Division of Endocrinology, Diabetes and Hypertension, Departments of Medicine and Cell Biology at State University of New York, Health Science Center at Brooklyn, Kings County Hospital Center, and Veterans Affairs Medical Centers of Brooklyn, New York 11203-2098
Address all correspondence and requests for reprints to: James R. Sowers, M.D., FACP, Professor of Medicine and Cell Biology, Director of Endocrinology, Diabetes and Hypertension Division, State University of New York Health Science Center at Brooklyn, 450 Clarkson Avenue, Box 1205, Brooklyn, New York 11203. E-mail: jsowers{at}downstate.edu.
Type 2 diabetes and its complications are increasing rapidly in Westernized, industrialized societies, in part, because the population is aging and becoming more obese and sedentary (1, 2, 3, 4, 5, 6). Type 2 diabetes is also more common in minority populations, including Hispanics and African Americans, whose relative numbers are increasing in this country (1). Up to 20 million people in the United States have diabetes, of whom approximately 45 million are unaware that they have this disorder (5, 6). Diabetes is the most frequent underlying cause of new blindness, end stage renal disease, and lower extremity amputations in the United States (1, 2, 3). Diabetes also leads to premature cardiovascular disease (CVD; Refs. 2, 3, 4), stroke (7, 8, 9, 10, 11, 12, 13), and markedly increased premature mortality (2, 3). The role of the renin-angiotensin aldosterone system (RAAS) in increasing the risk for hypertension and CVD in patients with type 2 diabetes has recently engendered considerable interest (13, 14, 15, 16, 17, 18, 19, 20, 21, 22). In this review, we will present the evidence supporting the role of aldosterone as a risk factor above and beyond that of angiotensin II (Ang II) in the pathophysiology of CVD in people with diabetes. We will also discuss the potential benefits of blocking the cardiovascular and renal actions of aldosterone in lessening the burden of CVD and renal disease in these patients (13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25).
CVD and diabetes
CVD, including stroke and congestive heart failure, accounts for up to 80% of excess deaths in people with type 2 diabetes (2, 3, 7, 8, 9, 10, 11, 12, 13). The risk of coronary artery disease is increased 2- to 4-fold in those with diabetes compared with those without diabetes, and the risk of stroke is two to three times higher in persons with diabetes (2, 4, 7, 8, 9, 10, 11, 12, 13). In women, diabetes is a particularly important factor for the development of coronary artery disease, stroke, and congestive heart failure (14). The major risk factors for CVD in patients with type 2 diabetes are hypertension, dyslipidemia, smoking, etc. (2, 3, 4, 7, 8, 9, 10, 11, 12), but the presence of type 2 diabetes markedly accentuates these conventional risk factors (7, 8, 9, 10, 11, 12). Hypertension, especially systolic hypertension, occurs much more frequently in persons with diabetes and is a major risk factor for CVD, end stage renal disease, and stroke in these patients (2, 3, 4, 8, 15, 16, 17). Hypertension, hyperglycemia, cigarette and alcohol use are modifiable risk factors for stroke (18, 19, 20). In 8 yr of observation in the United Kingdom Prospective Diabetes Study (UKPDS), increased risk of stroke was strongly associated with systolic hypertension as well as atrial fibrillation (10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21). Accumulating evidence indicates that diabetic renal disease (glomerulosclerosis) and vascular disease (atherosclerosis) run parallel courses in persons with type 2 diabetes (15, 17). There is also increasing data indicating that albuminuria is a predictor of CVD and stroke as well as progression of diabetic renal disease (5, 8, 15, 17). Albuminuria usually clusters with other components of the cardiometabolic syndrome (Ref. 17 ; Table 1).
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Considerable evidence suggests that components of the RAS exert similar pathological effects on the renal glomerulus as in the systemic and cerebral vasculature (21, 25, 26, 27, 28). Thus, interruption of the system would be anticipated to produce parallel improvement in renal and CVD outcome (13, 15).
Heart failure is growing in this country because of our aging population, because more persons are surviving their myocardial infarctions, and because of the increasing prevalence of diabetes, particularly in our elderly population (2, 3, 7, 12). There is also accumulating evidence that RAS activation is an important contributor to development of heart failure (Refs. 21 and 26 ; Fig. 1), and this will be explored further in this review. Data from several recent intervention trials also suggest that treatment strategies that reduce the RAS can impact stroke incidence, severity, and recurrence in patients with type 2 diabetes mellitus. For example, in the UKPDS trial for combined fatal and nonfatal stroke, tight blood pressure control [with either an angiotensin converting enzyme (ACE) inhibitor or ß-blocker] to a mean level 144/82 mm Hg resulted in a striking 44% relative risk reduction compared with less aggressive control, a mean level of 154/87 mm Hg (10, 12). In the Micro-HOPE subanalysis of the Heart Outcomes Prevention Evaluation (HOPE) study, 35% of diabetic patients treated with the ACE inhibitor, ramipril, had a stroke reduction of 37% (22). Recent studies have shown the benefits of angiotensin receptor blockers (ARBs; Ref. 23) and an ACE/diuretic combination (24) in reduction of primary and secondary strokes in high-risk patients, including patients with diabetes (24).
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Aldosterone is a steroid hormone that is primarily produced in the zona glomerulosa, the outer layer of the adrenal cortex. Classical effects of aldosterone are to promote sodium retention and potassium loss by the kidney, although it exerts similar but lesser effects on the colon, sweat, and salivary glands. The three principal factors that regulate aldosterone secretion are Ang II, ACTH, and potassium. Changes in aldosterone secretion in response to changes in volume status or alteration in salt intake are mediated primarily by Ang II. Most patients with type 2 diabetes have normal Ang II regulation of aldosterone and normal circulating level of this hormone (26). However, in diabetic patients with dysautonomia, usually associated with long-standing diabetes, there may be impaired conversion of the precursor of renin, prorenin, to renin by the diabetic kidney (26). This defect in the processing of renin may ultimately result in the syndrome of hyporenin-hypoaldosteronism, in which high levels of circulating prorenin are associated with unstimulatable renin, resulting in low aldosterone levels and a propensity to hyperkalemia (26). In these patients, the use of an ACE inhibitor or an ARB as an aldosterone antagonist should be exercised with caution to avoid hyperkalemia.
Aldosterone and hypertension in diabetic patients
Hypertension in diabetes is characterized by reduced nitric oxide (NO)-mediated vasorelaxation (13), reduced baroreflex sensitivity, and enhanced sympathetic activity (13), abnormalities that are promoted by aldosterone (Refs. 20 and 28 ; Fig. 4). Aldosterone appears to have effects on the brain, the heart, vasculature, and kidneys that lead to elevated blood pressure. These changes include enhanced sympathetic nervous system activity, reduced vascular compliance, and endothelial-derived vasorelaxation, increases in volume expansion and reduced serum potassium, and increases in left ventricular mass and cardiac output (20, 28). Aldosterone antagonists have been shown to substantially reduce blood pressure in patients as well as in animal models with hypertension (20, 21, 22, 23, 24, 25, 26, 27, 28). Aldosterone antagonists also appear to have considerable potential in treating the diabetic patient with hypertension (Fig. 2
). There are data in the stroke-prone spontaneously hypertensive rats (SHRSP), suggesting that aldosterone antagonists may also reduce strokes (28) However, there are no extant studies demonstrating the ability of aldosterone antagonists to prevent stroke in men.
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Many similarities exist between the structure and function of the renal glomerulus and those of the vasculature (15, 17, 29). Renal mesangial cells are modified vascular smooth muscle cells (VSMC) derived from the same progenitor mesenchymal cell line (29). Like VSMC, these cells produce growth factors (Ang II, IGF, and cytokines) and NO, which counterbalances the biological effects of these growth factors (29). The pathophysiological alterations that characterize glomerulosclerosis parallel those of atherosclerosis and include mesangial cell proliferation/hypertrophy, foam cell accumulation, build-up of extracellular matrix and amorphous debris, inflammation and evolving sclerosis (29). All of these changes lead to matrix expansion, basement membrane abnormalities, and loss of basement membrane permoselectivity, which in turn leads to proteinuria (29, 30).
There is considerable experimental evidence that aldosterone contributes to the development of nephrosclerosis and renal fibrosis in models of diabetes and hypertension (29, 31, 32, 33, 34). In the deoxycortisone acetate salt hypertensive rat model, exogenous administration of mineralocorticoids induced lesions of malignant hypertension and stroke (25). In the SHRSP, mineralocorticoid receptor blockade reduced proteinuria (28) as well as nephrosclerotic lesions. Furthermore, aldosterone infusion reversed the renal protective effects of captopril therapy in the SHRSP (28).
Microalbuminuria is associated with endothelial cell dysfunction and enhanced oxidative stress, increased inflammation, elevated systolic blood pressure, and a dyslipidemia characteristic of the cardiometabolic syndrome in type 2 diabetes (Refs. 17 ,26 , and 32 ; Table 1). Given the seminal role of aldosterone in all of the pathophysiological events associated with insulin resistance, enhanced RAAS and increased tissue aldosterone should be included as components of the metabolic syndrome (Table 1
). These observations underscore the pathophysiological significance of the RAAS in development of diabetic glomerulosclerosis.
Aldosterone effects on the vasculature
In addition to decreasing endothelial cell NO production (21), aldosterone contributes to vascular growth and remodeling (Refs. 21 and 34, 35, 36, 37, 38 ; Table 2). These effects of aldosterone are mediated by both genomic and nongenomic effects of this hormone. The genomic effects on the vasculature include increases in protein synthesis, inflammation, and fibrosis. Nongenomic effects on the vasculature include enhancement of tyrosine phosphorylation, inositol phosphate activation, and increased Na+/H+ exchange and alkalinization of VSMC (Refs. 21 and 34, 35, 36, 37, 38 ; Table 2
). Some of the effects are mediated, in part, through the activation of the enzyme 11 ß-hydroxyl steroid dehydrogenase (38), and some effects are mediated by the interaction of aldosterone and other growth factors such as Ang II (21). Many of the vascular actions of aldosterone are similar to those promoted by hyperglycemia and other metabolic abnormalities associated with diabetes (3, 21).
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Aldosterone, like Ang II, is capable of inducing cardiac fibrosis characterized by enhanced accumulation of collagen and increased fibroblast proliferation in vivo (39, 40, 41, 42, 43, 44, 45, 46, 47, 48). In fact, aldosterone has similar effects as hyperglycemia in mediating fibrosis through stimulation of myofibroblast growth (46, 47). Postmortem analysis of cardiac tissue from diabetic patients demonstrated interstitial and focal perivascular accumulation of collagen (48). The result of the Randomized Aldactone Evaluation Study showed that low-dose mineralocorticoid receptor antagonist therapy (spironolactone) markedly reduced morbidity and mortality in patients with severe heart failure, independent of hemodynamic effects (49). These results underscore the important role of aldosterone in promoting heart failure and the potential role of aldosterone antagonists in treating this disorder.
Aldosterone antagonists in microvascular disease
A study conducted by Epstein et al. (50) demonstrated that aldosterone antagonist eplerenone enhances the effects of enalapril in reducing albuminuria in type 2 diabetic patients (50). They conducted a 24-wk double-blind study that compared the renal and antihypertensive effects of eplerenone, enalapril, and combination therapy in hypertensive patients with diabetes, hypertension, and proteinuria. This study showed that eplerenone had a comparable antiproteinuria effect as enalapril and that the combination of enalapril and eplerenone further reduced proteinuria independent of blood pressure-lowering effects of this combination. These data suggest that the optimal approach to reducing proteinuria and progression of diabetic nephropathy may ultimately involve disruption of the entire RAAS.
Aldosterone antagonists in macrovascular disease in type 2 diabetes
There is increasing evidence that aldosterone excess contributes to CVD and renal disease in high-risk patients. Additionally, use of aldosterone receptor antagonists has been shown to reduce CVD and renal disease associated with high-risk conditions such as diabetes. Although specific studies in diabetic patients have been limited, there is much evidence for the role of aldosterone in the pathogenesis of CVD and renal disease in diabetic patients and the potential to lessen this burden in this high-risk population. One of the mechanisms by which aldosterone may potentiate the effects of hyperglycemia is via potentiation of the glucose effects on growth and fibrosis in cardiomyocytes, arterial smooth muscle cells, and renal cortical fibroblasts (25, 46, 47, 48). At least some of these potentiative effects of aldosterone and hyperglycemia appear to be mediated via protein kinase C and TNFß (31, 46, 47, 48). Another mechanism that is likely to play a role in the interactive effects of elevated glucose, aldosterone, and other metabolic abnormalities in diabetes (i.e. dyslipidemia and hyperinsulinemia) is that of activation of molecules mediating inflammation (Refs. 51, 52, 53 ; Table 2).
A potentially important atherosclerotic action of aldosterone is via its procoagulant properties (Refs. 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57 ; Table 2). Aldosterone as well as Ang II, glucose, and insulin stimulate the expression and the production of a major inhibitor of fibrinolysis, plasminogen activator inhibitor 1 (PAI-1). Indeed, it appears that aldosterone promotes the effects of Ang II and glucose on PAI-1 production, in part, through direct actions on the glucocorticoid response element of PAI-1 gene reporter (54). Aldosterone interacts with Ang II to increase PAI-1 expression in both endothelial cells and VSMCs (54). In a rodent model, aldosterone receptor antagonism attenuates renal PAI-1 expression after radiation injury (55). In man, plasma PAI-1 antigen concentrations correlate with serum aldosterone concentrations (54, 57). Furthermore, spironolactone treatment has been shown to increase plasminogen activator levels (57), resulting in a more favorable fibrinolytic balance. That aldosterone (55), along with Ang II (8, 13), contributes to inflammation and vasculopathy (25) may help explain the observation that coadministration of spironolactone in ACE-inhibitor-treated patients with congestive heart failure substantially reduced mortality (49).
Aldosterone and sudden cardiac death (SCD)
Patients with impaired glucose tolerance and type 2 diabetes have a 2- to 3-fold increased prevalence of SCD (58, 59, 60, 61). SCD has a particularly high prevalence in women with diabetes (14, 62). Autonomic dysfunction is one mechanism by which patients with diabetes may have an increased death rate after myocardial infarction as well as increased SCD (63, 64, 65). RR interval variability, another indicator of normal autonomic function, is reduced in patients with diabetes and SCD (64, 65). For example, the Hoorn study (65) showed increased mortality in diabetic patients with reduced RR variability as determined by frequency and time domain measurements. A prolonged QT interval is also a predictor of SCD in diabetic patients as well as persons without diabetes (65). Aldosterone is emerging as a risk factor for both prolongation of QT intervals (66) and reduction in RR variability (67). Furthermore, preliminary studies have shown that aldosterone blockade improves heart rate variability as well as cardiac fibrosis (67). These effects of aldosterone blockade may, in part, explain the reduced mortality in the Randomized Aldactone Evaluation Study trial in patients with congestive heart failure (49). Thus, in addition to the deleterious effects of aldosterone on the vasculature, cardiac tissue, mesangial cells, and the brain, this steroid also exerts deleterious effects on baroreflex sensitivity and the autonomic nervous system through mechanisms that remain to be elucidated (Fig. 4 and Table 2
).
Summary
There is accumulating evidence for the role of aldosterone as a risk factor for cardiovascular and renal disease in type 2 diabetes, above and beyond that of Ang II. Preliminary evidence suggests favorable cardiovascular and renal effects of blocking aldosterone actions. Further studies are needed to assess the potential benefits of a combination of ACE/ARB and aldosterone antagonists in reducing the burden of CVD and renal disease in such a high-risk patient population.
Acknowledgments
Footnotes
This work was supported by grants from the National Institutes of Health (RO1-HL-63904-01), the Department of Veterans Affairs, and the American Diabetes Association (to J.R.S.).
Abbreviations: ACE, Angiotensin converting enzyme; Ang II, angiotensin II; ARB, angiotensin receptor blocker; CVD, cardiovascular disease; NO, nitric oxide; PAI-1, plasminogen activator inhibitor 1; RAAS, renin-angiotensin aldosterone system; RAS, renin-angiotensin system; SCD, sudden cardiac death; SHRSP, stroke-prone spontaneously hypertensive rats; UKPDS, United Kingdom Prospective Diabetes Study; VSMC, vascular smooth muscle cell.
Received September 16, 2002.
Accepted November 14, 2002.
References