normal limits and improves blood lipid profile, especially triglycerides and very low-density lipoprotein cholesterol. Exercise improves glycemic control, reduces certain CV risk factors, and increases psychological wellbeing [122]. In addition, physical training has been shown to reverse insulin resistance by increasing the number of skeletal muscle glucose transporters, which may reduce the need for hypoglycemic agents [123].

### **7.2. Pharmacotherapy**

Patients with T2DM who do not show improvements in blood glucose levels with diet therapy are generally prescribed *oral hypoglycemic drugs*. These drugs control hyperglycemia by either increasing the release of insulin from the pancreatic beta cells or increasing the sensitivity of peripheral tissues to insulin [124–126]. The efficacy of these drugs depends on the endogenous capacity of insulin production in the T2DM patients. Among the main oral hypoglycemic drugs are biguanides and sulfonylureas. Other prominent groups include α-glucosidase inhibitors, meglitinides, thiazolidinediones, incretin mimetics, and dipeptidyl peptidase-4 (DPP-4) inhibitors.

Sulfonylureas act by promoting insulin secretion from the pancreatic islet beta cells and may improve insulin resistance in muscle and liver by improving insulin sensitivity in these target tissues. Metformin is the most commonly used biguanide and is suggested as the first-line drug of choice. It reduces hepatic glucose output, primarily by decreasing gluconeogenesis, and to a lesser extent, by enhancing insulin sensitivity in hepatic and peripheral tissues. Alphaglucosidase inhibitors such as acarbose, miglitol, and voglibose inhibit the α-glucosidase enzyme which is essential for the release of glucose from more complex carbohydrates and is found in the brush border of enterocytes of small intestine. Thus, α-glucosidase inhibit the absorbance of carbohydrates in the gut and help in prevention of hyperglycemia [127]. Rosiglitazone and pioglitazone belong to the group of thiazolidinediones. The thiazolidinediones enhance insulin sensitivity in the peripheral target tissues such as muscle and adipose tissue, and inhibit hepatic glucose production to some extent, but have no effect on insulin secretion. When used in combination with other antidiabetic drugs, the thiazolidinediones achieve significant improvement in insulin resistance. Importantly, the thiazolidinediones have also been shown to improve the dyslipidemia in patients with T2DM.

*Oscillometric BP measurement* can be used to estimate the arterial stiffness. The pattern of oscillations depends on arterial stiffness. As the cuff is deflated, oscillations are increased, reaching a peak at mean arterial pressure. By coupling this to a computer algorithm, an index of

CVD is a major complication and the leading cause of early death among people with T2DM [118]. Much of the diabetes-associated morbidity and mortality predominantly reflects its deleterious effect on macrovascular and microvascular diseases [119, 120]. As T2DM is a complex metabolic disorder characterized by hyperglycemia, hypertension, hypercoagulability, and dyslipidemia, the diabetic patients with CVD require therapy for each of these metabolic abnormalities to reduce atherogenesis and prevent CV complications [121]. The main strategies for an effective therapy are to reverse insulin resistance, restore beta cell function, and control hepatic glucose output. The key

Lifestyle management is an essential part of management of T2DM and CVD in diabetic patients. Dietary restriction is recommended to achieve weight loss and reduce the risk factors for CVD in T2DM. Calorie restriction and weight loss bring down the blood pressure to normal limits and improves blood lipid profile, especially triglycerides and very low-density lipoprotein cholesterol. Exercise improves glycemic control, reduces certain CV risk factors, and increases psychological wellbeing [122]. In addition, physical training has been shown to reverse insulin resistance by increasing the number of skeletal muscle glucose transporters,

Patients with T2DM who do not show improvements in blood glucose levels with diet therapy are generally prescribed *oral hypoglycemic drugs*. These drugs control hyperglycemia by either increasing the release of insulin from the pancreatic beta cells or increasing the sensitivity of peripheral tissues to insulin [124–126]. The efficacy of these drugs depends on the endogenous capacity of insulin production in the T2DM patients. Among the main oral hypoglycemic drugs are biguanides and sulfonylureas. Other prominent groups include α-glucosidase inhibitors, meglitinides, thiazolidinediones, incretin mimetics, and dipeptidyl peptidase-4

Sulfonylureas act by promoting insulin secretion from the pancreatic islet beta cells and may improve insulin resistance in muscle and liver by improving insulin sensitivity in these target tissues. Metformin is the most commonly used biguanide and is suggested as the first-line drug of choice. It reduces hepatic glucose output, primarily by decreasing gluconeogenesis, and to a lesser extent, by enhancing insulin sensitivity in hepatic and peripheral tissues. Alphaglucosidase inhibitors such as acarbose, miglitol, and voglibose inhibit the α-glucosidase

treatment modalities include lifestyle modification and pharmacological interventions.

arterial stiffness can be calculated.

78 Recent Trends in Cardiovascular Risks

**7.1. Lifestyle management**

**7.2. Pharmacotherapy**

(DPP-4) inhibitors.

**7. Treatment modalities of diabetic vasculopathy**

which may reduce the need for hypoglycemic agents [123].

A recent advance in the management of T2DM has been the development and clinical use of incretin-based therapies, i.e., glucagon-like peptide-1 (GLP-1) receptor analogs (e.g., exenatide) and DPP-4 inhibitors (e.g., sitagliptin, vildagliptin, saxagliptin) [128–131]. GLP-1 receptor agonists mimic the action of GLP-1 and increase the incretin effect in patients with T2DM, stimulating the release of insulin. DPP-4 inhibitors prevent degradation of endogenous GLP-1 and glucose-dependent insulinotropic polypeptide, thereby helping in glycemic control [129].

*Anti*-*hypertensive drugs* i.e. diuretics, angiotensin-converting enzyme (ACE) inhibitors, betablockers, angiotensin II receptor blockers, and calcium antagonists have been effectively used in the treatment of high blood pressure control. For the prevention of cardiovascular complications and treatment of hypertension these drugs have shown beneficial effects in T2DM patients. In such patients, thiazide diuretics have been found to be very effective either alone or in combination with other anti-hypertensive therapy [132]. ACE inhibitors have beneficial effects in reducing macrovascular complications, improving insulin sensitivity and glucose metabolism in T2DM patients [18, 133]. ACE inhibitors can be used alone, however, their effectiveness significantly increases when combined with a thiazide diuretic or other antihypertensive therapeutic drugs [132]. Calcium antagonists have been found to be beneficial in controlling hypertension when used as part of a combined regimen [132]. Anti-hypertensive therapy using a calcium channel blocker lowers the risks of developing complications associated with beta-blocker usage [134].

*Lipid*-*lowering agents* reduce the risk of major macrovascular events in patients with T2DM [135, 136]. Statins (HMG-CoA reductase inhibitors) are considered to be first-line therapy for the majority of T2DM patients [137] and has demonstrated benefit in both the primary and secondary prevention of CVD [135, 138, 139]. Several clinical studies have found beneficial effects associated with fibrate therapy [140–142]. Statins are effective in lowering plasma LDL-C, apolipoprotein B, and total cholesterol to HDL-C ratio, whereas fibrates are found to be beneficial in lowering triglycerides, shifting LDL particle size from smaller to larger, and raising HDL-C that results in lowering the total cholesterol to HDL-C ratio [18].

*Anti*-*platelet drugs* i.e. aspirin, clopidogrel, dipyridamole, and the glycoprotein IIb/IIIa receptor antagonists reduce CV risk in patients with T2DM [137] due to their antiplatelet effects. Aspirin irreversibly inhibits prostaglandin H synthase (cyclo-oxygenase-1) in platelets and megakaryocytes that prevents synthesis of thromboxane A2, which is a potent vasoconstrictor and platelet aggregant [143]. The thienopyridine derivatives, such as clopidogrel, ticlopidine, are converted to active metabolites in the liver which significantly decrease blood platelet activation via their action on the adenosine phosphate receptors on platelets. Dipyridamole increases cAMP concentration in platelets by inhibiting phosphodiesterase enzyme, and the increased cAMP levels inhibit activation of cytoplasmic second messengers. Dipyridamole also promotes prostacyclin release and inhibits thromboxane A2 synthesis. Glycoprotein IIb/ IIIa receptor antagonists inhibit the final common pathway for platelet aggregation.
