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Original Investigation |

Diabetes Mellitus and Cardiovascular Disease in Women FREE

James R. Sowers, MD
[+] Author Affiliations

From the Division of Endocrinology, Metabolism and Hypertension, Wayne State University School of Medicine, Detroit, Mich.


Arch Intern Med. 1998;158(6):617-621. doi:10.1001/archinte.158.6.617.
Text Size: A A A
Published online

Background  Coronary heart disease (CHD) is the leading cause of morbidity and mortality in women in the United States. Although CHD is less common in premenopausal women than in men, this difference begins to disappear after the onset of menopause, presumably related to reduced levels of female sex hormones.

Results  An association between both a postmenopausal increase in blood pressure and CHD that coincide with loss of ovarian function suggests that estrogen and/or progesterone may be protective against hypertension and CHD. Diabetes removes the normal sex difference in the prevalence of CHD. Increased mortality in women with CHD and diabetes compared with women without diabetes has been observed in epidemiological studies.

Conclusions  Diabetes appears to obviate the protective effects of female sex hormones. Possible reasons for this catastrophic effect of diabetes in women are discussed.

Figures in this Article

WHILE coronary heart disease (CHD) has generally been considered a disease affecting men, the World Health Organization in 19901 reported that heart disease is the leading cause of death for women of all ages in the United States. This disease accounts for nearly 30% of all deaths among women.2,3 The incidence of CHD in women rises exponentially with age in industrialized, westernized societies.4 Below the age of 55 years, the incidence of CHD in women is one third that of men; however, this ratio approaches unity at age 75 years. Indeed, more than a quarter of a million women aged 50 through 79 years die of CHD in the United States each year. As discussed in this article, the rising incidence of CHD parallels increases in the incidence of both hypertension and diabetes with increasing age in the United States.49 Since, as previously extensively reviewed,810 the mortality from CHD and myocardial infarction is significantly worse in women than in men, it is important that we better understand the underlying factors that predispose women both to CHD and associated mortality.11 This article examines those underlying factors with special attention to the important role of diabetes mellitus in promoting CHD and associated mortality in women.

The disparity between the incidence of CHD in premenopausal women and men of the same age suggests that either sex or endogenous sex hormones such as estrogen, progesterone, and/or androgens have a significant influence on the vasculature.1221 There is considerable evidence that estrogen exerts direct effects on the vasculature. There are receptors for estrogen on both vascular endothelial and smooth muscle cells.13,14 Estrogen exerts both genomic (gene expression) and nongenomic effects on vascular cells1319 (Figure 1). Estrogen also exerts indirect effects on the vasculature through its impact on lipoprotein metabolism.4,1821 Estrogen replacement therapy increases levels of high-density lipoprotein, reduces levels of low-density lipoprotein, and attenuates low-density lipoprotein oxidation.20 However, multiple regression analysis indicates that no more than 50% of the reduction in CHD with estrogen replacement therapy is attributable to beneficial effects on lipoprotein metabolism.21

Place holder to copy figure label and caption

Cardiovascular protective effects of estrogen. HDL indicates high-density lipoprotein; LDL, low-density lipoprotein.

Graphic Jump Location

Estrogen has been demonstrated to diminish vascular constriction in part by stimulating the release of vasodilators such as nitric oxide and prostacyclin from the vessel wall1418,22 (Figure 1). Since nitric oxide has been shown to attenuate platelet aggregation23 and diminish vascular growth,15,24 this is likely one mechanism by which estrogen exerts its antiatherogenic effects.2426 Another mechanism by which estrogen may exert antiatherogenic effects is through its influence on vascular smooth muscle cell calcium metabolism.14 An increase in vascular smooth muscle calcium increases cell proliferation,27 and estrogen directly attenuates the entry of calcium through L-channels in these cells.14 Finally, estrogen may inhibit coronary atherosclerosis through its genomic effects20 (Figure 1).

Considerable experimental evidence indicates that estrogen exerts its cardiovascular protective effects by acting through binding to its receptor on vascular tissue.27 Estrogen receptor expression has also been shown in cytoplasmic and nuclear regions of human aorta. Heterogeneity of estrogen receptor distribution has been demonstrated among various vascular beds, between female and male animals, and between normal and atherosclerotic vascular tissue.2831 In primates, the estrogen receptor quantity of cytoplasmic extracts of aorta of proesterus females is greater than that of males.31 In humans, atherosclerotic coronary arteries of premenopausal women demonstrate significantly diminished expression of estrogen receptors compared with normal arteries of premenopausal women.28 These investigations suggest that the antiatherogenic effects of estradiol are in part mediated through cardiovascular estrogen receptors, and that atherosclerosis is associated with decreased estrogen receptor expression.28,31,32

As previously noted, age-related increases in hypertension parallel increases in CHD in the United States and other industrialized nations. Following adolescence, men have a considerably greater prevalence of hypertension than women until 50 to 60 years of age, at which time the prevalence is similar in men and women.4 The absolute number of women with hypertension in the United States is greater than that for men as a result of greater longevity of women.5 Dyslipidemia is likely a predisposing factor for CHD in women as well as men. It has been reported that women with angiographically documented CHD had higher mean cholesterol levels than women without CHD.33,34 The Framingham data35,36 have clearly documented obesity as an independent risk factor for CHD in women as well as men. Other long-term follow-up studies37,38 have documented that weight gain in adulthood as well as obesity per se increase the risk of CHD in women as well as men. Despite the fact that risk factors for CHD are similar in both sexes, relatively few large, controlled, interventional studies that assess CHD risk factors, such as lipid levels and blood pressure, have been conducted in women. Exceptions include prospective clinical trials such as the Systolic Hypertension in the Elderly Program,39 the Treatment of Mild Hypertension Study Trial,40 and the ongoing Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial.41 These trials have included premenopausal and postmenopausal women, but precise hormonal status has not been delineated. Sex-specific analysis of the Systolic Hypertension in the Elderly Program and the Treatment of Mild Hypertension Study trials demonstrated equivalent benefits between men and women treated for hypertension. A meta-analysis examining trials of lipid therapy in women42 demonstrated that there is currently no evidence from primary prevention trials that lowering cholesterol levels decreases mortality in women; however, treatment of hypercholesterolemia in women with known CHD appears to decrease mortality.4,42 Hopefully, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial and other large interventional trials will supply us with additional information regarding the impact of reducing known CHD risk factors in women.

Diabetes mellitus removes the normal sex-related differences in the prevalence of CHD4,4345 and end-stage renal disease.46 In the Framingham Study,43 for individuals aged 50 to 59 years, diabetes mellitus was a greater risk factor for CHD in women than in men. Even when corrected for diabetes-associated hypertension, dyslipidemia, and obesity, the risk of coronary events in women with diabetes was double that of women without diabetes.45 Increased mortality in women with CHD and diabetes (mostly type 2 diabetes) compared with women without diabetes was observed in an epidemiological study from Rancho Bernardo, Calif.43,45 When adjusted for other CHD risk factors, the risk ratio was 3.5 for women with diabetes compared with 2.4 for men with diabetes.43,45 Moreover, women with diabetes are more likely to die following myocardial infarction than women without diabetes or men.4,11,47 Thus, the existence of diabetes in women appears to abrogate the cardiovascular protective effects of endogenous estrogen.4

The mechanisms by which diabetes obviates the cardiovascular protective effects of female sex hormones in premenopausal women are not well understood. However, data are emerging suggesting potential mechanisms involved in this process. Increased cardiovascular disease in individuals with diabetes mellitus appears to be related to a number of factors. Pathological factors include enhanced platelet aggregation,48,49 relatively greater coagulation and decreased fibrinolytic activity,10,50 lipoprotein abnormalities,51 endothelial dysfunction,10,5254 enhanced oxidative stress,10,55 vascular protein glycation,10 and enhanced growth factor stimulation.10,56 Thus, diabetes mellitus, associated hyperglycemia, and other attendant metabolic abnormalities may obviate the cardiovascular protective effects of estradiol through one or more of these mechanisms. One possible mechanism involves the interaction between hyperglycemia and estradiol in regulation of cardiovascular nitric oxide production. It has recently been reported that hyperglycemia decreases estradiol-mediated nitric oxide production from cultured endothelial cells.56 Thus, it appears that hyperglycemia may negate the protective effects of estradiol in part by decreasing vascular and perhaps platelet nitric oxide production. Since nitric oxide production reduces vascular tone, platelet aggregation,23 and vascular growth,2123 this hyperglycemia-related abnormality may help explain why premenopausal women with diabetes mellitus have a high prevalence of hypertension, platelet abnormalities, and premature atherosclerosis.

Evidence exists for a role for high levels of insulin as a potential cause for the high rate of atherosclerotic CHD among women with diabetes. In a 16-year follow-up study of the Framingham population,44 insulin therapy was associated with greater cardiovascular-related mortality in women with diabetes compared with men with diabetes.44 Indeed, the role of insulin and sex hormones in coronary disease in individuals with or without diabetes was considered to be of sufficient importance to warrant a workshop sponsored by the National Heart, Lung, and Blood Institute.57 Insulin may negate the antiatherogenic effects of estradiol through its influence on vascular smooth muscle cell proliferation58,59 as well as other less understood mechanisms.

Platelet adhesion and platelet aggregation are often enhanced in diabetes mellitus (Table 1). The precise cause of enhanced platelet reactivity and other functional abnormalities of the platelet in diabetes mellitus is complex, but it appears that abnormalities in platelet intracellular divalent cation metabolism may play an integral role. Platelet intracellular calcium has been reported to be high and magnesium to be low in platelets from individuals with diabetes.49,6065 High intracellular calcium and low intracellular magnesium both increase platelet aggregation.49,61 Nitric oxide produced by platelets,23 as well as vascular tissue, inhibits platelet aggregation23 and platelet adhesion to endothethial cells. In diabetes mellitus there is reduced nitric oxide production56 and/or increased nitric oxide destruction, which contributes to enhanced platelet aggregation. In this regard, observations that hyperglycemia attenuates nitric oxide production56 provides a possible mechanism by which women with diabetes may lose the protection afforded by estrogen.

Table Graphic Jump LocationTable 1. Abnormalities of Platelet Function in Diabetes Mellitus*

In individuals with diabetes mellitus the balance between coagulation and fibrinolytic activities in the circulation is affected in a number of ways6468 (Table 2). A procoagulant state in diabetes appears to be mediated in part by higher than normal levels of a number of coagulation factors. For example, an increase in the endothelium−derived von Willebrand factor occurs in diabetes mellitus, particularly in association with endothelial cell injury,67 microvascular and macrovascular damage,64 and poor diabetic control.6668 High concentrations of factor VIII,65,66 related to hyperglycemia, accelerate the rate of thrombin formation, and this may contribute to occlusive vascular disease in patients with diabetes. Levels of fibrinogen, factor VII, and thrombin-antithrombin complexes have also been reported to be elevated in patients with diabetes.65 Elevated levels of these coagulation factors, particularly fibrinogen, are important for increasing the survival of the provisional clot matrix at the site of injured endothelium.65 Increased levels of thrombin-antithrombin complexes have been observed in patients with diabetes in association with enhanced thrombin generation.65 High plasminogen activator inhibitor-1 levels have also been observed in patients with diabetes mellitus.6467 Elevated levels of plasminogen activator inhibitor-1 also appear to be associated with elevated serum levels of insulin and triglycerides.64,65,67 Indeed, insulin has been shown to stimulate plasminogen activator inhibitor-1 synthesis in hepatocytes.67 Thus, it appears that both hyperinsulinemia and hyperglycemia contribute to an abnormal balance between coagulation and fibrinolysis in individuals with diabetes68 (Table 2).

Table Graphic Jump LocationTable 2. Coagulation and Lipoprotein Abnormalities Seen in Individuals With Diabetes Mellitus*

A number of anatomical and functional abnormalities of the vascular endothelium are associated with diabetes mellitus6971 (Table 3). In diabetes mellitus, endothelial cell lipoprotein lipase activity is decreased, as is the conversion of cholesterol ester–enriched very low-density lipoprotein to low-density lipoprotein.71,72 The resulting large and abnormal cholesterol ester–enriched very low-density lipoprotein level is injurious to endothelial cells after receptor-mediated uptake.71,72 Hyperglycemia appears to contribute to endothelial dysfunction through several mechanisms.7274 Hyperglycemia attenuates the ability of estrogen to stimulate endothelial cell nitric oxide production.56 Furthermore, hyperglycemia alters endothelial cell matrix production, which may contribute to basement membrane thickening.74 Hyperglycemia increases endothelial cell collagen and fibronectin synthesis.74 Hyperglycemia also delays cell replication and increases endothelial cell death in part by enhancing oxidation and glycation.71

Table Graphic Jump LocationTable 3. Alterations in Vascular Endothelium Associated With Diabetes Mellitus

Additional metabolic factors may contribute to endothelial dysfunction in women with diabetes. Hypercholesterolemia and perhaps hypertriglyceridemia impair endothelium-dependent relaxation.75 Therefore, it is reasonable to assume that careful control of metabolic abnormalities (both hyperglycemia and dyslipidemia) may lessen the burden of cardiovascular disease in women with diabetes mellitus. Prospective clinical trials are needed to test this possibility.

This article summarizes available information regarding the disproportionate burden of diabetes on CHD in women. Considerable in vitro and in vivo animal data suggest that hyperglycemia, and perhaps hyperinsulinemia-insulin resistance undermine the cardiovascular protective effects of estrogen. Recent data suggest that hyperglycemia attenuates the ability of estrogen to stimulate endothelial cell production of nitric oxide. Local (paracrine-autocrine) production of nitric oxide by endothelial cells, vascular smooth muscle cells, cardiac myocytes, and platelets exerts a braking effect on platelet aggregation, vascular constriction, and cardiovascular growth and remodeling. Thus, hyperglycemia attenuates the cardiovascular protective effects afforded by estrogen stimulation of nitric oxide production. Hyperinsulinemia, as exists in type 2 diabetes, appears to interact with estrogen to have detrimental cardiovascular effects. Further clinical studies should address the potential ability of antioxidant therapy and the use of angiotensin-converting enzyme and angiotensin antagonists, and possibly arginine, to improve the cardiovascular and platelet production of nitric oxide in this patient population. Another potentially exciting therapeutic tool is afforded by the recent clinical availability of insulin-sensitizing drugs such as thiazolidinediones (Troglitazone) in attenuation of the degree of hyperinsulinemia and thus potentially adverse cardiovascular effects related to estrogen hyperinsulinemia interactions in women with type 2 diabetes mellitus.

Accepted for publication July 1, 1997.

Reprints: James R. Sowers, MD, Division of Endocrinology, Metabolism and Hypertension, Wayne State University School of Medicine, 4201 St Antoine, UHC-4H, Detroit, MI 48201 (e-mail: sowers@oncgate.roc.wayne.edu).

World Health Statistics Annual Report, Vital Statistics and Cause of Death.  Geneva, Switzerland World Health Organization1990;
Barrett-Connor  EBush  TL Estrogen and coronary heart disease in women. JAMA. 1991;2651861- 1867
Link to Article
Lerner  DJKannel  WB Patterns of coronary heart disease morbidity and mortality in the sexes: a 26-year follow-up of the Framingham population. Am Heart J. 1986;111383- 390
Link to Article
Hanes  DSWeir  MRSowers  JR Gender considerations in hypertension pathophysiology and treatment. Am J Med. 1996;101 (suppl 3A) 10S- 21S
Link to Article
Anastos  KCharney  PCharon  RA  et al.  Hypertension in women: what is really known? The Women's Caucus, Working Group on Women's Health of the Society of General Internal Medicine. Ann Intern Med. 1991;115287- 293
Link to Article
Maynard  CLitwin  PEMartin  JS  et al.  Gender differences in the treatment and outcome of acute myocardial infarction: results from the Myocardial Infarction Triage and Intervention Registry. Arch Intern Med. 1992;152972- 976
Link to Article
American Heart Association, Heart and Stroke Facts.  Dallas, Tex American Heart Association1992;
Bass  KMNewschaffer  CJKlag  MJBush  TL Plasma lipoprotein levels as predictors of cardiovascular death in women. Arch Intern Med. 1993;1532209- 2216
Link to Article
The National High Blood Pressure Education Working Program, National High Blood Pressure Education Program Working Group Report on Hypertension in Diabetes. Hypertension. 1994;23145- 158
Link to Article
Sowers  JREpstein  M Diabetes mellitus and hypertension: an update. Hypertension. 1995;26869- 879
Link to Article
Albert  C Sex differences in cardiac arrest survivors. Circulation. 1996;931170- 1176
Link to Article
Colburn  PBuonassisi  V Estrogen binding sites in endothelial cell cultures. Science. 1978;201817- 819
Link to Article
Horwitz  KBHorwitz  LD Canine vascular tissues are targets for androgens, estrogens, progestins, and glucocorticoids. J Clin Invest. 1982;69750- 758
Link to Article
Zhang  FRam  JLStandley  PRSowers  JR 17 beta-Estradiol attenuates voltage-dependent Ca2+ currents in A7r5 vascular smooth muscle cell line. Am J Physiol. 1994;193C975- C980
Hayashi  TFukuto  JMIgnarro  LJChaudhare  G Basal release of nitric oxide from aortic rings is greater in female rabbits than in male rabbits: implications for atherosclerosis. Proc Natl Acad Sci U S A. 1992;8911259- 11263
Link to Article
Conrad  KPJaffe  GMKruszyna  R  et al.  Identification of increased nitric oxide biosynthesis during pregnancy in rats. FASEB J. 1993;7566- 571
Weiner  CPLizasoain  IBaylis  SAKnowles  RGCharles  IGMoncada  S Induction of calcium-dependent nitric oxide synthases by sex hormones. Proc Natl Acad Sci U S A. 1994;915212- 5216
Link to Article
Hayashi  TYamada  KEsaki  T  et al.  Estrogen increases endothelial nitric oxide by a receptor mediated system. Biochem Biophys Res Commun. 1995;214847- 855
Link to Article
Williams  JKAdams  MRKlopfenstein  HS Estrogen modulates responses of atherosclerotic coronary arteries. Circulation. 1990;811680- 1687
Link to Article
Walsh  BWSchiff  IRosner  BGrienberg  LRavnikar  VSacks  F Effects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins. N Engl J Med. 1991;3251196- 1204
Link to Article
Hong  MKRomm  PAReagan  KGreen  CERackley  CE Effects of estrogen replacement therapy on serum lipid values and angiographically defined coronary artery disease in postmenopausal women. Am J Cardiol. 1992;69176- 178
Link to Article
Lieberman  EHGerhard  MDUehata  A  et al.  Estrogen improves endothelium-dependent, flow-mediated vasodilation in postmenopausal women. Ann Intern Med. 1994;121936- 941
Link to Article
Mehta  JLChen  LYKone  BCMehta  PTurner  P Identification of constitutive and inducible forms of nitric oxide synthase in human platelets. J Lab Clin Med. 1995;125 (3) 370- 377
Sullivan  JMVander Zwaag  RLemp  GF  et al.  Postmenopausal estrogen use and coronary atherosclerosis. Ann Intern Med. 1988;108358- 363
Link to Article
Stampfer  MJColditz  GAWillett  WC  et al.  Postmenopausal estrogen therapy and cardiovascular disease: ten-year follow-up from the Nurses' Health Study. N Engl J Med. 1991;325756- 762
Link to Article
The Writing Group for the PEPI Trial, Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women: The Postmenopausal Estrogen/Progestin Interventions Trial. JAMA. 1995;273199- 208
Link to Article
Simpson  LLZhang  FStandley  PRRam  JLWeir  MRSowers  JR Role of calcium in vascular smooth muscle proliferation: antiproliferative effects of verapamil enantiomers—independence from calcium channel blockade. J Vasc Med Biol. 1994;546- 53
Orimo  AInoue  SIkegami  A  et al.  Vascular smooth muscle cells as target for estrogen. Biochem Biophys Res Commun. 1993;195730- 736
Link to Article
Losordo  DWKearney  MKim  EAJekanowski  JIsner  JM Variable expression of the estrogen receptor in normal and atherosclerotic coronary arteries of premenopausal women. Circulation. 1994;891501- 1510
Link to Article
Knauthe  RDiel  PHagele-Haratung  CEngelhaapt  AFritzemeir  K Sexual dimorphoism of steroid hormone receptor messenger ribonucleic acid expression and hormonal regulation in rat vascular tissue. Endocrinology. 1996;1373220- 3227
Campisi  DCutolo  MCarruba  G  et al.  Evidence for soluble and nuclear site I binding of estradiol in human aorta. Atherosclerosis. 1993;103267- 277
Link to Article
Lin  ALGonzalez  RCarey  KDShain  SA Gender and baboon aortic steroid hormone receptors. Arteriosclerosis. 1987;7248- 255
Link to Article
Walsh  MFDominguez  LJSowers  JR Metabolic abnormalities in cardiac ischemia. Cardiol Clin. 1995;13529- 538
Welch  CCProudift  WLSheldon  WC Coronary arteriographic findings in 1,000 women under age 50. Am J Cardiol. 1975;35211- 215
Link to Article
Hubert  HBFeinleib  MMcNamara  PMCastelli  WP Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants of the Framingham Heart Study. Circulation. 1983;67968- 976
Link to Article
Lerner  DJKannel  WB Patterns of coronary disease morbidity and mortality in the sexes: a 26-year follow-up of the Framingham population. Am Heart J. 1986;111383- 390
Link to Article
Lapidus  LBengtsson  CLarsson  BPennert  KRybo  ESjostrom  L Distribution of adipose tissue and risk of cardiovascular disease and death: a 12-year follow-up of participants in the population study of women of Gothenburg, Sweden. Br Med J (Clin Res Ed). 1984;2891257- 1261
Link to Article
Gillum  RF The association of body fat distribution with hypertension, hypertensive heart disease, coronary heart disease, diabetes and cardiovascular risk factors in men and women aged 18-79 years. J Chronic Dis. 1987;40421- 428
Link to Article
Systolic Hypertension in the Elderly Program (SHEP) Cooperative Research Group, Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program. JAMA. 1991;2653255- 3264
Link to Article
Lewis  CEGrandits  GAFlack  JMcDonald  RElmer  PJ Efficacy and tolerance of antihypertensive treatment in men and women with stage 1 diastolic hypertension. Arch Intern Med. 1996;156377- 385
Link to Article
Davis  BRCutler  JAGordon  DJ  et al.  Rationale and design for the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Am J Hypertens. 1996;9342- 360
Link to Article
Walsh  JMEGrady  D The treatment of hyperlipidemia in women. JAMA. 1995;2741152- 1158
Link to Article
Barrett-Connor  EWingard  DL Sex differential in ischemic heart disease mortality in diabetics: a prospective population-based study. Am J Epidemiol. 1983;118489- 496
Garcia  MJMcNamara  PMGordon  TKannel  WB Morbidity and mortality in diabetics in the Framingham population: sixteen-year follow-up study. Diabetes Care. 1990;13631- 654
Link to Article
Barrett-Connor  ECohn  BAWingard  DLEdelstein  SL Why is diabetes mellitus a stronger risk factor for fatal ischemic heart disease in women than in men? JAMA. 1991;265627- 631
Link to Article
Not available, USRDS 1995 Annual Data Report: incidence and causes of treated ESRD. Am J Kidney Dis. 1995;26 (suppl) S39- S50
Link to Article
Goldberg  RJLarson  MLevy  D Factors associated with survival to 75 years of age in middle-aged men and women: the Framingham Study. Arch Intern Med. 1996;156505- 509
Link to Article
Darvi  GCatalons  IAverna  M  et al.  Thromboxane biosynthesis and platelet function in type II diabetes mellitus. N Engl J Med. 1990;3221769- 1774
Link to Article
Standley  PRAli  SBapna  CSowers  JR Increased platelet cytosolic calcium responses to low density lipoprotein in type II diabetes with and without hypertension. Am J Hypertens. 1993;6938- 943
Carmassi  FMorale  MPuccetti  R  et al.  Coagulation and fibrinolytic system impairment in insulin dependent diabetes mellitus. Thromb Res. 1992;67643- 654
Link to Article
Betteridge  DJ Diabetic dyslipidemia. Am J Med. 1994;96 (suppl 6A) 25S- 31S
Link to Article
Williams  SBCusco  JARoddy  MAJohnstone  MACreager  MA Impaired nitric oxide-mediated vasodilation in non–insulin-dependent diabetes. Circulation. 1994;90I-50- I-53
Link to Article
Goodfellow  JRamsey  MWLuddington  LA  et al.  Flow-related endothelial function is impaired in non–insulin dependent diabetes. Circulation. 1994;90I-513
Clarkson  PCelermajer  DSYue  DK  et al.  Endothelial dysfunction in insulin-dependent diabetes mellitus relates to the duration of disease and LDL-cholesterol level. Circulation. 1995;92I-1107
Guigliano  DCeriello  APaolisso  G Oxidative stress and diabetic complications. Diabetes Care. 1996;19257- 267
Link to Article
Sowers  JR Insulin and insulin-like growth factor in normal and pathological cardiovascular physiology. Hypertension. 1997;29691- 699
Link to Article
Donahue  RPBarrett-Connor  EOrchard  TJGutai  JP Endogenous insulin and sex hormones in atherosclerosis and coronary heart disease. Arteriosclerosis. 1988;8544- 548
Link to Article
Capron  LJarnet  JKusandjian  SHonsait  E Growth promoting effects of diabetes and insulin on arteries. Diabetes. 1986;35973- 978
Link to Article
Oppenheimer  MJSundquist  KBierman  EL Down-regulation of high-density lipoprotein receptor in human fibroblasts by insulin and IGF-1. Diabetes. 1989;38117- 122
Link to Article
Hamet  PSkuherska  RPang  SCTremblay  J Abnormalities of platelet function in hypertension and diabetes. Hypertension. 1985;7II135- II142
Link to Article
Nadler  JLMalayan  SLuong  HShaw  SNatarajan  RRude  B Intracellular free magnesium deficiency plays a key role in increased platelet reactivity in type II diabetes mellitus. Diabetes Care. 1992;15835- 841
Link to Article
Jacobs  DBSowers  JRHmeidan  ANiyogi  TSimpson  LStandley  PR Effects of weight reduction on cellular cation metabolism and vascular resistance. Hypertension. 1993;21308- 314
Link to Article
Levy  JGavin  JR  IIISowers  JR Diabetes mellitus: a disease of abnormal cellular calcium metabolism? Am J Med. 1994;96260- 270
Link to Article
Ford  ISingh  TPKitchen  SMakris  MWard  JDPreston  FD Activation of coagulation in diabetes mellitus in relation to the presence of vascular complications. Diabet Med. 1991;8322- 329
Link to Article
Carmassi  FMorale  MPuccetti  R  et al.  Coagulation and fibrinolytic system impairment in insulin dependent diabetes mellitus. Thromb Res. 1992;67643- 654
Link to Article
Vukovich  TCProidl  SKnöbl  PTeufelsbauer  HSchnack  OSchernthaner  G The effect of insulin treatment on the balance between tissue plasminogen activator and plasminogen activator inhibitor-1 in type 2 diabetic patients. Thromb Haemost. 1992;68253- 256
Landin  KTengborn  LSmith  U Elevated fibrinogen and plasminogen activator inhibitor (PAI-1) in hypertension are related to metabolic risk factors for cardiovascular disease. J Intern Med. 1990;227273- 278
Link to Article
Sowers  JRTuck  MSowers  DK Plasma antithrombin III and thrombin generation time: correlation with hemoglobin A1 and fasting serum glucose in young diabetic women. Diabetes Care. 1980;3655- 658
Link to Article
Ramirez  LCArauz-Pacheco  CLackner  CAlbright  GAdams  BWRaskin  P Lipoprotein (a) levels in diabetes mellitus: relationship to metabolic control. Ann Intern Med. 1992;11742- 47
Link to Article
Bucala  RMakita  ZKoschinsky  TCerami  AVlassara  H Lipid advanced glycosylation: pathway for lipid oxidation in vivo. Proc Natl Acad Sci U S A. 1993;906434- 6438
Link to Article
Lyons  TJLopes-Virella  MFBaystle  JW Glycation, oxidation, and glyoxidation in the pathogenesis of atherosclerosis in diabetes. Mod Med. 1993;61 (suppl 2) 4- 8
Hsueh  WAAnderson  PW Hypertension, the endothelial cell, and the vascular complications of diabetes mellitus. Hypertension. 1992;20253- 263
Link to Article
Tesfamariam  BBrown  MLCohen  RA Elevated glucose impairs endothelium-dependent relaxation by activating protein kinase C. J Clin Invest. 1991;871643- 1648
Link to Article
Cagliero  ERoth  TRoy  SLorenzi  M Characteristics and mechanisms of high-glucose-induced overexpression of basement membrane components in cultured human endothelial cells. Diabetes. 1991;40102- 110
Link to Article
Creager  MACooke  JPMendelsohn  M  et al.  Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans. J Clin Invest. 1990;86228- 234
Link to Article

Figures

Place holder to copy figure label and caption

Cardiovascular protective effects of estrogen. HDL indicates high-density lipoprotein; LDL, low-density lipoprotein.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Abnormalities of Platelet Function in Diabetes Mellitus*
Table Graphic Jump LocationTable 2. Coagulation and Lipoprotein Abnormalities Seen in Individuals With Diabetes Mellitus*
Table Graphic Jump LocationTable 3. Alterations in Vascular Endothelium Associated With Diabetes Mellitus

References

World Health Statistics Annual Report, Vital Statistics and Cause of Death.  Geneva, Switzerland World Health Organization1990;
Barrett-Connor  EBush  TL Estrogen and coronary heart disease in women. JAMA. 1991;2651861- 1867
Link to Article
Lerner  DJKannel  WB Patterns of coronary heart disease morbidity and mortality in the sexes: a 26-year follow-up of the Framingham population. Am Heart J. 1986;111383- 390
Link to Article
Hanes  DSWeir  MRSowers  JR Gender considerations in hypertension pathophysiology and treatment. Am J Med. 1996;101 (suppl 3A) 10S- 21S
Link to Article
Anastos  KCharney  PCharon  RA  et al.  Hypertension in women: what is really known? The Women's Caucus, Working Group on Women's Health of the Society of General Internal Medicine. Ann Intern Med. 1991;115287- 293
Link to Article
Maynard  CLitwin  PEMartin  JS  et al.  Gender differences in the treatment and outcome of acute myocardial infarction: results from the Myocardial Infarction Triage and Intervention Registry. Arch Intern Med. 1992;152972- 976
Link to Article
American Heart Association, Heart and Stroke Facts.  Dallas, Tex American Heart Association1992;
Bass  KMNewschaffer  CJKlag  MJBush  TL Plasma lipoprotein levels as predictors of cardiovascular death in women. Arch Intern Med. 1993;1532209- 2216
Link to Article
The National High Blood Pressure Education Working Program, National High Blood Pressure Education Program Working Group Report on Hypertension in Diabetes. Hypertension. 1994;23145- 158
Link to Article
Sowers  JREpstein  M Diabetes mellitus and hypertension: an update. Hypertension. 1995;26869- 879
Link to Article
Albert  C Sex differences in cardiac arrest survivors. Circulation. 1996;931170- 1176
Link to Article
Colburn  PBuonassisi  V Estrogen binding sites in endothelial cell cultures. Science. 1978;201817- 819
Link to Article
Horwitz  KBHorwitz  LD Canine vascular tissues are targets for androgens, estrogens, progestins, and glucocorticoids. J Clin Invest. 1982;69750- 758
Link to Article
Zhang  FRam  JLStandley  PRSowers  JR 17 beta-Estradiol attenuates voltage-dependent Ca2+ currents in A7r5 vascular smooth muscle cell line. Am J Physiol. 1994;193C975- C980
Hayashi  TFukuto  JMIgnarro  LJChaudhare  G Basal release of nitric oxide from aortic rings is greater in female rabbits than in male rabbits: implications for atherosclerosis. Proc Natl Acad Sci U S A. 1992;8911259- 11263
Link to Article
Conrad  KPJaffe  GMKruszyna  R  et al.  Identification of increased nitric oxide biosynthesis during pregnancy in rats. FASEB J. 1993;7566- 571
Weiner  CPLizasoain  IBaylis  SAKnowles  RGCharles  IGMoncada  S Induction of calcium-dependent nitric oxide synthases by sex hormones. Proc Natl Acad Sci U S A. 1994;915212- 5216
Link to Article
Hayashi  TYamada  KEsaki  T  et al.  Estrogen increases endothelial nitric oxide by a receptor mediated system. Biochem Biophys Res Commun. 1995;214847- 855
Link to Article
Williams  JKAdams  MRKlopfenstein  HS Estrogen modulates responses of atherosclerotic coronary arteries. Circulation. 1990;811680- 1687
Link to Article
Walsh  BWSchiff  IRosner  BGrienberg  LRavnikar  VSacks  F Effects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins. N Engl J Med. 1991;3251196- 1204
Link to Article
Hong  MKRomm  PAReagan  KGreen  CERackley  CE Effects of estrogen replacement therapy on serum lipid values and angiographically defined coronary artery disease in postmenopausal women. Am J Cardiol. 1992;69176- 178
Link to Article
Lieberman  EHGerhard  MDUehata  A  et al.  Estrogen improves endothelium-dependent, flow-mediated vasodilation in postmenopausal women. Ann Intern Med. 1994;121936- 941
Link to Article
Mehta  JLChen  LYKone  BCMehta  PTurner  P Identification of constitutive and inducible forms of nitric oxide synthase in human platelets. J Lab Clin Med. 1995;125 (3) 370- 377
Sullivan  JMVander Zwaag  RLemp  GF  et al.  Postmenopausal estrogen use and coronary atherosclerosis. Ann Intern Med. 1988;108358- 363
Link to Article
Stampfer  MJColditz  GAWillett  WC  et al.  Postmenopausal estrogen therapy and cardiovascular disease: ten-year follow-up from the Nurses' Health Study. N Engl J Med. 1991;325756- 762
Link to Article
The Writing Group for the PEPI Trial, Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women: The Postmenopausal Estrogen/Progestin Interventions Trial. JAMA. 1995;273199- 208
Link to Article
Simpson  LLZhang  FStandley  PRRam  JLWeir  MRSowers  JR Role of calcium in vascular smooth muscle proliferation: antiproliferative effects of verapamil enantiomers—independence from calcium channel blockade. J Vasc Med Biol. 1994;546- 53
Orimo  AInoue  SIkegami  A  et al.  Vascular smooth muscle cells as target for estrogen. Biochem Biophys Res Commun. 1993;195730- 736
Link to Article
Losordo  DWKearney  MKim  EAJekanowski  JIsner  JM Variable expression of the estrogen receptor in normal and atherosclerotic coronary arteries of premenopausal women. Circulation. 1994;891501- 1510
Link to Article
Knauthe  RDiel  PHagele-Haratung  CEngelhaapt  AFritzemeir  K Sexual dimorphoism of steroid hormone receptor messenger ribonucleic acid expression and hormonal regulation in rat vascular tissue. Endocrinology. 1996;1373220- 3227
Campisi  DCutolo  MCarruba  G  et al.  Evidence for soluble and nuclear site I binding of estradiol in human aorta. Atherosclerosis. 1993;103267- 277
Link to Article
Lin  ALGonzalez  RCarey  KDShain  SA Gender and baboon aortic steroid hormone receptors. Arteriosclerosis. 1987;7248- 255
Link to Article
Walsh  MFDominguez  LJSowers  JR Metabolic abnormalities in cardiac ischemia. Cardiol Clin. 1995;13529- 538
Welch  CCProudift  WLSheldon  WC Coronary arteriographic findings in 1,000 women under age 50. Am J Cardiol. 1975;35211- 215
Link to Article
Hubert  HBFeinleib  MMcNamara  PMCastelli  WP Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants of the Framingham Heart Study. Circulation. 1983;67968- 976
Link to Article
Lerner  DJKannel  WB Patterns of coronary disease morbidity and mortality in the sexes: a 26-year follow-up of the Framingham population. Am Heart J. 1986;111383- 390
Link to Article
Lapidus  LBengtsson  CLarsson  BPennert  KRybo  ESjostrom  L Distribution of adipose tissue and risk of cardiovascular disease and death: a 12-year follow-up of participants in the population study of women of Gothenburg, Sweden. Br Med J (Clin Res Ed). 1984;2891257- 1261
Link to Article
Gillum  RF The association of body fat distribution with hypertension, hypertensive heart disease, coronary heart disease, diabetes and cardiovascular risk factors in men and women aged 18-79 years. J Chronic Dis. 1987;40421- 428
Link to Article
Systolic Hypertension in the Elderly Program (SHEP) Cooperative Research Group, Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program. JAMA. 1991;2653255- 3264
Link to Article
Lewis  CEGrandits  GAFlack  JMcDonald  RElmer  PJ Efficacy and tolerance of antihypertensive treatment in men and women with stage 1 diastolic hypertension. Arch Intern Med. 1996;156377- 385
Link to Article
Davis  BRCutler  JAGordon  DJ  et al.  Rationale and design for the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Am J Hypertens. 1996;9342- 360
Link to Article
Walsh  JMEGrady  D The treatment of hyperlipidemia in women. JAMA. 1995;2741152- 1158
Link to Article
Barrett-Connor  EWingard  DL Sex differential in ischemic heart disease mortality in diabetics: a prospective population-based study. Am J Epidemiol. 1983;118489- 496
Garcia  MJMcNamara  PMGordon  TKannel  WB Morbidity and mortality in diabetics in the Framingham population: sixteen-year follow-up study. Diabetes Care. 1990;13631- 654
Link to Article
Barrett-Connor  ECohn  BAWingard  DLEdelstein  SL Why is diabetes mellitus a stronger risk factor for fatal ischemic heart disease in women than in men? JAMA. 1991;265627- 631
Link to Article
Not available, USRDS 1995 Annual Data Report: incidence and causes of treated ESRD. Am J Kidney Dis. 1995;26 (suppl) S39- S50
Link to Article
Goldberg  RJLarson  MLevy  D Factors associated with survival to 75 years of age in middle-aged men and women: the Framingham Study. Arch Intern Med. 1996;156505- 509
Link to Article
Darvi  GCatalons  IAverna  M  et al.  Thromboxane biosynthesis and platelet function in type II diabetes mellitus. N Engl J Med. 1990;3221769- 1774
Link to Article
Standley  PRAli  SBapna  CSowers  JR Increased platelet cytosolic calcium responses to low density lipoprotein in type II diabetes with and without hypertension. Am J Hypertens. 1993;6938- 943
Carmassi  FMorale  MPuccetti  R  et al.  Coagulation and fibrinolytic system impairment in insulin dependent diabetes mellitus. Thromb Res. 1992;67643- 654
Link to Article
Betteridge  DJ Diabetic dyslipidemia. Am J Med. 1994;96 (suppl 6A) 25S- 31S
Link to Article
Williams  SBCusco  JARoddy  MAJohnstone  MACreager  MA Impaired nitric oxide-mediated vasodilation in non–insulin-dependent diabetes. Circulation. 1994;90I-50- I-53
Link to Article
Goodfellow  JRamsey  MWLuddington  LA  et al.  Flow-related endothelial function is impaired in non–insulin dependent diabetes. Circulation. 1994;90I-513
Clarkson  PCelermajer  DSYue  DK  et al.  Endothelial dysfunction in insulin-dependent diabetes mellitus relates to the duration of disease and LDL-cholesterol level. Circulation. 1995;92I-1107
Guigliano  DCeriello  APaolisso  G Oxidative stress and diabetic complications. Diabetes Care. 1996;19257- 267
Link to Article
Sowers  JR Insulin and insulin-like growth factor in normal and pathological cardiovascular physiology. Hypertension. 1997;29691- 699
Link to Article
Donahue  RPBarrett-Connor  EOrchard  TJGutai  JP Endogenous insulin and sex hormones in atherosclerosis and coronary heart disease. Arteriosclerosis. 1988;8544- 548
Link to Article
Capron  LJarnet  JKusandjian  SHonsait  E Growth promoting effects of diabetes and insulin on arteries. Diabetes. 1986;35973- 978
Link to Article
Oppenheimer  MJSundquist  KBierman  EL Down-regulation of high-density lipoprotein receptor in human fibroblasts by insulin and IGF-1. Diabetes. 1989;38117- 122
Link to Article
Hamet  PSkuherska  RPang  SCTremblay  J Abnormalities of platelet function in hypertension and diabetes. Hypertension. 1985;7II135- II142
Link to Article
Nadler  JLMalayan  SLuong  HShaw  SNatarajan  RRude  B Intracellular free magnesium deficiency plays a key role in increased platelet reactivity in type II diabetes mellitus. Diabetes Care. 1992;15835- 841
Link to Article
Jacobs  DBSowers  JRHmeidan  ANiyogi  TSimpson  LStandley  PR Effects of weight reduction on cellular cation metabolism and vascular resistance. Hypertension. 1993;21308- 314
Link to Article
Levy  JGavin  JR  IIISowers  JR Diabetes mellitus: a disease of abnormal cellular calcium metabolism? Am J Med. 1994;96260- 270
Link to Article
Ford  ISingh  TPKitchen  SMakris  MWard  JDPreston  FD Activation of coagulation in diabetes mellitus in relation to the presence of vascular complications. Diabet Med. 1991;8322- 329
Link to Article
Carmassi  FMorale  MPuccetti  R  et al.  Coagulation and fibrinolytic system impairment in insulin dependent diabetes mellitus. Thromb Res. 1992;67643- 654
Link to Article
Vukovich  TCProidl  SKnöbl  PTeufelsbauer  HSchnack  OSchernthaner  G The effect of insulin treatment on the balance between tissue plasminogen activator and plasminogen activator inhibitor-1 in type 2 diabetic patients. Thromb Haemost. 1992;68253- 256
Landin  KTengborn  LSmith  U Elevated fibrinogen and plasminogen activator inhibitor (PAI-1) in hypertension are related to metabolic risk factors for cardiovascular disease. J Intern Med. 1990;227273- 278
Link to Article
Sowers  JRTuck  MSowers  DK Plasma antithrombin III and thrombin generation time: correlation with hemoglobin A1 and fasting serum glucose in young diabetic women. Diabetes Care. 1980;3655- 658
Link to Article
Ramirez  LCArauz-Pacheco  CLackner  CAlbright  GAdams  BWRaskin  P Lipoprotein (a) levels in diabetes mellitus: relationship to metabolic control. Ann Intern Med. 1992;11742- 47
Link to Article
Bucala  RMakita  ZKoschinsky  TCerami  AVlassara  H Lipid advanced glycosylation: pathway for lipid oxidation in vivo. Proc Natl Acad Sci U S A. 1993;906434- 6438
Link to Article
Lyons  TJLopes-Virella  MFBaystle  JW Glycation, oxidation, and glyoxidation in the pathogenesis of atherosclerosis in diabetes. Mod Med. 1993;61 (suppl 2) 4- 8
Hsueh  WAAnderson  PW Hypertension, the endothelial cell, and the vascular complications of diabetes mellitus. Hypertension. 1992;20253- 263
Link to Article
Tesfamariam  BBrown  MLCohen  RA Elevated glucose impairs endothelium-dependent relaxation by activating protein kinase C. J Clin Invest. 1991;871643- 1648
Link to Article
Cagliero  ERoth  TRoy  SLorenzi  M Characteristics and mechanisms of high-glucose-induced overexpression of basement membrane components in cultured human endothelial cells. Diabetes. 1991;40102- 110
Link to Article
Creager  MACooke  JPMendelsohn  M  et al.  Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans. J Clin Invest. 1990;86228- 234
Link to Article

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