**5. Determinants of cardiovascular risk in nondiabetic hemodialysis patients**

Diabetes is not only a traditional risk factor for CV disease, but also one of the most common causes of end-stage renal disease. While a decline in CV deaths has occurred in the general population, a similar trend has not been observed in dialysis patients. This discrepancy is in part due to the demographics of patients about to be started on dialysis: about 40 percent are diabetic. Also, the average age of hemodialysis patients is approximately 60 years and about 20 percent are over 75 years, and many patients have underlying cardiac disease

Determinants of Cardiovascular Risk in Hemodialysis Patients Without Significant Comorbidities 289

thickness and plaque occurrence were compared with 40 healthy control subjects. Nondiabetic patients with chronic kidney disease showed advanced atherosclerosis, intima-media thickness, and plaque occurrence, and their numbers increased directly with the level of renal

**Vascular calcification**: The uremic state is associated with numeous metabolic abnormalities and endocrine disturbances primarily involving calcium and phosphorus metabolism. Vascular calcification is highly prevelant in dialysis patients and increases CV mortality. The presence and progression of vascular calcification in hemodialysis patients have been significantly associated with chronic inflammation, malnutrition, and disorders of mineral metabolism. Through a review of the literature examining vascular calcification in end stage renal failure patients, hyperphosphatemia is significantly associated with vascular calcification in nondiabetic patients, while it may not be a significant risk factor for vascular calcification in diabetic patients. In diabetic patients vascular calcification occurs long before the initiation of dialysis therapy and and the factors associated with vascular calcification in non-uremic diabetics appear to be hyperglycemia and related metabolic disorders, such as increased glycation and oxidative stress. In diabetic end stage renal failure patients, hyperglycemia is also suggested to be a significant factor associated with the progression of vascular calcification. Thus, the importance of glycemic control in diabetic and phosphate control in nondiabetic end stage renal failure patients is suggested (Ishimura et al., 2008). The accumulating data demonstrate the role of abnormalities of calcium, phosphorus, vitamin D, and parathyroid hormone in CV disease and the importance of phosphate control is suggested for preventing vascular calcification and CV risk (Andress, 2008;

Diabetes mellitus and ethnicity are known factors that affect the extent of CV calcifications. The extent of CV calcifications was assessed in non-diabetic Caucasian hemodialysis patients by a novel composite calcification score. Body mass index, cholesterol, triglycerides, intact PTH, and serum levels of fetuin-A and uncarboxylated matrix Gla protein were not associated with CV calcifications. Age, male gender, dialysis vintage, smoking, calciumphosphate product, CRP, and lower Kt/V were independent risk factors for CV calcifications (Schlieper et al., 2009). Increasing dialysis efficiency and lowering calciumphosphate product can reduce CV calcifications. Generally, a calcium X phosphate product of less than 55 is the therapeutic optimum and it is possible that even lower levels offer further survival advantage. However, no prospective randomized studies have demonstrated a CV benefit and/or a survival advantage with any of the current therapeutic options. But observational studies have shown improved survival in hemodialysis patients

**Metabolic abnormalities:** Chronic kidney disease is associated with complex metabolic changes including insulin resistance, and insulin resistance is associated with increased CV risk (O'Sullivian&Kelly, 2007). In contrast to the general population, a higher body mass index is associated with better survival among hemodialysis patients. Theoretically, high energy supplementation in nondiabetic hemodialysis patients might adversely affect insulin resistance, and with this goal in mind, the effects of high energy supplementation on nondiabetic hemodialysis patients was investigated. According to the results, body fat mass and CRP were the primary determinants of insulin resistance in nondiabetic hemodialysis patients. High energy supplementation, increased adiposity, and inflammation exacerbated insulin resistance. However, long term metabolic effects of this strategy were unclear (Hung

treated with active vitamin D analogues (Levin&Li, 2005).

dysfunction. Another important risk factor was hypertension (Ekart et al., 2008).

London et al., 2000).

& Tang, 2009).

(Mailloux, 2010). Thus, epidemiologic studies concerning the predictive factors of CV disease in nondiabetic hemodialysis patients are less available.

### **5.1 Association with traditional and nontraditional risk factors**

In a study of the CV assessment of 75 nondiabetic hemodialysis patients, the main cause of renal failure was hypertension. Compared with normal controls, the patients were found to have increased inflammatory cytokines such as interleukin- 6, tumor necrosis factor alpha, and intercelluler adhesion molecule, as well as a high frequency of carotid intima media thickening, left ventricular hypertrophy, and aortic calcifications (Kunstmann et al., 2009).

Mortality predictors among 84 diabetic and 161 nondiabetic patients undergoing hemodialysis were investigated for two years. Forty-three diabetic patients and 30 nondiabetic patients died. Among diabetic patients, oliguria, elevated CRP, and elevated D-dimer levels predicted all-cause mortality. Oliguria was the most important predictor, particularly for infectious disease-related death. Among nondiabetic patients elevated cardiac troponin T levels, elevated D-dimer levels, and low cholesterol levels predicted all-cause mortality rates. Subdivision of the causes of death among nondiabetic patients revealed that cardiac troponin T levels predicted CV mortality rates. According to those results, mortality predictors among hemodialysis patients differed between diabetic and nondiabetic patients (Hocher et al., 2003). In one comparison, two groups of nondiabetic hemodialysis patients (both groups n=30) matched for age and sex, were selected according to the absence or presence of symptomatic atherothrombotic vascular disease affecting the coronary, cerebral, or peripheral arteries. The two groups were identical regarding primary renal disease, duration of hemodialysis, and Epo treatment. The presence of hypertension, lipoprotein (a), and fibronectin levels were independent predictors for the presence of atherothrombotic CV disease which may contribute to the high prevalence of CV risk. Smoking was not a predictor. (Tzanatos et al., 2009).

**Left ventricular hypertrophy:** Left ventricular hypertrophy is one of the strongest predictors of CV mortality in the general dialysis population. It is an independent predictor of survival in patients with chronic renal failure and it is present in a large number of patients on hemodialysis. In 30 nondiabetic hemodialysis patients, predictive factors associated with left ventricular hypertrophy at baseline and in the follow-up period (at 0, 12, and 24 months) were studied. Systolic blood pressure, residual glomerular filtration rate and serum albumin levels were the predictive factors for left ventricular mass index at initiation of hemodialysis. Systolic blood pressure, human atrial natriuretic peptide, and hemoglobin levels were independent risk factors for left ventricular mass index, after 24 months. Systolic blood pressure, human atrial natriuretic peptide, and hemoglobin levels were also predictive factors for left ventricular mass index after initiation of hemodialysis (Io et al., 2010). Better management of hypertension and anaemia may be priorities for preventing or improving CV risk in these patients.

**Carotid intima**-**media thickness:** Carotid intima-media thickness is a strong predictor of CV events in the general population. The predictive value of carotid intima-media thickness in 99 nondiabetic hemodialysis patients was investigated. During a follow-up of 42.4±19.5 months, 33 patients died, 19 (57.6%) of them of CV causes. In those 19 patients carotid thickness was significantly higher than in those who survived. So carotid intima-media thickness was an independent predictor of CV death in nondiabetic hemodialysis patients (Ekart et al., 2005). Asymptomatic atherosclerosis and major risk factors in 104 nondiabetic patients with different stages of chronic kidney disease (stage 1-5) were also investigated. Carotid intima-media

(Mailloux, 2010). Thus, epidemiologic studies concerning the predictive factors of CV

In a study of the CV assessment of 75 nondiabetic hemodialysis patients, the main cause of renal failure was hypertension. Compared with normal controls, the patients were found to have increased inflammatory cytokines such as interleukin- 6, tumor necrosis factor alpha, and intercelluler adhesion molecule, as well as a high frequency of carotid intima media thickening, left ventricular hypertrophy, and aortic calcifications (Kunstmann et al., 2009). Mortality predictors among 84 diabetic and 161 nondiabetic patients undergoing hemodialysis were investigated for two years. Forty-three diabetic patients and 30 nondiabetic patients died. Among diabetic patients, oliguria, elevated CRP, and elevated D-dimer levels predicted all-cause mortality. Oliguria was the most important predictor, particularly for infectious disease-related death. Among nondiabetic patients elevated cardiac troponin T levels, elevated D-dimer levels, and low cholesterol levels predicted all-cause mortality rates. Subdivision of the causes of death among nondiabetic patients revealed that cardiac troponin T levels predicted CV mortality rates. According to those results, mortality predictors among hemodialysis patients differed between diabetic and nondiabetic patients (Hocher et al., 2003). In one comparison, two groups of nondiabetic hemodialysis patients (both groups n=30) matched for age and sex, were selected according to the absence or presence of symptomatic atherothrombotic vascular disease affecting the coronary, cerebral, or peripheral arteries. The two groups were identical regarding primary renal disease, duration of hemodialysis, and Epo treatment. The presence of hypertension, lipoprotein (a), and fibronectin levels were independent predictors for the presence of atherothrombotic CV disease which may contribute

to the high prevalence of CV risk. Smoking was not a predictor. (Tzanatos et al., 2009).

preventing or improving CV risk in these patients.

**Left ventricular hypertrophy:** Left ventricular hypertrophy is one of the strongest predictors of CV mortality in the general dialysis population. It is an independent predictor of survival in patients with chronic renal failure and it is present in a large number of patients on hemodialysis. In 30 nondiabetic hemodialysis patients, predictive factors associated with left ventricular hypertrophy at baseline and in the follow-up period (at 0, 12, and 24 months) were studied. Systolic blood pressure, residual glomerular filtration rate and serum albumin levels were the predictive factors for left ventricular mass index at initiation of hemodialysis. Systolic blood pressure, human atrial natriuretic peptide, and hemoglobin levels were independent risk factors for left ventricular mass index, after 24 months. Systolic blood pressure, human atrial natriuretic peptide, and hemoglobin levels were also predictive factors for left ventricular mass index after initiation of hemodialysis (Io et al., 2010). Better management of hypertension and anaemia may be priorities for

**Carotid intima**-**media thickness:** Carotid intima-media thickness is a strong predictor of CV events in the general population. The predictive value of carotid intima-media thickness in 99 nondiabetic hemodialysis patients was investigated. During a follow-up of 42.4±19.5 months, 33 patients died, 19 (57.6%) of them of CV causes. In those 19 patients carotid thickness was significantly higher than in those who survived. So carotid intima-media thickness was an independent predictor of CV death in nondiabetic hemodialysis patients (Ekart et al., 2005). Asymptomatic atherosclerosis and major risk factors in 104 nondiabetic patients with different stages of chronic kidney disease (stage 1-5) were also investigated. Carotid intima-media

disease in nondiabetic hemodialysis patients are less available.

**5.1 Association with traditional and nontraditional risk factors** 

thickness and plaque occurrence were compared with 40 healthy control subjects. Nondiabetic patients with chronic kidney disease showed advanced atherosclerosis, intima-media thickness, and plaque occurrence, and their numbers increased directly with the level of renal dysfunction. Another important risk factor was hypertension (Ekart et al., 2008).

**Vascular calcification**: The uremic state is associated with numeous metabolic abnormalities and endocrine disturbances primarily involving calcium and phosphorus metabolism. Vascular calcification is highly prevelant in dialysis patients and increases CV mortality. The presence and progression of vascular calcification in hemodialysis patients have been significantly associated with chronic inflammation, malnutrition, and disorders of mineral metabolism. Through a review of the literature examining vascular calcification in end stage renal failure patients, hyperphosphatemia is significantly associated with vascular calcification in nondiabetic patients, while it may not be a significant risk factor for vascular calcification in diabetic patients. In diabetic patients vascular calcification occurs long before the initiation of dialysis therapy and and the factors associated with vascular calcification in non-uremic diabetics appear to be hyperglycemia and related metabolic disorders, such as increased glycation and oxidative stress. In diabetic end stage renal failure patients, hyperglycemia is also suggested to be a significant factor associated with the progression of vascular calcification. Thus, the importance of glycemic control in diabetic and phosphate control in nondiabetic end stage renal failure patients is suggested (Ishimura et al., 2008).

The accumulating data demonstrate the role of abnormalities of calcium, phosphorus, vitamin D, and parathyroid hormone in CV disease and the importance of phosphate control is suggested for preventing vascular calcification and CV risk (Andress, 2008; London et al., 2000).

Diabetes mellitus and ethnicity are known factors that affect the extent of CV calcifications. The extent of CV calcifications was assessed in non-diabetic Caucasian hemodialysis patients by a novel composite calcification score. Body mass index, cholesterol, triglycerides, intact PTH, and serum levels of fetuin-A and uncarboxylated matrix Gla protein were not associated with CV calcifications. Age, male gender, dialysis vintage, smoking, calciumphosphate product, CRP, and lower Kt/V were independent risk factors for CV calcifications (Schlieper et al., 2009). Increasing dialysis efficiency and lowering calciumphosphate product can reduce CV calcifications. Generally, a calcium X phosphate product of less than 55 is the therapeutic optimum and it is possible that even lower levels offer further survival advantage. However, no prospective randomized studies have demonstrated a CV benefit and/or a survival advantage with any of the current therapeutic options. But observational studies have shown improved survival in hemodialysis patients treated with active vitamin D analogues (Levin&Li, 2005).

**Metabolic abnormalities:** Chronic kidney disease is associated with complex metabolic changes including insulin resistance, and insulin resistance is associated with increased CV risk (O'Sullivian&Kelly, 2007). In contrast to the general population, a higher body mass index is associated with better survival among hemodialysis patients. Theoretically, high energy supplementation in nondiabetic hemodialysis patients might adversely affect insulin resistance, and with this goal in mind, the effects of high energy supplementation on nondiabetic hemodialysis patients was investigated. According to the results, body fat mass and CRP were the primary determinants of insulin resistance in nondiabetic hemodialysis patients. High energy supplementation, increased adiposity, and inflammation exacerbated insulin resistance. However, long term metabolic effects of this strategy were unclear (Hung & Tang, 2009).

Determinants of Cardiovascular Risk in Hemodialysis Patients Without Significant Comorbidities 291

activator inhibitor type-1 and an upregulated expression of plasminogen activator inhibitor type- 1 in the vasculature could indicate a chronic endothelium activated state and that may identify the risk of atherothrombosis related with inflammation in nondiabetic hemodialysis patients (Peng et al., 2008). Among nondiabetic patients, generalized endothelial dysfunction is

**Gene polymorphisms:** Cytokine gene polymorphisms have been implicated as potential genetic risk factors for CV disease. The study assessed the role of cytokine gene polymorphisms in carotid intima-media thickness and left ventricular mass index, as surrogate markers for CV risk, in nondiabetic hemodialysis patents. Carotid intima-media thickness and left ventricular mass index progression for 2 years were detected at higher levels in patients with high-producer genotypes than in the patients with the low-producer genotype during the study period. The TNF-alpha-308 G/A polymorphism was closely associated with CRP. So polymorphisms in inflammatory genes could be additional factors affecting inflammation and

Synthesis of nitric oxide by endothelial nitric oxide synthase plays a key role in the atherosclerotic process. Several polymorphisms of the gene encoding endothelial nitric oxide synthase are known and have been investigated with respect to their influence on CV disease risk in the general population. The association between endothelial nitric oxide synthase gene polymorphism and CV events in nondiabetic Japanese hemodialysis patients was also investigated. Three endothelial nitric oxide synthase polymorphisms were genotyped for the patients and two endothelial nitric oxide synthase polymorphisms were found to be associated with major cardiac, cerebrovascular, or peripheral vascular events

It is increasingly appreciated that chronic renal failure alone is an independent risk factor for the development of coronary artery disease. For evaluating the determinants of coronary artery disease in nondiabetic hemodialysis patients, among 312 consecutive patients on regular hemodialysis, 26 nondiabetic patients with angiographically defined coronary artery disease were compared with a subject group of nondiabetic hemodialysis patients of the same gender, smoking status, and hypertension with similar ages and body mass indexes, who had normal electrocardiography and myocardial perfusion scintigraphy. Demographics, CRP, ESR, Hct-corrected ESR, beta 2 microglobulin, cardiac troponin I, parathyroid hormone, albumin, calcium X phosphorus, and lipid profiles were compared between the groups. The nondiabetic patients with coronary artery disease had higher CRP, higher cardiac troponin I, and lower HDL-cholesterol levels than the patients without coronary artery disease. Backwards stepwise logistic regression analysis revealed that high CRP and troponin I levels and low HDL cholesterol levels were independently related with coronary artery disease in nondiabetic hemodialysis patients (Zumrutdal et al., 2007). The predictive value of CRP in CV risk and mortality in hemodialysis patients was previously shown in numerious studies, and underlying coronary artery disease may be one of the possible links for this elevation. Additionally, even small elevations of serum cardiac troponin I concentration, at levels lower than those traditionally used for the diagnosis of acute events, were independently associated with the presence of coronary artery disease in asymptomatic hemodialysis patients. Thus, small and non-specific increases in cardiac troponin I levels may

associated with an increase in CV risk.

(Asakimori et al., 2004).

CV risk in non diabetic hemodialysis patients (Yilmaz et al., 2010).

**5.2 Coronary artery disease in nondiabetic hemodialysis patients** 

reflect underlying coronary artery disease in nondiabetic hemodialysis patients.

Another study on nondiabetic hemodialysis patients showed that liver fat, visceral adiposity, and sleep disturbances contributed to the development of insulin resistance and glucose intolerance. However, further studies in the long term are still needed to clarify whether interventions that improve insulin sensitivity improve clinical outcomes and CV risk in nondiabetic hemodialysis patients (Sakkas et al., 2008). The study comparing fasting glucose levels and impaired fasting glucose levels with malnutrition and inflammatory parameters in nondiabetic hemodialysis patients demonstrated that fasting glucose levels predict one-year all-cause mortality in non-diabetic hemodialysis patients. And they also showed that basal fasting glucose levels, or the presence of impaired fasting glucose, plays an important role in inflammation, malnutrition and short term mortality (Lin-Tan, 2007).

Diabetes mellitus and deficiency in n-3 long-chain polyunsaturated fatty acids are known to increase the incidence of CV disease. The study investigated the relationship between n-3 long-chain polyunsaturated fatty acids and the pulse wave velocity from the brachium to the ankle, which was measured as a marker of atherosclerosis in 54 diabetic and 93 nondiabetic hemodialysis patients. The mean pulse wave velocity in diabetic patients was significantly higher than that of nondiabetic patients. There was a significant inverse association between pulse wave velocity and docasahexaenoic acid levels and docasahexaenoic acid/aracidonic acid ratios in nondiabetic patients. It was concluded that n-3 long-chain polyunsaturated fatty acids may be a negative risk factor for CV disease in nondiabetic hemodialysis patients (Hamazaki et al., 2009).

Numerous abnormalities of lipid and lipoprotein metabolism are described in renal disease. These abnormalities are caused by complex alterations in several pathways of lipoprotein metabolism. In addition, nonenzymatic modification of lipoprotein particles enhances their atherogenicity without affecting the measured levels of cholesterol, triglycerides, or the HDL, LDL and very-low-density lipoprotein fractions (Tomson, 2000). Dyslipidemia may be present in more than 90 % of hemodialysis patients and has been reported to correlate with CV disease in some, but not all, cross sectional studies of nondiabetic patients on hemodialysis. Among other lipid parameters, low HDL cholesterol was one of the independent determinants of coronary artery disease in nondiabetic hemodialysis patients (Zumrutdal et al., 2007). However there are limited data concerning the effectiveness of lipid lowering with statins in decreasing CV outcomes in patients on hemodialysis.

**Coagulation defects:** In 68 nondiabetic hemodialysis patients, the probable association of circulating levels of plasminogen activator inhibitor type-1 and the expression of plasminogen activator inhibitor type-1 in internal iliac artery walls with atherosclerotic disease was investigated. Fifty age- and sex-matched healthy normotensive controls participated in the study. Atherosclerotic disease in both groups was assessed by measuring carotid intima-media thickness. Compared with control subjects, hemodialysis patients had significantly increased carotid thickness. Atherosclerotic plaques were detected in 61.7% of hemodialysis patients and 4% of controls. Carotid intima-media thickness was correlated with age, systolic blood pressure, low-density lipoprotein, CRP, and interleukin-6. In hemodialysis patients, a close correlation was found between serum plasminogen activator inhibitor type-1 level, CRP, and interleukin-6 level. Also, carotid intima-media thickness and plaque score were correlated with circulating levels of plasminogen activator inhibitor type-1 and with the expression of it in internal iliac artery walls. The circulating levels of plasminogen activator inhibitor type-1 and the expression of plasminogen activator inhibitor type-1 in internal iliac rtery walls were statistically associated with CRP, interleukin-6, and low density lipoprotein cholesterol. With all of those correlations, authors have suggested that increased circulating plasminogen

Another study on nondiabetic hemodialysis patients showed that liver fat, visceral adiposity, and sleep disturbances contributed to the development of insulin resistance and glucose intolerance. However, further studies in the long term are still needed to clarify whether interventions that improve insulin sensitivity improve clinical outcomes and CV risk in nondiabetic hemodialysis patients (Sakkas et al., 2008). The study comparing fasting glucose levels and impaired fasting glucose levels with malnutrition and inflammatory parameters in nondiabetic hemodialysis patients demonstrated that fasting glucose levels predict one-year all-cause mortality in non-diabetic hemodialysis patients. And they also showed that basal fasting glucose levels, or the presence of impaired fasting glucose, plays an important role in inflammation, malnutrition and short term mortality (Lin-Tan, 2007). Diabetes mellitus and deficiency in n-3 long-chain polyunsaturated fatty acids are known to increase the incidence of CV disease. The study investigated the relationship between n-3 long-chain polyunsaturated fatty acids and the pulse wave velocity from the brachium to the ankle, which was measured as a marker of atherosclerosis in 54 diabetic and 93 nondiabetic hemodialysis patients. The mean pulse wave velocity in diabetic patients was significantly higher than that of nondiabetic patients. There was a significant inverse association between pulse wave velocity and docasahexaenoic acid levels and docasahexaenoic acid/aracidonic acid ratios in nondiabetic patients. It was concluded that n-3 long-chain polyunsaturated fatty acids may be a negative risk factor for CV disease in

Numerous abnormalities of lipid and lipoprotein metabolism are described in renal disease. These abnormalities are caused by complex alterations in several pathways of lipoprotein metabolism. In addition, nonenzymatic modification of lipoprotein particles enhances their atherogenicity without affecting the measured levels of cholesterol, triglycerides, or the HDL, LDL and very-low-density lipoprotein fractions (Tomson, 2000). Dyslipidemia may be present in more than 90 % of hemodialysis patients and has been reported to correlate with CV disease in some, but not all, cross sectional studies of nondiabetic patients on hemodialysis. Among other lipid parameters, low HDL cholesterol was one of the independent determinants of coronary artery disease in nondiabetic hemodialysis patients (Zumrutdal et al., 2007). However there are limited data concerning the effectiveness of lipid

**Coagulation defects:** In 68 nondiabetic hemodialysis patients, the probable association of circulating levels of plasminogen activator inhibitor type-1 and the expression of plasminogen activator inhibitor type-1 in internal iliac artery walls with atherosclerotic disease was investigated. Fifty age- and sex-matched healthy normotensive controls participated in the study. Atherosclerotic disease in both groups was assessed by measuring carotid intima-media thickness. Compared with control subjects, hemodialysis patients had significantly increased carotid thickness. Atherosclerotic plaques were detected in 61.7% of hemodialysis patients and 4% of controls. Carotid intima-media thickness was correlated with age, systolic blood pressure, low-density lipoprotein, CRP, and interleukin-6. In hemodialysis patients, a close correlation was found between serum plasminogen activator inhibitor type-1 level, CRP, and interleukin-6 level. Also, carotid intima-media thickness and plaque score were correlated with circulating levels of plasminogen activator inhibitor type-1 and with the expression of it in internal iliac artery walls. The circulating levels of plasminogen activator inhibitor type-1 and the expression of plasminogen activator inhibitor type-1 in internal iliac rtery walls were statistically associated with CRP, interleukin-6, and low density lipoprotein cholesterol. With all of those correlations, authors have suggested that increased circulating plasminogen

lowering with statins in decreasing CV outcomes in patients on hemodialysis.

nondiabetic hemodialysis patients (Hamazaki et al., 2009).

activator inhibitor type-1 and an upregulated expression of plasminogen activator inhibitor type- 1 in the vasculature could indicate a chronic endothelium activated state and that may identify the risk of atherothrombosis related with inflammation in nondiabetic hemodialysis patients (Peng et al., 2008). Among nondiabetic patients, generalized endothelial dysfunction is associated with an increase in CV risk.

**Gene polymorphisms:** Cytokine gene polymorphisms have been implicated as potential genetic risk factors for CV disease. The study assessed the role of cytokine gene polymorphisms in carotid intima-media thickness and left ventricular mass index, as surrogate markers for CV risk, in nondiabetic hemodialysis patents. Carotid intima-media thickness and left ventricular mass index progression for 2 years were detected at higher levels in patients with high-producer genotypes than in the patients with the low-producer genotype during the study period. The TNF-alpha-308 G/A polymorphism was closely associated with CRP. So polymorphisms in inflammatory genes could be additional factors affecting inflammation and CV risk in non diabetic hemodialysis patients (Yilmaz et al., 2010).

Synthesis of nitric oxide by endothelial nitric oxide synthase plays a key role in the atherosclerotic process. Several polymorphisms of the gene encoding endothelial nitric oxide synthase are known and have been investigated with respect to their influence on CV disease risk in the general population. The association between endothelial nitric oxide synthase gene polymorphism and CV events in nondiabetic Japanese hemodialysis patients was also investigated. Three endothelial nitric oxide synthase polymorphisms were genotyped for the patients and two endothelial nitric oxide synthase polymorphisms were found to be associated with major cardiac, cerebrovascular, or peripheral vascular events (Asakimori et al., 2004).
