Type 2 Diabetes mellitus (DM) is a common metabolic disorder characterized by hyperglycemia and disturbances of carbohydrate, lipid and protein metabolism. The term Metabolic Syndrome describes the clustering of these conditions. The lipid abnormalities are prevalent in DM because insulin resistance or deficiency affects key enzymes and pathways in lipid metabolism. The altered metabolisms of carbohydrate, lipid and protein play a role in diabetic complications like hypercholesterolemia and hypertriglyceridemia, because of this hyperlipidemia in type 2 DM having the diabetic complication. The traditional risk factors that are associated with coronary artery disease (CAD) in the general population including obesity, physical inactivity, hypertension (HT), and dyslipidemia are prevalent in the diabetic population. Persons with diabetes tend to have a clustering of these risk factors in what is termed the metabolic syndrome hence multiplying their overall risk. Obesity increases the risk of CAD in adults and has been strongly associated with insulin resistance in normoglycemic persons and in individuals with type 2 DM.
KEYWORDS: Diabetes mellitus, Hypertension, Coronary artery disease, Obesity, Macro vascular complication.
Type 2 diabetes mellitus (DM) and hypertension (HT) are among the most common non-communicable chronic diseases in developed and developing countries around the world. The study reports the increased risk of coronary artery disease in diabetes patients with HT. This multifactorial disorders affecting both developed and developing countries and occur at a higher prevalence in the older age group and result from both genetic and environmental etiological factors.1,2 They are the main preventable risk factors for coronary artery disease (CAD), stroke, end-stage renal failure, disability and increased health-care costs. Although DM and HT are not among the top leading causes of death, such as cancer and stroke, these two diseases draw attention from the public due to their increasing trends, while cancer and stroke are declining.3 DM is a chronic disease increasing in explosive pattern in India.4 The term DM describes a metabolic disorder of multiple etiologies characterized by chronic hyperglycemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion or insulin action or both. It continues to increase in numbers and significance, as changing lifestyles lead to reduced physical activity, and increased obesity.5,6 A strong genetic basis, environmental factors and lifestyle changes have been implicated in the etiology of type 2 DM.7 There is a significant amount of overlap between the complications of DM and HT; these complications can be divided into macro vascular and micro vascular disorders. Macro vascular complications include CAD, myocardial infarction (MI), congestive heart failure (CHF), stroke, and peripheral vascular disease (PVD).8
HYPERTENSION IN DIABETES PATIENTS
People with diabetes are more at risk of developing high blood pressure if they: (1) are from the Indian sub-continent; (2) have a family history of high blood pressure; (3) have certain lifestyle factors – for example, those who are overweight; (4) eat a lot of salt;(5) do not eat much fruit and vegetables; (6) do not take much exercise; (7) drink a lot of alcohol. HT is often found at the time of diagnosis of type 2 DM even in the absence of microalbuminuria. It is postulated that hyperinsulinemia, arterial stiffness as well as extracellular fluid volume expansion all play a role. Instead hyperinsulinemia is linked to weight gain, as well as increased sympathetic activation. In addition, when hyperglycemia is mild, it results in increased glucose filtration and subsequent reabsorption at the glomerulus, driving sodium reabsorption with it and causing extracellular fluid volume expansion. Treatment of HT in DM is essential to prevent development of renal disease, retinopathy as well as cardiovascular diseases like CAD, stroke.9
CHANGES OCCURING IN DIABETES WITH MACROVASCULAR COMPLICATION
Functional changes occurring in diabetic patients typically involve the impaired diastolic function of heart, which may precede the systolic dysfunction.10 However, diastolic dysfunction is not pathogenomonic for macrovascular complication in diabetes.11 Obesity is a major risk factor for the development of type 2 DM, and the current increase in obesity in our society has fueled a major increase in the expression of this disease. Not only does weight, through the mechanism of insulin resistance, aggravate hyperglycemia, it also increases the risk for HT, hyperlipidemia, and other conditions that lead to CAD12. It is estimated that in nearly half of all coronary artery disease cases, regardless of the presence of diabetes, diastolic dysfunction is present along with normal or near-normal left ventricular ejection fraction. Changes in diastolic function were reported in diabetic patients in dependent of HT, CAD, or any other known cardiac disease, before they were clinically apparent.13The left ventricular (LV) ejection time is often reduced, but the pre-ejection period and the ratio of pre-ejection period to LV ejection time are often increased. Several studies suggest that patients with type 2 DM are more likely to have diastolic dysfunction than type 1 DM patients. However, diastolic dysfunction was not observed in all studies, especially in younger patients with type 1 DM. There is also a significant association of dilated cardio myopathy with DM.14 Changes typical for systolic dysfunction may indicate an increased risk for the development of CAD, particularly in the presence of coexisting hypertension.15,16 The severity of diastolic dysfunction correlated with HbA1c level. The most likely cause of diastolic dysfunction is advanced glycation end-product (AGE)-induced formation of reactive oxygen species (ROS), leading to deposition of collagen in myocardium, fibrosis and insulin resistance syndrome leading to left ventricular hypertrophy. A growing body of evidence confirms strong associations between Obstructive sleep apnea and cardiovascular diseases, including CAD, HT, LV dysfunction, and arrhythmias17.
DM promotes the accumulation of foam cells in the sub endothelial space by increasing the production of leukocyte adhesion molecules and pro inflammatory mediators.18This augmented vascular inflammatory reaction may result from over expression of receptor for advanced glycation end products, which correlates linearly with hemoglobin A1C levels. Receptors for advanced glycation end products enhance matrix metalloproteinase activity that can destabilize plaques. Endothelial dysfunction has been documented in diabetic patients who have normal coronary arteries and no other risk factors for coronary disease. But bone morphogentic protein receptor 2 and gremlin -1 are the markers for detection and diagnosis of pulmonary arterial hypertension19, 20. The presence of insulin resistance alone may be associated with coronary endothelial dysfunction. Several hypotheses have been proposed to explainthe mechanisms responsible for decreasedmyocardial contractility in the diabetic population.These include metabolic disturbances, accumulationof AGE, myocardial fibrosis, small vessel disease,impaired calcium homeostasis, autonomicneuropathy insulin resistance endothelial dysfunction, hypercoagulability,and platelet dysfunction, with hyperglycemia
Role of hyperglycemia
Hyperglycemia results in multiple biochemical changes, a few of which we will list: an increase in the reduction of nicotinamide adenine dinucleotide (NAD+) to NADH is thought but not proven yet to be a cellular oxidative stressor; an increase in the production of uridinediphosphate (UDP) N-acetyl glucosamine is thought to alter cellular enzymatic function. Very importantly, the glycosylation of proteins in the arterial wall is thought to contribute to diabetic atherosclerosis. The non enzymatic reaction between glucose and arterial wall proteins results in the formation of advanced glycation end products (AGE), process that is enhanced in hyperglycemia. AGEs are thought to directly interfere with endothelial cell function and accelerate atherosclerosis. Additionally, hyperglycemia increases the formation of reactive oxygen species (ROS); these ROS inhibit endothelial production of nitric oxide, a potent vasodilator and regulator of platelet activation. Furthermore, those ROS prevent the migration of vascular smooth muscle cells into the intimal plaques, a step necessary to the stabilization of coronary plaques. Such plaques then carry an increased risk of rupture, as is known of diabetic coronary plaques.
In diabetes metabolic changes are triggered by hyperglycemia.21In normal conditions, the myocytes use free fatty acids (FFA) as a primary source of energy during aerobic exercise. During ischemia or increased work glycolysis and pyruvate oxidation become increasingly important.22In diabetic patients, the major factors limiting glucose utilization are the slow rate of glucose transport into the myocardium probably associated with depletion of glucose transporters (GLUT) 1 and 4 and the inhibitory effect of FA oxidation on pyruvate dehydrogenase complex. In diabetes, an increase in adipose tissue lipolysis and hydrolysis of myocardial triglyceride stores is responsible for elevated circulating levels of FFA.23Metabolism of high levels of FFA requires high oxygen consumption and leads to intracellular accumulation of toxic intermediates, which may negatively influence myocardial performance through reduced availability of ATP.24
Although no theory is completely accepted as a single cause of coronary artery disease in diabetic patients, it is regarded that ROS generated in vivo may play an important role in myocardial damage.25In diabetic patients, poor glycemic control leads to chronic hyperglycemia. The oxidation of elevated levels of glucose within the cell stimulates production of ROS and increases oxidative stress. Increased generation of ROS such as superoxide, hydrogen peroxide and hydroxyl radical is the cause of oxidation and modification of structure of cellular proteins, nucleic acids, and membrane lipids. Higher levels of peroxynitrate were found by in biological fluids of type 2 DM patients compared to healthy subjects.26 Damage of the cellular structure and impairment of its function leads to cell necrosis and activation of genes involved in cell damage.27 Increased ROS-mediated cell death may promote cardiac remodeling, which may contribute to the morphological and functional abnormalities of the heart in diabetic patients. Increased ROS content may lead to cardiac dysfunction via mechanisms other than cellular injury. In diabetic patients increased oxidative stress may be associated not only with overproduction of ROS, but also with a significant decrease in the effectiveness of antioxidant defenses or both. Insufficient anti-oxidative cellular mechanisms may also be involved in cardiac damage. Its seems that the activity of cellular antioxidants such as the enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) may be crucial to this process decreased activity of primary antioxidant enzymes such as CAT, SOD and GPX in peripheral blood of type 2 DM patients with coexisting distal symmetric polyneuropathy (DSPN).28
Endothelial dysfunction occurs in coronary vessels of diabetic patients and may lead to impaired blood flow. It was observed that in diabetic patients the endothelium-dependent dilatation of the epicardial coronary arteries is impaired. It is found that chronic high glucose concentration induced the decrease of plasma nitric oxide (NO) level in diabetic patients.28 Endothelial NO, along with prostacyclin I2 (PGI2), is the main vasodilator and the most important factor involved in the function of blood vessels. Endothelial dysfunction is characterized by low bioavailability of endothelium-derived NO. It seems that reduced antioxidative defense in diabetic patients is associated with increased vascular oxidative stress through decreased NO bioavailability. The NO is inactivated by the superoxide radical and the peroxynitrite anion, which can cause endothelial damage. Moreover, free radicals, especially superoxide anion, may react NO and can inhibit endothelial nitric acid synthase. This interaction is one of the most important mechanisms involved in the endothelial dysfunction in diabetic patients.29 The ROS have been reported to contribute to impairment of endothelium-dependent vascular relaxation by the inactivation of NO, and generally to the vascular dysfunction resulting in accelerated atherosclerosis in diabetic patients. It is suggested that increased production of ROS, induced by hyperglycemia, is involved in cardiac tissue remodeling via activation of metalloproteinase 9, which in turn leads to attenuation of sarco-endoplasmic reticulum-calcium ATPase 2 and alters expression of mRNA. Alterations in mRNAs may lead to altered contractility of myocardium.30
Accumulation of advanced glycation end-products
Hyperglycemia leads to glycation of numerous macromolecules. AGEs accumulate in tissues and may cause morphological changes in the heart. Accumulation of AGE results not only in decreased elasticity of the vessel walls but also in myocardial dysfunction. It is reported that in diabetic patients, prolongation of isovolumic relaxation time correlates with serum levels of AGE even after adjustment for age, diabetes duration, renal function, blood pressure and autonomic function.31
Impaired calcium homeostasis
Intracellular calcium (Ca2+) is a major regulator of cardiac contractility and disturbances in its homeostasis may contribute to alteration of cardiac performance. It is believed that diminished activity of ATPases, decreased ability of the sarcoplasmic reticulum to take up calcium, and reduced activities of Na+-Ca2+ and Ca2+ ATPase may all contribute to this effect32. It was observed that in diabetes reduced activity of the sarcoplasmic reticular calcium pump, and diminished rate of Ca2+ removal from the cytoplasm in diastole, may be responsible for diastolic dysfunction.33
The results of numerous studies have revealed not only structural but also functional changes in diabetic heart, which may play a role in deterioration of cardiac performance.34 The most typical finding in diabetic patients is fibrosis, which may be both perivascular and interstitial. Hyperglycemia may cause abnormal gene expression and alteration of signal transduction, which may activate the pathways leading to apoptosis.35 Hyperglycemia may also directly induce necrosis of myocytes, which results in increased deposition of collagen.36 Myocardial fibrosis was confirmed in autopsy studies.
SCREENING FOR MACROVASCULAR DISEASE IN DIABETIC PATIENTS
Screening for CAD may help to prevent its progression and reduce mortality in diabetic patients. In everyday practice echocardiogram with Doppler examinations is the most sensitive method to diagnose CAD.37, 38 However, considering the costs of this examination in the diabetic population, one should consider a simpler and less expensive screening test. Estimation of microalbuminuria as an adequate prescreening test.39 The results of the Study showed that the degree of diastolic dysfunction was proportional to the level of microalbuminuria, even after adjusting for age, sex, body mass index (BMI), systolic blood pressure duration of DM, left ventricular mass, and presence of CAD40. Microalbuminuria was initially entrench predicator for renal failure and risk factor of cardiovascular diseases in type 2 DM41. Additionally, the results of the Heart Outcomes Prevention Evaluation (HOPE) study indicate that microalbuminuria is associated with significant risk for CHF. That is why it seems reasonable to perform echocardiography screening for CAD in diabetic subjects with microalbuminuria. Identification of functional changes should result in the initiation of treatment in order to slow down the progression to CAD and reduce mortality. Microalbuminuria was initially entrench predicator for renal failure and risk factor of cardiovascular diseases in type 2 diabetes mellitus. In the overt macrovascular complication in the diabetic population symptoms do not differ from those in non-diabetics, and the diagnosis of CAD and its staging are typical.
RISK FACTORS FOR MACROVASCULAR DISEASE IN DM
The traditional risk factors that are associated with CAD in the general population including obesity, physical inactivity, hypertension, and dyslipidemia are prevalent in the diabetic population. Persons with diabetes tend to have a clustering of these risk factors in what is termed the metabolic syndrome hence multiplying their overall risk. Obesity increases the risk of CAD in adults and has been strongly associated with insulin resistance in normoglycemic persons and in individuals with type 2 DM. Apart from the degree of obesity the risk is also dependent on the distribution of body fat as it has been found that visceral adiposity is more closely linked to CAD than peripheral adiposity.42 Visceral adipocytes are more lipolytically active and release increased amounts of non-esterified fatty acids, glycerol, hormones, pro-inflammatory cytokines and other factors that cause resistance of the body to the actions of insulin resulting in increased production of this hormone by the pancreas and ensuing hyperinsulinemia. Insulin resistance in obesity and type 2 DM is manifested by decreased insulin-stimulated glucose transport and metabolism in adipocytes and skeletal muscle and by impaired suppression of hepatic glucose output.43Through this mechanism of insulin resistance, obesity has been found to increase the risk of HT and dyslipidemia in diabetic individuals thus multiplying their overall cardiovascular risk. Microalbuminuria is a marker of endothelial dysfunction and increased oxidative stress which predispose to atherosclerosis. It is an independent risk factor for the development of CAD and is associated with a doubling of the risk of early death, mainly from coronary heart disease.44 It is associated with insulin resistance, atherogenic dyslipidemia, central obesity, and the absence of nocturnal drop in both systolic and diastolic pressures and is a part of the metabolic CAD associated with hypertension.45 Patients with type 2 DM have a high rate of CAD as determined by the presence of coronary artery calcification on electron beam CT scanning and by inducible silent ischemia on stress imaging. 46 Roughly half of all heart attacks and strokes come out of the people with no diagnosed heart disease, so identifying risk factors early in healthy people is a must to delay disease and prevent death. Modifiable factors played an important role in causing HT along with some biological factors like obesity, DM etc.47 Diabetic patients with CAD tend to have worse ischemic events than non diabetic people with CAD and this may be attributed to sympathetic denervation and prolongation of angina perceptual threshold that has been found during exercise testing, predisposing diabetic patients to silent myocardial ischemia.48
Modification of life habits should be at the heart of the public health strategy for reducing rates of type 2 DM and its macro vascular complications. It is advisable that the patients with type 2 DM and HT having increased risk of CAD. There are consistent evidences that optimal glycemic control, along with control of HT, dyslipidaemia, smoking cessation, and weight loss and fewer intakes of salt and also by improving physical activity are necessary for reducing coronary artery risk in type 2 DM patients. Cardiovascular benefits are obtained if the control of traditional cardiovascular risk factors begins early in subjects with short duration of DM and low macro vascular complications. Screening for coronary artery disease may help to prevent its progression and reduce mortality in diabetic patients.