Correlation between cardiovascular disease and diabetes mellitus: current concepts

Correlation Between Cardiovascular Disease and Diabetes Mellitus: Current Concepts Richard W. Nesto, MD

Individuals exhibiting precursor symptoms of diabetes mellitus or reaching diagnostic thresholds for diabetes are at increased risk of death due to cardiovascular disease (CVD). Moreover, patients with diabetes alone, as well as those who have diabetes paired with established CVD, remain undertreated for cardiovascular risk factors. The clear correlation between these disease processes has led many to speculate that they share common pathogenetic processes. Recent research has made it increasingly evident that the core metabolic defects that mark diabetes, including impaired glucose tolerance, insulin resistance, and proinflammatory and prothrombotic states, lead to endothelial dysfunction and accelerate atherogenesis. Moreover, increases in sympathetic tone with diabetes are associated with changes in cardiac and vascular function that lead to hypertension, left ventricular dysfunction, and cardiac autonomic neuropathy; such changes set the stage for arrhythmia, silent infarction, and sudden death. Furthermore, diabetes-related changes in metabolic and autonomic functioning, as well as increases in inflammatory and thrombotic signaling, compromise the ability of myocardial and vascular tissue to remodel after injury and to recover and sustain functionality. Because potentiation of atherogenesis and cardiac dysfunction occurs in the presence of early diabetic symptoms as well as in the established disease, early implementation of strategies to reduce cardiovascular risk factors and to slow diabetes progression may help to improve longterm outcomes for at-risk individuals. Such interventions may include well-established treatments for hypertension and dyslipidemia, diet improvements, weight loss, and exercise as well as novel pharmacologic interventions aimed at newly identified therapeutic targets. Am J Med. 2004;116(5A):11S–22S. © 2004 by Excerpta Medica, Inc.

From the Department of Cardiovascular Medicine, Lahey Clinic Medical Center, Burlington, Massachusetts, and Harvard Medical School, Boston, Massachusetts, USA. Requests for reprints should be addressed to Richard W. Nesto, MD, Department of Cardiovascular Medicine, Lahey Clinic Medical Center, 41 Mall Road, Burlington, Massachusetts 01805. © 2004 by Excerpta Medica, Inc. All rights reserved.

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he link between diabetes mellitus and cardiovascular disease (CVD) is well established and widely recognized. In the most recent Adult Treatment Panel (ATP) guidelines of the National Cholesterol Education Program (NCEP), diabetes is considered a factor for cardiovascular risk development.1 Thus, it is recommended that greater precautionary measures, similar to those of established CVD, be taken with dyslipidemias in patients with diabetes. These changes are based on findings from several investigations showing that CVD occurs at a significantly higher rate in individuals with diabetes than in the general population.2– 4 The Nurses’ Health Study is among the largest and most extensive of these investigations conducted so far in the United States.2 In this study, 117,629 nurses aged 35 to 55 years in 1976 were followed for 20 years, until 1996. About 6,000 nurses in the study developed diabetes during follow-up; 1,508 others had type 2 diabetes at baseline.2 For all participants who exhibited diabetes during the study, the relative risk of myocardial infarction (MI) or stroke was elevated, ranging among various diabetic subgroups from 2.4 to 5.0 times that seen for participants who remained nondiabetic throughout the study. Importantly, this investigation provided the first documented evidence of increased risk for CVD events before the clinical diagnosis of diabetes—preceding diagnosis by as much as 15 years—with risk levels increasing further after diabetes diagnosis.2 The authors also found that cardiovascular risk levels remained elevated in this participant subgroup even after adjustment for the presence or absence of obesity and family history of diabetes.2 Findings from other recent studies support the proposition that the subclinical syndromes characteristic of insulin resistance and CVD are intertwined.3,4 In 1 investigation, glucose tolerance testing on hospital discharge determined that 66% of patients who had just experienced their first MI had either impaired glucose tolerance or frank diabetes.3 Similar results from glucose tolerance testing of men referred for coronary angiography on the basis of positive exercise stress test results have also been reported, with 36% of these patients meeting World Health Organization (WHO) criteria for impaired glucose tolerance and 16% meeting WHO criteria for type 2 diabetes.4 Moreover, plasma concentrations of both postload and fasting insulin and glycosylated hemoglobin (HbA1c), respective markers for insulin resistance and hyperglycemia, were directly related to the number 0002-9343/04/$22.00 11S doi:10.1016/j.amjmed.2003.10.016

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Figure 1. Mortality associated with first myocardial infarction by diabetes status. Data are the percentages of mortality and survival for patients with (DM) and without (Non-DM) diabetes in Finland between 1988 and 1992, adjusted for age and geographic area. Out-of-hospital deaths were based on review of death certificates and data extracted from medical records. SCD ⫽ sudden cardiac death. (Reproduced with permission from Diabetes Care.6)

of involved atherosclerotic vessels.4 It is a disturbing possibility that some of the patients in these studies may have had diabetes or some of its symptoms for years without receiving appropriate treatment or preventive intervention.

DIABETES AND CARDIOVASCULAR DISEASE–RELATED MORTALITY Compared with nondiabetic individuals, patients with diabetes carry a greatly increased risk not only for sustaining cardiovascular events but also for poorer outcomes associated with CVD, marked by significantly increased mortality. Over the last 30 years, early mortality due to acute MI in the general population has been dramatically reduced: presently, mortality during the first 6 weeks after a first MI is about 6%.5 However, MI-related mortality rates remain significantly greater for patients with diabetes versus without diabetes (Figure 1).6 If a heart attack occurs outside the hospital, a man with diabetes is more likely than his nondiabetic counterpart to die before reaching the hospital.6 During hospitalization in the first year after a first MI, patients with diabetes are about twice as likely as nondiabetic patients to die (Figure 1).6 In a separate study, researchers found that the relation between the presence of diabetes and increased mortality 12S March 8, 2004 THE AMERICAN JOURNAL OF MEDICINE威

risk following MI persists after adjustment for other variables known to influence cardiovascular risk, such as age, sex, and the extent of coronary artery disease (CAD).7 In fact, on the basis of the most recent percutaneous coronary intervention data on acute MI, the extent of CAD is remarkably similar between patients with and without diabetes.7 Such findings strongly imply that factors central to diabetes as a metabolic disorder are probably operative in producing the relative difference in early postinfarction mortality seen between patients with and without diabetes. The state of impaired glucose tolerance also seems to increase mortality risk associated with CVD. Evidence from Japan’s Funagata Diabetes Study indicates that impaired glucose tolerance is a highly significant predictive risk factor for the occurrence of a fatal coronary event. In this study, those with impaired glucose tolerance were about twice as likely to die of CAD as those with normal glucose tolerance.8 Recently, a prospective study in Finland with a large cohort of men aged 42 to 60 years at baseline showed that patients with the metabolic syndrome were at significantly greater risk of CVD-related death than were patients without the metabolic syndrome.9 Factor analysis using a model that included 13 age-adjusted variables yielded a “metabolic syndrome factor” that accounted for the highest variance in the data

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Figure 2. Management of cardiovascular disease (CVD) risk factors in patients with diabetes. Data are derived from prospective observation of patients with diabetes (n ⫽ 235) who underwent elective cardiac catheterization between 1997 and 2000 at a Midwestern US hospital. (A) The percentages of patients who did and did not achieve treatment goals for modifiable CVD risk factors. (B) The percentage of patients treated with various cardioprotective medications. ACE ⫽ angiotensin-converting enzyme; BMI ⫽ body mass index; BP ⫽ blood pressure; HbA1c ⫽ glycosylated hemoglobin; HDL-C ⫽ high-density lipoprotein cholesterol; LDL-C ⫽ low-density lipoprotein cholesterol. (Adapted with permission from Am Heart J.12)

set; this factor was strongly associated with variables included in the WHO and NCEP definitions of the metabolic syndrome (i.e., body mass index [BMI], fasting levels of plasma glucose and insulin, etc.).9 Clinically, this implies that strategies such as diet improvement, weight loss, exercise, and potentially drugs under development—all aimed at the clinical characteristics of the metabolic syndrome—may improve outcomes for these patients. Underdetection and Undertreatment of CVD Risk in Patients with Diabetes Despite the need to engage in aggressive cardiovascular risk management in patients with diabetes, current practice falls far short of achieving treatment targets in most patients. Several studies demonstrated that many patients with diabetes do not achieve current targets for glycemic control, hypertension, or high blood cholesterol.10 –12 A similar pattern of suboptimal treatment exists in the case of patients with diabetes who have established CVD, with only small proportions of such patients reaching treatment targets for blood pressure, high-density lipoprotein cholesterol (HDL-C) plasma concentration, and HbA1c value (Figure 2).12 According to 2 separate investigations,

only about half of patients with diabetes are prescribed drugs such as ␤-blockers, angiotensin-converting enzyme inhibitors, and antihyperlipidemics, which are known to decrease CVD risk.11,12 In 1 study, most patients (86%) were using a daily aspirin regimen.12 Even among patients with type 2 diabetes who receive aggressive disease management, some evidence suggests that achieving and maintaining desired levels of glycemic control is unlikely to occur over an extended period.13 In a report from the United Kingdom, patients (n ⫽ 3,867) receiving intensive treatment with insulin or a sulfonylurea exhibited progressive increases in both fasting plasma glucose and HbA1c concentrations over the course of a 14-year follow-up, with levels eventually exceeding desired American Diabetes Association– defined targets approximately 3 to 6 years after treatment initiation.13 In view of these difficulties, as well as findings suggesting the importance of other variables in determining cardiovascular risk,9 patients and clinicians must gain a broader perspective on management of cardiovascular risk than simply focusing on glycemic control. A growing body of data clearly indicates that, very early in the course of diabetes development, a broad panoply of diabetic

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pathogenetic factors may potentiate vascular and myocardial dysfunction, and that several of these factors may be useful targets for preventive or therapeutic interventions.

ATHEROSCLEROSIS, PLAQUE DISRUPTION, AND CARDIOVASCULAR EVENTS Most coronary event–related deaths in patients with or without diabetes result from atherosclerotic plaque disruption and thrombosis, most frequently involving a soft, modestly stenotic plaque.14,15 The rupture of an atherosclerotic plaque releases atheromatous, fibrous, and necrotic materials into the vascular system, along with various types of activated immune system cells; likely sequelae of rupture are thrombosis, arterial occlusion, and subsequent stroke or MI. In individuals both with and without diabetes, a wide variety of variables contribute to the atherosclerotic processes that often precede MI; variables such as tissue factor, platelet aggregation, fibrinolysis, nitric oxide, plasminogen activator inhibitor type–1 (PAI-1), C-reactive protein (CRP), and even aspects of sympathetic tone all have roles in atherogenesis and plaque rupture (Figure 3).16 Researchers and clinicians are only now beginning to understand that the hyperglycemia, insulin resistance, and dyslipidemia associated with diabetes cause dysfunction of many cell types involved in the circulatory system (e.g., endothelial cells, smooth muscle cells, monocytes, and platelets) and, in combination with autonomic and cardiac changes, yield a milieu highly conducive to atherogenesis and coronary events. Accelerated Development of Atherosclerosis Certain characteristics typical of diabetes—including hyperglycemia, insulin resistance, and obesity— often occur in tandem with other, traditional, cardiovascular risk factors. Disturbingly, research indicates that these diabetic traits are associated with the accelerated development of atherosclerotic lesions and plaques.17,18 In a study by McGill et al.,17 atherosclerosis in the right coronary artery was examined postmortem in youthful individuals (n ⫽ 1,532), ranging in age from 15 to 34 years, who died of external causes. Fatty streaks covered a significantly greater percentage of the intimal surface of the right coronary artery in individuals with hyperglycemia (based on HbA1c value) than in individuals without hyperglycemia (Table 1).17 Moreover, compared with the euglycemic arteries, the hyperglycemic right coronary arteries were twice as likely to have fatty streaks on ⬎5% of the intimal surface and 3 times more likely to have macroscopic raised lesions (Table 1).17 Findings from this same group of investigators further indicate that body weight in young individuals is positively correlated with the accelerated development of ath14S March 8, 2004 THE AMERICAN JOURNAL OF MEDICINE威

erosclerosis.18 In males aged 15 to 24 years, increases in BMI were significantly (P ⬍0.0001) associated with increases in the extent of fatty streaks and raised atherosclerotic lesions in the right coronary artery (Figure 4).18 A cluster of other cardiovascular risk factors was also significantly correlated with BMI, including direct associations between BMI and non–HDL-C plasma levels and HbA1c values as well as prevalence of hypertension; inverse relations were seen between BMI and HDL-C plasma levels and prevalence of smoking (Table 2).18 The findings reported by McGill et al.,17,18 revealing the relations of hyperglycemia and obesity to accelerated atherosclerosis, suggest that the prevention or remediation of these factors may help to arrest the atherosclerotic process in the general population. Modest Coronary Artery Occlusion Most of the atherosclerotic plaques that cause MI and sudden death occlude the coronary arteries only mildly to modestly.14,15 Stenosis of this nature also seems to be the type most common in patients with abnormal fasting plasma glucose levels, “mild” diabetes, and WHO-defined diabetes.19 Ultrasonography shows that such patients typically exhibit extensive and diffuse, yet modest, circumferential CAD with severity of stenosis ranging from ⬍25% to ⬍75% of the arterial diameter.19 Although patients with diabetes exhibited a significantly higher number of diseased vessel segments and significantly greater lesion extent, few patients with diabetes exhibited severe coronary artery occlusion (i.e., ⬎95%).19 Findings of research concerning the content of vascular smooth muscle cells (VSMCs) within the atheromas of patients with diabetes further support the tendency for the formation of atheromas that are unstable and more vulnerable to rupture. Normally, VSMCs migrate to the intimal lesion from the arterial tunica media, helping to form a complex extracellular matrix that strengthens atheromas and makes them less likely to rupture. Some evidence indicates that such cells are significantly less abundant in the lesions of patients with diabetes than in their nondiabetic counterparts20; lesions relatively deficient in VSMCs may be more likely to rupture and cause fatal thrombosis. The findings by McGill et al.17,18 and Ledru et al.19 have given rise to some debate about the usefulness of screening for coronary artery disease in patients with diabetes. Whereas atherosclerosis and coronary artery occlusion are likely to be present in these individuals, results of typical angiography and exercise testing may yield results indicative of “nonhemodynamically significant” obstructive lesions, thus leading to undertreatment of cardiovascular risk in these individuals.19 Despite the possibility of negative results, clinicians must remain mindful that such patients still have a higher prevalence of ⬍50% stenoses and higher occlusion rates than do patients without

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Figure 3. Metabolic perturbations that arise in association with diabetes mellitus, such as hyperglycemia, insulin resistance, and increased release of free fatty acids, engender a cascade of endothelium-mediated changes that potentiate vasoconstriction, inflammation, and thrombosis. NF-␬B ⫽ nuclear factor–␬B. (Adapted with permission from JAMA.16)

Table 1. Prevalence of Cases where ⬎5% Atherosclerotic Involvement of Right Coronary Artery Is Linked to Glycosylated Hemoglobin (HbA1c) Levels and Obesity in Young Persons* Right Coronary Artery Variable

Group (n)

HbA1c

⬍8% (1,247) ⱖ8% (28)

P value Body mass index

⬍25 (892) 25–30 (401) ⬎30 (162)

P value

Fatty Streaks (%)

Raised Lesions (%)

22.97 47.79 0.0085 19.92 26.65 40.96 0.0001

5.21 16.73 0.0240 5.15 4.95 12.29 0.0003

* Both increased HbA1c levels ⱖ8% and body mass index are related to significant increases in the prevalence of cases with fatty streaks and raised lesions involving ⬎5% of the intimal surface of the right coronary artery of males aged 15 to 34 years. Reproduced with permission from Arterioscler Thromb Vasc Biol.17 March 8, 2004

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Figure 4. Sudan staining for atherosclerosis. Coronary atherosclerosis linked to obesity in young males aged 15 to 24 years. Prevalence map of right coronary artery lesions by body mass index (BMI) and 10-year age group. (Adapted with permission from Circulation.18) Table 2. Relation of Coronary Heart Disease Risk Factors to Body Mass Index (BMI) Mean ⫾ SD Adiposity Index BMI

Category

HDL-C (mg/dL)

HbA1c (%)

Prevalence of Smoking (%)

Prevalence of Hypertension (%)

⬍25 25–30 ⬎30

55.0 ⫾ 0.8 53.1 ⫾ 1.1 51.3 ⫾ 1.5

6.4 ⫾ 0.03 6.6 ⫾ 0.05 6.8 ⫾ 0.06

47.9 ⫾ 1.8 41.3 ⫾ 2.5 30.9 ⫾ 3.1

12.6 ⫾ 0.9 11.3 ⫾ 1.2 15.5 ⫾ 1.8

HbA1c ⫽ glycosylated hemoglobin; HDL-C ⫽ high-density lipoprotein. Reproduced with permission from Circulation.18

diabetes.19 Moreover, the findings from McGill et al.17,18 indicate that younger patients with diabetes, metabolic syndrome, or insulin resistance are likely to have atherosclerotic plaque distributed diffusely throughout the coronary arteries. Such results highlight the fact that the form of atherosclerosis seen in patients with diabetes is qualitatively different, tending to be mild or modest in occlusive severity, diffuse and extensive, and inherently more vulnerable to acute disruption.

PATHOPHYSIOLOGIC MECHANISMS UNDERLYING ACCELERATED ATHEROGENESIS AND INCREASED RISK OF CARDIOVASCULAR DISEASE IN PATIENTS WITH DIABETES Advances in vascular biology during the last 10 years have increased the understanding of atherosclerosis, plaque formation, and thrombogenesis—as well as why these processes are potentiated in diabetes. A key component in each of these phenomena is endothelial dysfunction. The endothelium is an autocrine/paracrine organ consisting of a single cell layer that lines the intimal surface of all blood vessels in the body and acts as an interface between the blood and body tissues. The endothelium responds to 16S March 8, 2004 THE AMERICAN JOURNAL OF MEDICINE威

a variety of factors contained within the blood, such as glucose, insulin, lipoproteins, and CRP levels, by secreting biologically active substances that modulate vascular tone, lipid metabolism, platelet activation, and thrombogenesis.21 With a relatively healthy vascular environment, proper endothelial function helps to keep atherogenesis and thrombosis in check. With metabolic derangements, endothelial dysfunction occurs; in the case of diabetes, endothelial dysfunction promotes both atherogenesis and thrombosis, contributing to the risk of MI and stroke. Central to normal endothelial functioning is the production and release of nitric oxide, a potent vasodilative substance that inhibits platelet aggregation, leukocyte adhesion, and VSMC proliferation. With normal nitric oxide production, atherogenesis is inhibited and blood vessel integrity is maintained; in patients with diabetes, hyperglycemia, insulin resistance, and increased inflammatory signaling inhibit endothelial nitric oxide production and bioavailability.21 Other traditional cardiovascular risk factors also disturb endothelial function via a variety of mechanisms, and the influence of these factors seems to be synergistic: the greater the number of risk factors, such as hypertension, diabetes, and smoking,

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the greater the derangement of endothelial function.21 A growing body of data (vide infra) suggests that the presence of the core metabolic pathology that underlies diabetes—insulin resistance, the related excess concentrations of free fatty acids, and impaired glucose metabolism—potentiates the vascular pathophysiologic processes that underlie CVD (Figure 1). Perturbation of Endothelium-Mediated Vasodilation In healthy individuals, endothelium-mediated vasodilation is suppressed temporarily in response to postprandial surges in plasma concentrations of glucose.22,23 This suppression is most likely mediated by decreased bioavailability of the endothelium-derived vasodilator nitric oxide in response to postprandial increases in glucose, free fatty acids, and insulin. In patients with diabetes or those with impaired glucose tolerance, however, these normal patterns of reactive vasodilation are deranged.22,23 For instance, in individuals with normal glucose tolerance, consumption of a standard glucose load temporarily causes depressed flow-mediated vasodilation, characterized by a decrease in the bioavailability of the vasodilator nitric oxide, which recovers to baseline levels about 2 hours after glucose loading.22 In contrast, patients with impaired glucose tolerance exhibit a similar decrease in vasodilation with a subnormal return toward baseline at 2 hours postloading.22 Individuals with type 2 diabetes exhibit a drop in vascular reactivity that is sustained 2 hours after glucose consumption. Thus, postprandial increases in plasma glucose concentrations impair responses of the vascular endothelium, and these impairments are of greater severity and longer duration in patients with impaired glucose tolerance and type 2 diabetes.22 The impact of the vasodilative impairments seen in prediabetic and diabetic patients may be quite significant if one considers that people are in the postprandial state for 11 to 12 hours each day and frequently consume a greater amount of carbohydrates than used experimentally. Consequently, vascular function may be deranged for the greater part of the day in many individuals, particularly if they have baseline impaired glucose tolerance or diabetes. A similar suppression of endothelium-mediated vasodilation was recently reported to occur after consumption of a high-fat meal.23 In a group of healthy individuals without glucose intolerance, maximal decreases in flowmediated vasodilation were seen about 1 hour after loading with either a high-fat or a high-glucose meal; suppression of vasodilation was even more pronounced in this group after combined high-fat and glucose loading than when either nutrient was taken alone. For these participants, return to baseline levels of dilation with any of the given nutrient loads was seen between 2 and 3 hours after loading.23 For patients with type 2 diabetes, the generally

more pronounced decreases in vasodilation after both high-fat loading and combined high-fat/glucose loading were sustained up to 4 hours after loading; with glucose loading alone, depressed vasodilation recovered to baseline values at 3 hours postloading.23 These findings indicate that the effects of hypertriglyceridemia and hyperglycemia on endothelial functioning are additive and are more pronounced in patients with impaired glucose tolerance and type 2 diabetes. It seems likely that metabolic abnormalities such as the hyperglycemia and insulin resistance seen in patients with diabetes may impede recovery to normal levels of nitric oxide bioavailability. Taken together, the findings of Kawano et al.22 and Ceriello et al.23 indicate that in individuals with impaired glucose tolerance or diabetes, a perturbation of normal vascular function may be present throughout much of the day and is likely to account, in part, for the increased risk of vascular disease seen in these patients. Postprandial increases in plasma glucose, low-density lipoprotein cholesterol (LDL-C), and insulin concentrations also cause further vasoconstriction by triggering increased expression and activity of vasoconstrictors, including endothelin-1, angiotensin II, and prostanoids.16,24,25 Endothelin-1 induces vasoconstriction and vascular smooth muscle hypertrophy via interaction with receptors on VSMCs. It also stimulates the reninangiotensin system, resulting in increased renal salt and water retention. Endothelin-1 production is likely to be heightened by the presence of advanced glycation end products produced in patients with diabetes in response to hyperglycemia.26 A Proinflammatory State Over the last several decades, immune responses and inflammatory signaling have come to be appreciated as prominent mechanisms in atherogenesis and plaque disruption. One of the first steps in atherogenesis is the adhesion of monocytes and T lymphocytes to the endothelium, probably triggered by increased endothelial expression of adhesion molecules induced by certain humoral conditions, such as decreased levels of nitric oxide, high levels of LDL-C or angiotensin II, bacterial infection, or oxidative stress.27,28 Adherent immune cells then migrate into the arterial wall in response to chemoattractant signals, forming the beginnings of an atheroma. CRP, an inflammatory marker, is likely to be among the factors involved in monocyte adhesion and migration: it acts as a chemoattractant for these monocytes, which bear surface receptors for it.29 CRP also exhibits other pathophysiologic actions that are likely to potentiate atherogenesis, including interaction with tissue-deposited LDL molecules, activation of the complement system, formation of foam cells, induction of adhesion molecule expression by endothelial cells, and suppression of endothelial nitric oxide production.29 –34 Recent findings from the US

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Women’s Health Study (N ⫽ 28,263) also indicate that CRP is an independent predictor of CVD risk: elevated CRP plasma levels were associated with a relative risk for cardiovascular events as high as 4-fold greater than that seen in women with low CRP plasma levels.35 Several metabolic abnormalities that characterize the states of impaired glucose tolerance and diabetes augment the immune and inflammatory responses involved in atherogenesis. The oxidative stress, decreased production of nitric oxide, presence of advanced glycation end products induced by hyperglycemia, and postprandial surges of free fatty acids released from adipose tissue with hyperinsulinemia are all associated with increased activation of the transcription factors nuclear factor–␬B and activator protein 1.16 In turn, these factors increase endothelial gene expression for leukocyte– cell adhesion molecules, chemokines that attract monocytes, and proinflammatory cytokines such as interleukin-1 and tumor necrosis factor. With such diabetes-enhanced production of endothelial adhesion molecules and increases in inflammatory signaling, monocytes and T lymphocytes are more likely to bind to the endothelial cell layer, beginning the formation of an atheroma. Not surprisingly, then, atherosclerotic plaques in patients with diabetes exhibit what may be considered a proinflammatory or hyperinflammatory composition. Macrophages are far more abundant in atheromas of patients with diabetes than of patients without diabetes,20 and these cells in turn secrete cytokines; levels of tissue factor are likely to be increased as well.36 The presence of advanced glycation end products in atherosclerotic plaques seems to have a pivotal role in creating the proinflammatory milieu conducive to atherogenesis and plaque rupture.37 For instance, CRP and advanced glycation end products colocalize in the atherosclerotic plaques of patients with diabetes. Moreover, the cell surface receptor for advanced glycation end products may help to attract monocytes and transform them into macrophages,37 and its activation associated with oxidant stress induces the production of tissue factor by macrophages.36 The proinflammatory features of diabetes also promote plaque instability and rupture. Plaque stability is normally maintained by the production of collagen by VSMCs that have migrated to the site of the lesion. Whereas hyperglycemia promotes enhanced migration of VSMCs to the site of lesions rich with advanced glycation end products and macrophages,38 smooth muscle cells seem to undergo increased levels of apoptosis in patients with diabetes, possibly in response to an elevated concentration of oxidized glycated LDL particles in the atheromas of these individuals.39 With fewer smooth muscle cells, production of collagen is compromised. Furthermore, in diabetes, elevated endothelial expression of cytokines suppresses VSMC production of collagen, and any collagen produced may be subject to more rapid 18S March 8, 2004 THE AMERICAN JOURNAL OF MEDICINE威

enzymatic breakdown by matrix metalloproteinases, which patients with diabetes produce in excess.40 With a relative imbalance between collagen synthesis and breakdown, the plaque becomes more susceptible to rupture when exposed to hemodynamic stresses.16,27 A Prothrombotic State Diabetic proinflammatory signaling is also associated with a prothrombotic state that is marked not only by hyperaggregability of platelets in the blood but also by the disruption of fibrinolysis within the blood vessel walls and atheromas of individuals with diabetes.16,41 Elevated plasma glucose levels trigger within platelets the activation of protein kinase C, decreased production of nitric oxide, formation of oxidant ions, and disruption of the calcium homeostasis that controls aggregation and thromboxane formation. Certain endothelial responses to hyperglycemia—including decreased production of the antiaggregants nitric oxide and prostacyclin as well as increased production of compounds that activate platelets (e.g., thrombin and von Willebrand factor)—also contribute to increased platelet aggregability and increased thrombus formation. Such changes occurring together in the platelets and the endothelium increase the likelihood of thrombosis.16 Some evidence further suggests that the enzymatic breakdown of fibrinogen particles may be inhibited in patients with type 2 diabetes, setting the stage for increased blood coagulability and predisposition to accelerated atherosclerosis, thrombosis, and acute arterial occlusion.41 Immunolabeling of PAI-1, a factor that decreases fibrinolysis, revealed much more intense concentrations of this factor within atheromatous material of patients with diabetes, presumably in vessel walls, than in nondiabetic individuals41; evidence of increased concentrations of PAI-1 in the blood of individuals with obesity and diabetes has also been found.42 As already noted, diabetic atheromas may exhibit increased expression of tissue factor,36 a substance that acts as a potent procoagulant.16 Persistence of thrombi, with their associated mitogens, may accelerate macrovascular disease, causing adverse effects on vessel walls and increased severity of stenosis.41 Sympathovagal Imbalance It has long been understood that many patients with diabetes have measurable abnormalities of autonomic tone marked by a decrease in parasympathetic tone and a relative increase in sympathetic tone. Such increases in sympathetic activity have been proposed to be related to hyperglycemia and hyperinsulinemia; when insulinmediated glucose uptake increases within certain areas of the brain that control autonomic functioning (e.g., the hypothalamus), sympathetic regulatory centers are disinhibited and sympathetic activity increases.43 This is evidenced postprandially in humans. After a meal, sympathetic activity increases; rises in sympathetic system

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adrenergic signaling are marked by increases in heart rate, blood pressure, and renal function.44 In patients with diabetes, the role of insulin-mediated sympathetic activational imbalance in the generation of cardiovascular events cannot be understated; it is likely to have a key etiologic role in the hypertension that develops in about 50% of patients with type 2 diabetes.45– 47 Comorbid hypertension and diabetes are associated with even poorer outcomes than diabetes alone, with a 2- to 3-fold increased risk of heart failure.46 This increased risk may be due in part to the ultimate development of systolic dysfunction, with left ventricular hypertrophy evolving into ventricular dilation; the presence and extent of left ventricular dysfunction, marked by abnormal left ventricular contraction and decreased ejection fraction, is evidently a better predictor of coronary-related death than is the extent of coronary artery disease (Figure 5).48 Diabetes has been proposed to potentiate left ventricular hypertrophy because hyperinsulinemia, as a consequence of insulin resistance, slows the rate of protein breakdown, creating conditions that may allow a buildup of tissue mass.46 These and other findings49 –51 indicate that treatments targeting hypertension and sympathetic activity may have a role in limiting or reducing left ventricular hypertrophy and thus reducing mortality among patients with diabetes at risk (Figure 6).49 Other cardiac consequences of diabetic autonomic perturbations are less well understood. For example, certain patients with diabetes (more typically those with type 1 disease) may lack overt signs of heart failure while having cardiac abnormalities marked by diminished fractional shortening and left ventricular ejection fraction as well as increased left ventricular mass.46 With exercise stress testing, many such patients may also exhibit impaired left ventricular ejection fraction augmentation; in otherwise healthy patients with diabetes without any evidence of hypertension or atherosclerosis, this may be a reflection of altered autonomic activation. A broad variety of diastolic abnormalities, e.g., delayed mitral valve opening and abnormal transmitral flow velocity, have also been observed in diabetic patient populations.46 Other cases may involve cardiac autonomic neuropathy (i.e., silent infarction), detected by positron emission tomography perfusion scanning performed after administration of the norepinephrine analogue hydroxyephedrine. Cardiac autonomic neuropathy is characterized by areas of the myocardium with severe or complete loss of neural signaling that are juxtaposed with areas exhibiting overexpression of sympathetic nerve terminals.46 This creates a substrate for arrhythmia, even in the absence of coronary disease; with the development of ischemia or infarction in such patients, a high rate of sudden death is seen.

Diabetic Energy Production and Myopathy Hypertension also interacts with diabetic metabolic dysfunction to produce myopathy. Specifically, energy production is shifted in patients with diabetes from glycolysis to glucose oxidation to free fatty acid oxidation; this shift results in less adenosine triphosphate production per mole of oxygen consumed. Such perturbations of energy use and release may be particularly evident within the infarct zone itself; in this anoxic ventricular environment, the opportunity to create energy is reduced to almost zero in patients with diabetes. Moreover, after an MI, throughout much of the noninfarcted zone that controls the remodeling process, there is autonomic neuropathy that causes both diastolic and systolic dysfunction and is likely to hamper normal remodeling processes.

SUMMARY A large proportion of the US population exhibits signs of impaired glucose tolerance and insulin resistance and, therefore, may also be at increased risk for CVD. Some 60% of all patients with established CVD fit within this category. Moreover, many patients who require treatment related to CVD, such as cardiac catheterization or medication for dyslipidemia (often marked by elevated plasma triglyceride levels and low plasma HDL-C levels), also have signs of type 2 diabetes (e.g., impaired glucose tolerance, insulin resistance) or frank diabetes. Similarly, about half of all patients who present with hypertension exhibit insulin resistance or diabetes. These findings demonstrate that a large proportion of the patients seen and treated by private, office-based physicians is at risk for both CVD and diabetes. The evidence reviewed here indicates that well before either disease process reaches clinical diagnostic thresholds or detection, the dysmetabolic state that gives rise to diabetes potentiates atherogenesis, thrombosis, lesion disruption, and cardiac dysfunction, setting the stage for increased vulnerability to acute coronary events and sudden death. Such derangements of vascular and cardiac function occur across a spectrum of metabolic changes associated with diabetes, namely impaired glucose tolerance to the clinically diabetic state. By focusing on preventive strategies aimed at the early warning signs of diabetes, general practitioners can establish the first line of defense against the insidious onset of both diabetes and CVD. Preventive strategies must also be aggressively directed at reducing the progression toward the development of both diabetes and CVD by targeting poor dietary habits, sedentary lifestyles, and other associated modifiable risks. In addition, physicians must be encouraged to treat patients with impaired glucose tolerance or diabetes to desired target levels of glycemic control, body weight, blood pressure, and plasma lipid parameters. Although many may regard the progressive nature of both type 2 diabetes and CAD as

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Figure 5. Left ventricular (LV) dysfunction predicts survival of patients with coronary artery disease. The degree of LV dysfunction, based on ejection fraction and degree of LV contraction derangement, was inversely related to survival, i.e., greater LV dysfunction was associated with lower survival rates. (Reproduced with permission from Circulation.48)

Figure 6. Antihypertensive treatment reduces mortality after acute myocardial infarction in patients with diabetes. In several large postinfarction clinical trials,49 diabetic patients using ␤-adrenergic blocking agents to manage hypertension experienced significantly lower mortality rates than did placebo-treated diabetic patients. BHAT ⫽ Beta Blocker Heart Attack Trial. 20S March 8, 2004 THE AMERICAN JOURNAL OF MEDICINE威

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discouraging, much of the evidence reviewed here indicates that patients and their health care practitioners are often given ample time to implement important therapeutic strategies to improve, manage, or even eliminate the largely modifiable risk factors associated with the development of these diseases. The keys to realizing the current potential to reduce diabetes- and CVD-related morbidity and mortality lie in early detection and aggressive treatment.

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41. Sobel BE, Woodcock-Mitchell J, Schneider DJ, et al. Increased plasminogen activator inhibitor type 1 in coronary artery atherectomy specimens from type 2 diabetic compared with nondiabetic patients: a potential factor predisposing to thrombosis and its persistence. Circulation. 1998; 97:2213–2221. 42. McGill JB, Schneider DJ, Arfken CL, et al. Factors responsible for impaired fibrinolysis in obese subjects and NIDDM patients. Diabetes. 1994;43:104 –109. 43. Landsberg L, Young JB. Insulin-mediated glucose metabolism in the relationship between dietary intake and sympathetic nervous system activity. Int J Obes. 1985;9(suppl 2):63–68. 44. Landsberg L, Young JB. The role of the sympathoadrenal system in modulating energy expenditure. Clin Endocrinol Metab. 1984;13:475–499. 45. Reaven GM, Lithell H, Landsberg L. Hypertension and associated metabolic abnormalities—the role of insulin resistance and the sympathoadrenal system. N Engl J Med. 1996;334:374 –381. 46. Young LH, Russell RR, Chyun D, Ramahi T. Heart failure in diabetic patients. In: Johnstone MT, Veves A, eds. Diabetes and Cardiovascular Disease. Totowa, NJ: Humana Press, 2001:281–297. 47. Zavaroni I, Mazza S, Dall’Aglio E, et al. Prevalence of hyperinsulinaemia in patients with high blood pressure. J Intern Med. 1992;231:235–240. 48. Mock MB, Ringqvist I, Fisher LD, et al. Survival of medically treated patients in the coronary artery surgery study (CASS) registry. Circulation. 1982;66:562–568. 49. Tse WY, Kendall M. Is there a role for beta-blockers in hypertensive diabetic patients? Diabet Med. 1994;11:137– 144. 50. Wachtell K, Dahlof B, Rokkedal J, et al. Change of left ventricular geometric pattern after 1 year of antihypertensive treatment: the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. Am Heart J. 2002;144: 1057–1064. 51. Rakic D, Rumboldt Z, Bagatin J, Polic S. Effects of four antihypertensive monotherapies on cardiac mass and function in hypertensive patients with left ventricular hypertrophy: randomized prospective study. Croat Med J. 2002;43:672–679.

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