Criteria for Metabolic Syndrome including Insulin Resistance (50)
1. Introduction
Elevated sympathetic activation, as assessed using a variety of indices, has been observed in lean hypertensive and diabetic patients, and obese individuals [Huggett et al. 2006; Masuo et al. 2000]. Similarly, many epidemiological studies have shown that hypertensive patients, even those without increased adiposity, display a higher prevalence of insulin resistance, thereby indicating the possible association between sympathetic activation and insulin resistance in the pathogenesis of hypertension [Esler et al. 2006; Masuo et al. 2002; de Silva et al. 2009]. Overweight and obesity is a growing problem across the globe and has reached “epidemic” proportions. The prevalence of diabetes, especially type 2 diabetes, and hypertension are significantly increased with the prevalence of obesity. Obesity, itself, and type 2 diabetes and hypertension associated with obesity are known to be more closely linked with insulin resistance and elevated sympathetic nervous activity. It has been well documented that obesity, hypertension, and diabetes are risk factors for subsequent cardiovascular and renal complications. Many patients are both diabetic and hypertensive while they are obese, but not all diabetic patients have hypertension, indicating that insulin resistance is not the only mechanism for blood pressure elevation in diabetic-hypertensive patients. Several investigators have reported that sympathetic nervous activation plays an important role in cardiovascular complications in patients with hypertension, diabetes, and obesity.
Sympathetic nervous activation accompanying insulin resistance is closely linked with left ventricular hypertrophy in otherwise healthy subjects [Masuo, et al. 2008]. In addition, sympathetic activation may predict the development of renal injury in healthy normotensive subjects [Masuo, et al. 2010]. Weight loss associated suppression of sympathetic nervous activity is associated with improvement of insulin sensitivity and resultant improvement in renal function in obese patients [Masuo, et al. 2011b; Straznicky, et al. 2009b & 2011]. Furthermore, weight loss improved the prevalence of left ventricular hypertrophy [Masuo, et al. 2008], which is one of the predictors for future cardiac complications, renal complications (injury) [Masuo, et al. 2007] and hyperuricacidemia [Straznicky, et al. 2011].These findings suggest that elevated sympathetic nerve activity associated with insulin resistance may contribute to the onset and maintenance of cardiovascular and renal complications in diabetes, and hypertension in obesity.
Furthermore, genetic polymorphisms of the β2- and β3-adrenoceptor gene have been associated with obesity [Masuo, et al. 2005 & 2011a; Kawaguchi, et al. 2006], hypertension [Masuo, et al. 2005b & 2010b; Kawaguchi, et al. 2006], type-2 diabetes and insulin resistance [Masuo, et al. 2005 & 2010} in epidemiological studies and may also be implicit in the close relationship between insulin resistance and sympathetic nerve activation. Recently, Masuo
This chapter will provide a synthesis of the current findings on the mechanisms of the onset and maintenance of cardiovascular and renal complications in obesity, hypertension and type 2 diabetes, with a particular focus on sympathetic nervous activity and insulin resistance. A better understanding of the relationships between sympathetic nervous activity and insulin resistance in these important clinical conditions might help with the clinical treatment of diabetes and hypertension in obesity and prevent further cardiovascular and renal complications in this at risk group.
2. Prevalence of type 2 diabetes and hypertension in obesity
The clustering of cardiovascular risk factors associated with obesity, in particular abdominal obesity, is well established [Athyrus, et al. 2011]. The prevalence of obesity and overweight increased in the United States between 1978 and 1991 [Mokdad, et al. 2001], and recent reports have suggested continuing increases [Ogden, et al. 2004]. The National Health and Nutrition Examination Survey (NHANES) I (1971-1974), NHANES II (1976-1980), and NAHNES III (1988-1994) were conducted by the National Center for Health Statistics, Centers for Disease Control and Prevention (CDC). These data from the continuous NHANES studies have showed that the prevalence of obesity and overweight people increased significantly in the United States between 1960 and 2003 [Preis, et al. 2009; Ogden, et al. 2004; Flegal, et al. 2012]. Evidence from several studies indicates that obesity and weight gain are associated with an increased risk of hypertension [Masuo, et al. 2000 & 2005a, b, c] and diabetes [Resnick, et al. 2000; Ford, et al. 1997], and that intentional weight loss reduces the risk that overweight individuals will develop hypertension [Masuo, et al. 2001b; Straznicky, et al. 2009b] or diabetes [Will, et al. 2002].
Recent large cohort studies have showed an increasing prevalence of obesity in children and, importantly, obesity in children is strongly associated with several major health risk factors, including type 2 diabetes mellitus and hypertension [Hedley, et al. 2004].
Focusing on the close associations between obesity, hypertension and diabetes, the NHANES and the Behavioural Risk Factor Surveillance System (BRFSS) investigations [Mokdad,
3. Sympathetic nervous activity in obesity, hypertension and diabetes
The sympathetic nervous system represents a major pathophysiological hallmark of both hypertension and renal failure, and is an important target of the therapeutic intervention [Grassi, et al. 2012; Schlaich, et al. 2009]. The sympathetic nervous system participates in regulating the energy balance through thermogenesis. Reduced energy expenditure and resting metabolic rate are predictive of weight gain (obesity). It is also widely recognized that insulin resistance or hyperinsulinemia relates to obesity [Minicardi,
The response of the sympathetic nervous system to change in plasma insulin levels after oral glucose loading (oral glucose tolerance test) are different between subjects with and without insulin resistance [Masuo, et al. 2005], between nonobese and obese subjects [Straznicky, et al. 2009a], and between subjects with and without the metabolic syndrome [Straznicky. 2009b]. Recently, changes in the sympathetic nerve firing pattern were observed with sympatho-inhibition during weight loss [Lambert, et al. 2011]. In addition, different regulation by insulin of regional (i.e. hind limb, kidney and brown adipose tissue) sympathetic outflow to peripheral tissue was observed in agouti obese mice compared to lean control mice [Morgani, et al. 2010]. These observations provide the evidence of a strong linkage between the activity of the sympathetic nervous system and insulin levels. Huggett
Several investigations on the contributions of β2- and β3-adrenoceptor polymorphisms to type 2 diabetes also support a strong relationship between sympathetic nerve hyperactivity and insulin resistance in type 2 diabetes [Masuo,
4. Insulin resistance in obesity, hypertension and type 2 diabetes
Insulin resistance [Ferrannini, et al. 1998] is one of the criteria underpinning the development of the metabolic syndrome. The clinical evaluation of insulin resistance is growing interest because it is a strong predictor and plays an important role in the development of the metabolic syndrome, type 2 diabetes mellitus and hypertension. Table 1 shows the criteria for metabolic syndrome characterisation, as can be seen insulin resistance is prominent [Alberti, et al. 1998; Grundy, et al. 2004] (Table 1). Measuring insulin sensitivity is important to define insulin resistance. Table 2 summarizes the methods usually used in clinical and epidemiological studies (Table 2). The hyperinsulinemic-euglycemic glucose clamp method is the gold standard and may be suitable for research investigations in specialized laboratories, but the homeostasis model assessment of insulin resistance (HOMA-IR) or fasting plasma insulin concentrations is more practical for epidemiological studies comprising a large number of subjects.
4.1. Hyperinsulinemia as a marker of insulin resistance
Insulin is an exceptional hormone in that its action is regulated not only by changes in concentration but also by changes in the sensitivity of target tissues. Inadequate insulin action can be the consequence of: (
For any amount of insulin secreted by the pancreas, the biological response of a given effector is dependent on its insulin sensitivity. The term insulin resistance customarily refers to glucose metabolism. Any decrease in insulin sensitivity (insulin resistance) is immediately translated into minute increases in blood glucose concentrations that will in turn act on the β-cell to produce a compensatory stimulus of insulin secretion, leading to a degree of hyperinsulinemia that is approximately proportional to the degree of effector resistance. Therefore, hyperinsulinemia may be responsible for insulin resistance. In steady-state conditions, this compensatory hyperinsulinemia prevents a more exaggerated hyperglycaemia. The inability of β-cells to enhance insulin secretion means that blood glucose will keep increasing until the level of hyperglycaemia produces an adequate β-cell stimulus to attain the required insulin response. When the β-cell is unable to compensate for the prevalent insulin resistant state by further augmenting insulin secretion, hyperglycaemia continues to increase, producing impaired fasting glucose, impaired glucose tolerance and diabetes mellitus development.
4.2. Relationships between sympathetic nervous activity and insulin resistance in obesity, hypertension, and type 2 diabetes
It is widely recognized that insulin resistance or hyperinsulinemia relates to obesity [Ferrannini, et al. 1991 & 1995; Ward, et al. 1996], but the precise relationships linking those factors remain controversial. Many epidemiological and clinical studies have shown a close relationship between sympathetic nervous system activity and insulin levels in obesity [Anderson, et al. 1991; Ward, et al. 1996; Masuo, et al. 2002]. Several studies of longitudinal design have examined the effect of body weight changes (weight loss or weight gain) on sympathetic nervous system activity and insulin sensitivity (fasting plasma insulin levels and HOMA-IR). Elevations of sympathetic nervous system activity and insulin levels during weight gain [Masuo, et al. 2000; Bernes,
Reduced energy expenditure and resting metabolic rate are predictive of weight gain and obesity development. The sympathetic nervous system participates in regulating energy balance through thermogenesis (Figure 1). Landsberg and other investigators hypothesized that energy intake stimulates hyperinsulinemia and sympathetic nerve activity resulting in blood pressure elevations in a cycle in order to inhibit thermogenesis. Insulin-mediated sympathetic nerve stimulation in obese subjects is therefore considered part of a compensatory mechanism aimed at restoring the energy balance by increasing the metabolic rate [Landsberg. 2001]. Hyperinsulinemia and insulin resistance in obese subjects are all part of a response to limit further weight gain via stimulating sympathetic nerve activity and thermogenesis [Landsberg, 2001].
On the other hand, Julius and Masuo generated a hypothesis based on data from their longitudinal studies that increased sympathetic nerve activity in skeletal muscle causes neurogenic vasoconstriction, thereby reducing blood flow to muscle and consequently inducing a state of insulin resistance by lowering glucose delivery and uptake in hypertension and obesity. Both blood pressure elevations and weight gain may reflect a primary increase in sympathetic nervous tone. Masuo
Very recently, Masuo et al. [Masuo, et al. 2012} showed the differences in mechanisms of weight loss-induced blood pressure reductions with neurohormonal parameters changes over 24 weeks with loss regimens (Figure 2). A calorie restricted diet caused suppression/normalization of sympathetic activation measured with plasma norepinephrine levels followed by improvements of insulin resistance, whereas exercise improved insulin resistance followed by normalization of norepinephrine levels. BMI and blood pressure decreased after significant reductions in both plasma norepinephrine and HOMA-IR (Figure 2). Their investigations may help to explain why discordant results have been observed. However, at least their hypotheses showed a strong linkage between sympathetic activation, insulin resistance, obesity and hypertension.
Valentine
Hoffmann
4.3. Sympathetic nervous activity and leptin in obesity and the metabolic syndrome
Interactions between the sympathetic nervous system and leptin are widely acknowledged with each being able to influence the other. Indeed, the leptin system mediates some of its action through the sympathetic nervous system [Haynes, et al. 1997; Kuo, et al. 2003]. Trayhurn
Masuo et al. [Masuo, et al. 2008] showed during oral glucose loading that plasma insulin and plasma norepinephrine increased in both insulin-sensitive and insulin-resistant subjects, but plasma leptin levels decreased in insulin-sensitive nonobese subjects and increased in insulin- resistant nonobese subjects. Straznicky
4.4. Sympathetic nervous activity and insulin resistance in the metabolic syndrome
The metabolic syndrome is a cluster of abnormalities with basic characteristics being insulin resistance and visceral obesity. The criteria/definitions of metabolic syndrome are shown in Table 1. Importantly, obesity and the metabolic syndrome are associated with significant co-morbidities, such as type 2 diabetes, cardiovascular disease, stroke, and certain types of cancers.
Huggett
5. Cardiovascular and renal complications in obesity, obesity-related hypertension and diabetes
It has been documented that patients with obesity, hypertension and type 2 diabetes frequently have cardiovascular and renal complications. Obesity was closely associated with an increase in blood pressure, left ventricular mass, and with early signs of disturbed left ventricular diastolic function [Wikstrand, et al. 1993], and changes in left ventricular morphology and diastolic function [Alpert, et al. 2012]. It is well known that sudden cardiac death is the most common cause of death in dialysis patients and is usually preceded by sudden cardiac arrest due to ventricular tachycardia or ventricular fibrillation [Alpert, et al. 2011]. Left ventricular (LV) mass and loading conditions that may affect LV mass are important determinants of corrected QT intervals (QTc) in normotensive severely obese subjects [Mukergi, et al. 2011]. The RICARHD study (Cardiovascular risk in patients with arterial hypertension and type 2 diabetes study), was a multicenter and cross-sectional study, conducted in Spain and included 2,339 patients who were 55 years or more with hypertension and type 2 diabetes of greater than 6 months duration. Left ventricular hypertrophy (LVH) or renal damage (GFR<60 ml/min/1.73 m2 and/or albumin/creatinine ratio ≥0 mg/g or an urinary albumin excretion ≥30 mg/24 hours) were compared between these hypertensive and type 2 diabetes patients and healthy controls. The combined presence of both hypertension and type 2 diabetes were associated with an increased prevalence of established cardiovascular diseases. Similarly, the presence of both cardiac and renal damage was associated to the higher prevalence of cardiovascular diseases [Cea-Calvo, et al. 2006].
The Lifestyle Interventions and Independence for Elders (LIFE) study in 8,029 patients with stage II-III hypertension with LVH on ECG showed high prevalence of co-existence of LVH and albuminuria [Wachtell, et al. 2002]. In patients with moderately severe hypertension, LVH on two consecutive ECGs is associated with increased prevalence of micro- and macro-albuminuria compared to patients without persistent LVH on ECG. High albumin excretion was related to LVH independent of age, blood pressure, diabetes, race, serum creatinine or smoking, suggesting parallel cardiac damage and albuminuria.
5.1. Hyperglycemia and insulin resistance as risk factors of cardiovascular complications in type 2 diabetes
Hyperglycemia and hyperinsulinemia or insulin resistance that is a characteristic of type 2 diabetes and obesity play major roles in the cardiovascular complications of type 2 diabetes mellitus and obesity. Hyperglycemia is the major risk factor for microvascular complications (retinopathy, neuropathy, and nephropathy) in type 2 diabetes, however 70% or 80% of patients with type 2 diabetes die of macrovascular disease. Atherogenic dyslipidemia (elevated triglyceride levels, low HDL-cholesterol levels, high LDL-cholesterol levels) is the major cause of atherosclerosis in patients with type 2 diabetes [Reasner,
Several investigators have demonstrated that insulin resistance could predict future type 2 diabetes even in nonobese individuals [Morrison, et al. 2008], and even in children [Koska, et al. 2007; Morrison, et al. 2008] Insulin resistance accompanying sympathetic nerve activation may also predict future hypertension development [Masuo, et al. 1997, 1998, 2003, & 2005]. Insulin resistance coexisting with inflammation may predict cardiac disease but, interestingly, not stroke in the Japanese diabetic population [Matsumoto, et al. 2006]. Hyperglycemia (
5.2. Sympathetic nervous activity as a risk factor for cardiovascular complications and renal complications
Heightened sympathetic nerve activity plays an important role in cardiovascular complications and cardiac risk in humans [Esler, et al. 2000]. There is consistent evidence that high plasma norepinephrine level, as an index of heightened sympathetic nerve activity, predicts mortality in cardiovascular diseases such as chronic congestive heart failure [Cohn et al. 1984; Brum, et al. 2006], left ventricular dysfunction [Grassi, et al. 2009], remodelling [Abel, et al. 2010], structural changes in obesity {Benedict, 1996}, and end-stage renal disease (ESRD) [Masuo, et al. 2007; Grassi, et al. 2012; Benedict, et al. 1996; Ksiazck, et al. 2008]. Renal injury also predicts the development of cardiovascular disease [Masuo, et al. 2007; Joles, et al. 2009].
Hogarth
Changes in heart rates during exercise and recovery from exercise are mediated by the balance between sympathetic and vagal activity, and changes in heart rates were evaluated in a total of 5,713 asymptomatic working men cohort (between the ages of 42 and 53 years) in whom there was no evidence of the presence or history of cardiac disease over the preceding 23 years. Baseline heart rates, changes in heart rates during exercise and recovery were strongly related to an increased risk of sudden death from myocardial infarction [Jeuven, et al. 2005].
Zoccali
Petersson et al. [Petersson, et al. 2002] showed that increased cardiac sympathetic nervous activity in renovascular hypertension might lead to high cardiovascular mortality and morbidity. Prolonged sympathetic nerve stimulation and elevated circulating norepinephrine levels can induce changes in intra-renal blood vessels. Catecholamines can induce proliferation of smooth muscle cells and adventitial fibroblasts in vascular wall.
The association between hypertension, obesity and chronic kidney disease (CKD) is well recognized [White, et al. 2005; Hall,
Joles
These investigations have shown strong associations between sympathetic nervous activation, cardiovascular complications and renal complications. Given these observations it may be of importance to aim antihypertensive treatments or anti-diabetic treatment not only at the reduction of raised blood pressure or blood glucose but also at the excessive sympathetic activation and insulin resistance that may underpin these effects.
5.3. Sympathetic nerve hyperactivity in patients with ESRD
Evidence now strongly indicates a role for the sympathetic nervous system in the pathogenesis of hypertension in renal failure (ESRD) [Hausberg, et al. 2002; Schlaich, et al. 2009; Masuo, et al. 2010a]. Hypertension occurs commonly and early in renal disease and is paralleled by increases in sympathetic nerve activity, as indicated by increased muscle sympathetic nerve activity and circulating norepinephrine. This appears to be driven by the diseased kidneys, because nephrectomy or denervation has been shown to correct blood pressure and sympathetic nerve activity both in human and animal studies [Jacob, et al. 2003].
Masuo et al. [Masuo, et al. 1995 & 2010] showed that plasma norepinephrine levels were significantly higher in patients with ESRD regardless of hemodialysis compared with those in blood pressure- and body mass index-matched hypertensive patients or healthy normotensive subjects (Figure 3). Further, this was recognized significantly in subjects with a shorter duration of ESRD with hemodialysis compared with those with longer duration, suggesting that sympathetic nerve hyperactivity may be of particular importance in the onset or the early development of ESRD or, alternatively, be influenced by long-term renal replacement therapy (hemodialysis). In the normal state, interactions between the kidney and sympathetic nervous system serve to maintain blood pressure and glomerular filtration rate within tightly controlled levels, but in renal failure, a defect in renal sodium excretory function leads to an abnormal pressure natriuresis relationship and activation of the renin-angiotensin system (RAS), contributing to the development of hypertension and progression of kidney disease [Hall, et al. 1997; Lohmeier, et al. 2001]. Another mechanism could involve the sympathetic nervous modulation of baroreflex regulation and vasculature tone through the central nervous system and angiotensin II [Burke, et al. 2008]. Afferent signals from the kidney, detected by chemoreceptors and mechanoreceptors, feed directly into central nuclei regulating sympathetic nerve activity by circulating and brain-derived angiotensin II [Philips,
Sympathetic nerve activity is consistently elevated in patients with ESRD, and in obese subjects and hypertensive patients in cross-sectional studies [Masuo, et al. 1995, 2011a & 2011b). The sympathetic nerve hyperactivity is at least in part independent of increased blood pressure levels or obesity. Further, patients with early-ESRD without hemodialysis had already significantly higher plasma norepinephrine levels compared with hypertensive subjects as well as normotensive subjects. Therefore, sympathetic nervous activation in ESRD patients may be independent from obesity or hypertension.
The amount of norepinephrine in plasma is only a fraction of the amount released into the synaptic cleft, and plasma norepinephrine levels are affected by dialysis therapy, so it is difficult to discount that the elevated plasma norepinephrine levels did not derive in part from reduced plasma norepinephrine clearance rather than solely from elevated sympathetic nerve activity. Grassi
5.4. β2-adrenoceptor polymorphisms accompanying sympathetic nervous activation may relate to renal injury
Rao et al. [Rao, et al. 2007] and Masuo et al. [Masuo, et al. 2007] have shown strong associations between β2-adrenoceptor polymorphisms, elevated plasma norepinephrine levels and elevated HOMA-IR (insulin resistance) or future renal injury, suggesting that stimulated sympathetic nerve activity associated with insulin resistance, may independently play a major role in the onset and development of ESRD without obesity or hypertension. However, the precise mechanisms underlying sympathetic activation in CKD and ESRD have not been clarified.
Furthermore, Masuo et al. [Masuo, et al. 2011b] measured renal function (creatinine, BUN and creatinine clearance), plasma norepinephrine levels and HOMA-IR (insulin sensitivity) annually over a 5-year period in nonobese, normotensive men with normal renal function. Subjects who had a significant deterioration of renal function (more than 10% increases from baseline of creatinine and BUN or decrease in creatinine clearance) over a 5-year period had higher plasma norepinephrine at the entry period, and greater increases in plasma norepinephrine over 5 years [Masuo, et al. 2011b]. In this study, subjects who had significant changes in body weight or blood pressure were excluded, indicating the contributions of obesity or hypertension might be excluded. Further, subjects who had significantly higher levels of plasma norepinephrine had a higher frequency of the Gly16 allele of the β2-adrenoceptor polymorphism [Masuo, et al. 2007] (Figure 4). The Gly16 allele of the β2-adrenoceptor polymorphism has been shown to be related to obesity [, Masuo, et al. 2005, 2005a, 2005b], hypertension [Masuo, et al. 2005a, 2005b, 2010b, 2011c] and metabolic syndrome development [Masuo, et al. 2005b]. Thus, high plasma norepinephrine levels appear to be a predictor that is determined genetically by the β2-adrenoceptor polymorphism (Arg16Gly) for renal injury, obesity, hypertension and metabolic syndrome.
These observations show that plasma norepinephrine levels associated with insulin resistance are strongly linked with the onset and development of renal injury.
6. Other medical conditions in obesity
6.1. Obstructive sleep apnea in obesity is a risk factor for cardiovascular diseases
Vozoris [Vozoris. 2012] investigated the relationships between prevalence of obstructive sleep apnea (OSA), obesity, and hypertension, diabetes, congestive heart failure, myocardial infarction, and stroke using a population-based multi-year cross-sectional study design including 12,593 individuals with data from the 2005-2008 United States National Health and Nutrition Examination Surveys (NHANES). They found individuals with OSA had elevated rates of cardiovascular diseases compared to the general population [Vozoris. 2012]. OSA is a common disorder that has been associated with many cardiovascular disease processes, including hypertension and arrhythmias. OSA has also been identified as an independent risk factor for stroke and all-cause mortality. OSA is highly prevalent in patients with transient ischemic attacks and stroke [Das, et al. 2012]. Indeed, the majority of patients with OSA suffer from hypertension [Ziegler, et al. 2011]. The mechanisms underlying the link between OSA and cardiovascular disease are not completely established. However, there is increasing evidence that autonomic mechanisms are implicated. A number of studies have consistently shown that patients with OSA have high levels of sympathetic nerve traffic [Narkiewicz, et al. 2003]. In animal studies, intermittent hypoxia that simulates changes seen in OSA leads to chemoreceptor and chromaffin cell stimulation of sympathetic nerve activity, endothelial damage and impaired blood pressure modulation. Human studies reveal activation of sympathetic nerves, endothelial damage and exaggerated pressor responses to sympathetic neurotransmitters and endothelin [Ziegler, et al. 2011]. OSA is also frequently observed in obese individuals [Dos,
6.2. Gout and hyperuricacidemia in obesity
Gout is a growing worldwide health problem, and is associated with increased prevalence of obesity. Gout and hyperuricacidemia are associated with the metabolic syndrome, diabetes mellitus, obesity and hypertension. Masuo
Straznicky
7. Conclusion
The role of the sympathetic nervous activity and insulin resistance plays important roles in the etiology of obesity, hypertension, and type 2 diabetes. Several investigations have demonstrated that the sympathetic nervous activation and insulin resistance are strongly related to cardiovascular complication (
Recently, it has been demonstrated that renal sympathetic nerve denervation provides promising results in patients with refractory hypertension [Krum, et al. 2009; Symplicity HTN-1 Investigators. 2011]. Besides the demonstrable effect on reducing blood pressure, renal denervation significantly and favourably influences LV mass and improves diastolic function, which might have important prognostic implications in patients with resistant hypertension at high cardiovascular risk [Brandt, et al. 2012]. Further, renal denervations showed an accompanying improvements in insulin resistance [Mahfoud, et al. 2011,: Witkowski, et al. 2012] and OSA [Brandt,
A better understanding of the relationships between sympathetic nervous activity, insulin resistance, cardiovascular complications, and renal complications, will help to develop appropriate treatment strategies targeting renal injury or cardiac risk in hypertensive and diabetes patients with and without ESRD or LVH.
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