Diabetes Mellitus: A Fundamental and Clinical Text
3rd Edition

Diabetic Vasculopathy
S. I. McFarlane
P. Kumar
R. Muniyappa
F. El-Atat
A. Aneja
J. R. Sowers
Both type 1 and type 2 diabetic patients have an increased incidence of ischemic heart disease, peripheral vascular disease, and congestive heart failure. Cardiovascular disease (CVD) accounts for up to 80% of the excess mortality in patients with type 2 diabetes. The burden of CVD is especially pronounced in diabetic women and diabetic patients who have several coexisting risk factors. Factors that promote CVD include long-standing hypertension, metabolic derangements such as hyperglycemia and dyslipidemia, and autonomic neuropathy. Diabetic patients have an increased prevalence of stroke and associated mortality and morbidity. There is also increased sudden death associated with diabetes, which is due in part to the underlying autonomic neuropathy. This review deals with diabetic vascular disease, with an emphasis on underlying pathophysiologic mechanisms.
Diabetes and CVD Risk
Both diabetes and impaired glucose tolerance are associated with an enhanced risk for CVD (1,2,3,4,5,6,7,8,9,10) (Fig. 102.1). Furthermore, coronary heart disease (CHD) mortality is increased threefold in diabetic men (1,2,9) and two- to fivefold in diabetic women (5,8) compared with age- and sex-matched nondiabetic persons. Impaired glucose tolerance and diabetes are also associated with a high prevalence of congestive heart failure (CHF) (6,7,9).
The pathophysiology of vascular disease in patients with diabetes involves both conventional risk factors such as hyperglycemia, hypertension, and dyslipidemia (3,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51), as well as nonconventional risk factors such as inflammation, oxidative stress, and endothelial dysfunction (3,10,52,53,54,55). Both conventional and novel risk factors for diabetic vasculopathy will be discussed in this review.
Conventional Risk Factors for Diabetic Vasculopathy
In persons with type 2 diabetes, which constitutes over 90% of the diabetes mellitus population in the United States (10), conventional CVD risk factors are amplified (1,2,10,11,24). For example, the Multiple Risk Factor Intervention Trial (MRFIT) evaluated the impact of blood cholesterol levels on CVD risk in diabetic and nondiabetic individuals (24). In MRFIT, the higher the cholesterol levels, the greater the risk for CHD. However, at any given cholesterol level, the risk was three- to fourfold higher in the diabetic patients. In the United Kingdom Prospective Diabetes Study (UKPDS), the major risk factors for CVD in type 2 diabetes were hyperglycemia, hypertension, increased low-density lipoprotein (LDL) cholesterol, low levels of high-density lipoprotein (HDL), and smoking (33). The same CVD risk factors were also observed in a 10-year follow-up of the Prospective Cardiovascular Münster (PROCAM) study (15). Each of these conventional risk factors will be discussed with respect to their impact on diabetic vasculopathy.
In diabetic patients, the higher the plasma glucose, the greater the incidence of CVD (19,24,25,27,28). These reports suggest that the risk for CVD increases 10% to 30% for every 1% increase in glycated hemoglobin. Intervention trials (19,35,36,37) also showed disease reduction in diabetic patients with improved glycemic control. The Honolulu Heart Program study showed during 23 years of follow-up that baseline glucose tolerance test results predicted which patients would develop coronary heart disease (CHD) (25). Persons in this cohort who were not symptomatic but had postload blood glucose levels of greater than or equal to 224 mg/dL were much more likely to develop CHD and had twice the risk for CVD death compared with persons with low normal (<150 mg/dL) glucose levels. These findings are consistent with the notion that over 50% of newly diagnosed type 2 diabetic patients present with CHD (2).
A study of insulin-based intensive control of glucose in Japanese patients with type 2 diabetes reported a 46% risk reduction for intensively treated patients (35). In an investigation of insulin-based treatment after a myocardial infarction, a hemoglobin A1C (HbA1C) level of 7.1% versus 7.9% after 1 year of therapy was associated with a 29% lower mortality rate (36).

A recent metanalysis of all glycemic intervention trials in patients with type 1 diabetes showed that intensive therapy with insulin reduced macrovascular events by 28% (37). These observations helped to shape the recommendations of the American Diabetes Association (ADA) that HbA1C be less than 7% (20).
Figure 102.1. Risk for coronary events as it relates to glycemia. (From
Haffner SM, Alexander CM, Cook TJ, et al. Reduced coronary events in simvastatin-treated patients with coronary heart disease and diabetes or impaired fasting glucose levels: subgroup analyses in the Scandinavian Simvastatin Survival Study. Arch Intern Med 1999;159:2661–2667
, with permission.)
In diabetic patients there is a graded risk at every level of systolic blood pressure or diastolic blood pressure for CVD risk (3,16,24,33,43). Because of high CVD and renal disease risk, even at high normal levels of blood pressure, there have been recent recommendations for blood pressure goals of less than 130/80 mm Hg by several national organizations (9,16,38) (Fig. 102.2). These organizations also recognize that a major aspect of initial treatment should consist of lifestyle modifications such as weight loss and reduction of salt, processed foods, and alcohol intake, with increases in potassium and fruits and vegetables as outlined in an algorithm (9,21,22) (Fig. 102.2).
Randomized prospective trials have demonstrated that rigorous treatment of blood pressure in patients with diabetes with a number of pharmacologic agents reduces macrovascular as well as microvascular disease (26,40,41,42,43,44). The Hypertension Optimal Treatment (HOT) study reported that in the diabetic subgroup, CVD events were reduced by 51% in those randomized to a diastolic blood pressure goal of less than 80 mm Hg compared with a goal of less than 90 mm Hg (39). In the UKPDS,1,148 hypertensive type 2 diabetic patients were randomized to either tight blood pressure control (<150/85 mm Hg) or less tight blood pressure control (<180/105 mm Hg). Tight blood pressure control was accompanied with a reduction in diabetes-related end points of 24%, deaths related to diabetes by 37%, strokes by 44%, and microvascular end points by 37% after a median follow-up of 8.4 years (26). Average blood pressure over 9 years was 144/82 mm Hg and 154/87 mm Hg in the tight and less tight blood pressure control groups, respectively, for a blood pressure difference of 10/5 mm Hg. In a placebo-controlled trial of treatment of isolated systolic hypertension, the Systolic Hypertension in Europe (Syst-Eur) trial, the 492 patients with diabetes were reported in a post hoc analysis to have significant reductions in CVD (40).
The seminal role of the renin-angiotensin-aldosterone system (RAAS) in diabetic vasculopathy is further evidenced by the inordinate benefits observed with therapy aimed at interrupting this system. In the Captopril Prevention Project (CAPP) the diabetic patients treated with captopril fared significantly better compared with conventional therapy (β-blockers and diuretics) for the primary end points as well as for myocardial infarction, all cardiac events, and total mortality (41). These relative beneficial effects of angiotensin-converting enzyme (ACE) inhibitor therapy were particularly beneficial in those at highest risk, with highest medium fasting glucose, highest blood pressure, and more elevated serum cholesterol/ decreased HDL.
In the MICRO-HOPE (42), a substudy of the Heart Outcomes and Prevention Study, the relative risk reduction in the 3,577 patients who had diabetes and one other CVD risk factor, there was a risk reduction of 25% for combined CVD events, 37% for CVD mortality, 22% for myocardial infarction, and 33% for stroke. All-cause mortality was reduced by 24%, and albuminuria/overt nephropathy was also decreased in those who were randomized to ramipril treatment. Additionally, in the ramipril treatment group there was a 34% reduction in new-onset diabetes (42). This exceeded the 15% reduction seen with captopril treatment in the CAPP study (41).
Trials with angiotensin receptor antagonists indicate that these agents may have renal and CVD protection in patients with

type 2 diabetes (44,45). In a trial of losartan versus placebo in 1,513 patients with type 2 diabetes and albuminuria/nephropathy, losartan treatment reduced the composite end point, after adjustment for blood pressure, of doubling of creatinine, end-stage renal disease, or death. The investigators concluded that the renoprotective effect of losartan was beyond that attributable to blood pressure control. Additionally, the combination of ACE inhibitor therapy and aldosterone antagonist therapy (14) may provide additional vascular and renal protection. The use of combination therapy (40) and aggressive treatment of systolic blood pressure (12,13,40) have been shown to substantially reduce CVD morbidity and mortality. In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), reduction of systolic blood pressure by 2 mm Hg in whites and 4 mm Hg in African Americans using a low-dose diuretic resulted in markedly reduced CVD risk (12,13). In the Syst-Eur study, all CVD events and stroke were significantly reduced, with the mean systolic blood pressure reduced from 175 to 153 mm Hg (40). These trial data suggest that more rigorous blood pressure control in these patients is very important.
Figure 102.2. Antihypertensive therapy in people with diabetes.
The Renin-Angiotensin System and Antihypertensive Therapy in Diabetic Vasculopathy
There is accumulative evidence that pharmacologic therapy that interrupts the RAAS may afford special benefits in reducing CVD and renal disease in diabetic patients with hypertension (41,42,43,44,45). These data suggest that angiotensin (Ang II) and aldosterone have especially detrimental effects on the vasculature in diabetes (3,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90).

Many of the actions of Ang II and aldosterone are mediated via direct effects on endothelial cells and vascular smooth muscle cells (VSMCs). One of the major deleterious effects of Ang II is to increase the generation of reactive oxygen species (ROS) (67,68,69,70,71,72,73,74). A homeostatic balance between nitric oxide (NO) and ROS (i.e., superperoxide anion and hydrogen peroxide) regulates cell redox balance, inflammatory state, and vasomotion (67,68,69,70,71,72,73,74,75) (Fig. 102.3). In addition, to its role in endothelial-derived relaxation (75), NO is an inhibitor of VSMC growth and remodeling and migration (75,87), and reduces the activity of the gene transcription factors nuclear factor κB and activator protein-1 (88) and of the expression of proinflammatory molecules (89).
Ang II has different effects on these processes, opposing the vascular action of NO (87,88,89). Ang II stimulates local production of metaloproteins, plasminogen activator inhibitor-1 (PAI-1), and cellular adhesion molecules (66,67,68,69,70,71,72,73,74), processes contributing further to vascular inflammation and increased thrombosis (74). Activated inflammatory cells in turn release enzymes (including ACE) that generate Ang II, which is a powerful contributor, along with dyslipidemia, hyperglycemia, and

hypertension, to the generation of ROS in the vasculature (66,67,68,69,70,71,72,73,74) (Fig. 102.3). Ang II activates a potent membrane oxidase (NADH/NADPH oxidase), which results in the production of superoxide anion, and subsequently, hydrogen peroxide (66,67,68). These ROS result in destruction of NO and impaired endothelial-mediated vascular relaxation. Ang II also increases the expression of adhesion molecules by endothelial cells and induces monocyte and VSMC chemotactic protein-1 expression, thus increasing the adhesion of monocytes, leukocytes, and platelets to the endothelial surface, further perpetuating the inflammatory state of the vasculature (69,70,71) (Table 102.1).
Figure 102.3. Angiotensin II in diabetic vasculopathy and interaction with conventional cardiovascular risk factors: hypertension, dyslipidemia, and hyperglycemia. NADPH oxidase is activated by several stimuli, including angiotensin II, hypertension, hyperglycemia, and oxidized low-density lipoprotein (LDL) to produce oxygen radicals (·O-2) and hydrogen peroxide (H-O2), which leads to the destruction of nitric oxide (NO) in the endothelium and vascular smooth muscle cells.
Ang II increases coagulability, which is particularly enhanced in the presence of both diabetes and hypertension (76,77,78,90). Ang II, along with hyperglycemia, hyperlipidemia, and hyperinsulinemia promote the formation of PAI-1 (76,77,78,90). PAI-1 is the major endogenous inhibitor of fibrinolysis in vivo, and increased PAI-1 is associated with accelerated atherosclerosis (66,67,68). In vascular tissues, PAI-1 impairs matrix degradation, increases fibrosis, and impairs fibrinolysis (66,67,68). Risk factors such as diabetes, insulin resistance, and hypertension are also associated with decreased tissue plasminogen activator (tPA) (66,67,68). Tissue ACE downregulates tPA production via degradation of bradykinin, which is a potent stimulator of PA production by endothelial cells. These observations may help explain why ACE inhibitor therapy improves the fibrinolytic balance in high-risk patients (91,92).
Table 102.1. Angiotensin II in diabetes: effects on the vasculature
Effects Inflammation Remodeling Thrombosis Vasoconstriction Compliance
Mechanisms Increased expression of MCP-1, TNF-α, IL-6VCAM, and ICAM Stimulation of matrix glycoproteins and metalloproteinase production Increased platelet activation, aggregation, and adhesion Stimulation of AT1 receptors
Increased destruction of NO
Increased destruction of NO
Increased fibrosis
Activation of NADH/NADPH oxidase Stimulation of VSMC hypertrophy, migration, and proliferation Stimulation of PAI-1 synthesis Enhanced release of norepinephrine and endothelin Increased inflammation
Production of superoxide anions   Reduced PA   Decreased vasodilatory prostaglandins
  Increased expression of growth factors Alteration of the tPA/PAI-1 ratio Decreased baroreceptor sensitivity  
Activation of monocyte and macrophages cytokine production Increased fibrosis Increased inflammation Reduced vasodilatory prostaglandins  
VSMC, vascular smooth muscle cells; MCP-1, monocyte chemoattractant protein-1; TNF-α, tumor necrosis factor-α; VCAM, vascular adhesion molecule; ICAM, intercellular adhesion molecule; PAI-1, plasminogen activator inhibitor type 1; PA, plasminogen activator; tPA, tissue plasminogen activator; AT1, angiotensin type 1 receptor; NO, nitric oxide.
Increasing evidence suggests that aldosterone excess contributes to CVD diabetics and other high-risk patients (14). Additionally, aldosterone antagonists have 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 cardiovascular 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 potentate the effects of hyperglycemia appears to be mediated via protein kinase and tumor necrosis factor-β. 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 activation of molecules mediating inflammation (85) (Table 102.2).
Aldosterone decreases endothelial cell production (83,84) and contributes to vascular growth and remodeling. 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 VSMCs (14,83,84) (Table 102.2).
A potentially important atherosclerotic action of aldosterone is via its procoagulant properties (70,71,72,73,74,75,76,77,78,79,80,81). Aldosterone, as well as Ang II, glucose, and insulin, stimulate the expression and production of PAI-1. Aldosterone appears to enhance the effects of Ang II and glucose on PAI-1 production, in part through direct actions on the glucocorticoid response element of the PAI-1 gene reporter (79). Aldosterone interacts with Ang II to increase PAI-1 expression in both endothelial and vascular smooth muscle cells (79). In a rodent model, aldosterone receptor antagonism attenuates renal PAI-1 expression after radiation injury. In humans, plasma PAI-1 antigen concentrations correlate with serum aldosterone concentrations (79,82). Furthermore, spironolactone treatment has been shown to increase PA levels (82), resulting in a more favorable fibrinolytic balance. That aldosterone (80), along with Ang II, contributes to inflammation and vasculopathy may help explain the observation that coadministration of spironolactone in an ACE inhibitor–treated patients with CHF substantially reduced mortality (95).
Dyslipidemia and Diabetic Vasculopathy
Dyslipidemia contributes substantially to vasculopathy in patients with diabetes (10,46). Furthermore, the additive effects of dyslipidemia, hypertension, and smoking substantially increases


the CVD death rate in diabetic patients compared with nondiabetics (24) (Fig. 102.4). Patients with type 2 diabetes often have low HDLs and hypertriglyceridemia and increased numbers of small, dense LDL particles (46). Given that the diabetic dyslipidemic profile is more atherogenic (46), the fact that diabetic patients have a CVD risk equivalent to that of a history of myocardial infarction (1,2) and the proven benefits of statin therapy in these patients, statin therapy is indicated in most patients with diabetes.
Table 102.2. Aldosterone in diabetic vasculopathy: effects of the vasculature, heart, kidney, brain, and autonomic nervous system
Site of action Adolesterone actions
Mechanisms Net effects
Vascular smooth muscle cells Genomic  
   Increased protein synthesis  
   Increased collagen synthesis Vascular growth and remodeling
   Increased PAI-1 expression Reduced relaxation
   Increased Ang II, type I receptor expression Increased Inflammation
Nongenomic Increased atherosclerosis
   Activation of Na+-H+ exchange  
   Increased tyrosine phosphorylation  
   Increased protein kinase C isoform activation  
Endothelial cells Increased PAI-1 Increased thrombosis
Decreased PA Decreased vasorelaxation
Decreased NO production Increased adhesion of platelets, monocytes, and leukocytes
Cardiomyocytes Genomic  
   Increased collagen production  
   Increased protein synthesis  
   Increased steroidogenesis Hypertrophy
   Increased inflammation Fibrosis
Nongenomic Increased myocardial ischemia
   Activation of Na+-H+ exchange Impaired systolic and diastolic function
   Increased tyrosine phosphorylation and inositol  
      3-P activation Heart failure
Protein kinase C isoform activation  
Increased inflammation  
Kidney Genomic  
   Increased mesangial cell hyperplasia Salt retention
   Increased extracellular matrix Potassium depletion
   Increased inflammation Increased glomerular
Nongenomic extracellular matrix
   Increased mesnegeal cell NA+-H+ exchange
   Increased ENaC activity
Increased blood pressure
Brain and baroreceptors Increased vascular atherosclerosis  
Increased inflammation
Increased SNS
Increase stroke prevalence
Enhanced RAS  
Reduced baroreceptor sensitivity  
Autonomic nervous system Reduced RR variability  
Prolongation of the QT interval Reduced RR variability  
Enhanced sympathetic activity
Reduced parasympathetic activity
Increased risk of sudden cardiac death
Ang II, angiotensin II; PAI-1, plasminogen activator inhibitor-1; PA, plasminogen activator; NO, nitric oxide; ENaC, epithelial Na+ channel; SNS, sympathetic nervous system; RAS, renin angiotensin system.
Figure 102.4. Risk of cardiovascular disease death in patients with diabetes; additive effects of hypertension, hypercholesterolemia, and smoking. (From
Stamler J, Vaccaro O, Neaton JD, et al. Diabetes, other risk factors, and 12-year cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 1993;16: 434–444
, with permission.)
Subgroup analysis of several primary and secondary prevention studies showed substantial benefits of treatment with statin in patients with type 2 diabetes (47,48,49). In the recently reported Heart Protection Study (50), diabetic patients and women had a striking reduction in CVD, stroke, and revascularization. In the overall population, subjects had a reduction even when their baseline LDL cholesterol levels were less than 100 mg/dL. The incidence of CVD events declines from 18.5% to 14%, for an overall decline of 24%. Some of the beneficial effects probably relate to direct (pleiotropic) beneficial effects of these agents (51).
In summary, diabetes and its complications are increasing. Vascular disease is common and contributes to the marked increase in CHD and peripheral vascular disease associated with impaired glucose intolerance and diabetes. Conventional risk factors for CVD in patients with diabetes, such as hypertension and dyslipidemia, are magnified, and novel unconventional risk factors, such as enhanced vascular oxidative stress and inflammation, appear to be important contributors to diabetes vasculopathy. Finally, enhancement of the vascular RAAS appears to contribute to this vasculopathy. Treatments designed to interrupt the RAAS likely abrogate oxidative stress/inflammation and lower blood pressure.
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