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Heart Disease in Women With Diabetes

Thomas C. Smitherman, MD, and Steven E. Reis, MD

Unfortunately, it is unrecognized by most women and by many health-care providers that cardiovascular disease is the most common cause of death for women in the United States, usually due to complications of atherosclerosis. The burden is significantly greater for women with diabetes. Cardiovascular death due to heart disease accounts for a large fraction of these deaths. Again, the burden is greater for women with diabetes and accounts for a disproportionately large fraction of morbidity and health-care expenditures in women with diabetes.

Three types of heart disease account for most of the heart disease in women with diabetes: 1) ischemic heart disease, principally atherosclerotic coronary artery disease, 2) a cardiomyopathic disorder (or disorders), which can be characterized by either disorders of both contraction (systolic dysfunction) and filling (diastolic dysfunction) or predominantly by a disorder of filling alone, and 3) a cardiac dysautonomia.

Much of what has been observed, tested, and written about atherosclerotic heart disease has been based disproportionately on studies in men. As it has become clear that atherosclero-tic heart disease is a major women's health problem as well, much of what was observed and determined from studies in men has been simply extrapolated to women, sometimes with infelicitous results. It has been observed that in some ways women's hearts are different from those of men in regard to ischemic heart disease, and many studies are under way to obtain more gender-specific information.¹ The pathology, pathophysiology, clinical presentations, and treatment strategies of cardiac disease are sometimes different in patients with diabetes and in those without diabetes, and sometimes there are differences between women with diabetes and men with diabetes. This review focuses on heart disease in women with diabetes.

RISK FACTORS FOR ATHEROSCLEROSIS
Atherosclerosis appears to be a nearly inevitable outcome of aging. It is not unreasonable in 1997 to consider atherosclerosis that occurs before a very advanced age as premature. Pre-mature atherosclerotic heart disease afflicting middle-aged and younger people has become a scourge of modern industrialized societies.

Particularly important risk factors for premature atherosclerosis are tobacco smoking, serum lipid disorders, diabetes, hypertension, age, gender, obesity, and physical inactivity. The effects of the last two are mediated, at least in part, through their effects on promoting diabetes, serum lipid disorders, and hypertension. The effects of the risk factors are highly interactive, so that the presence of one risk factor enhances the effects of a second one. This interaction is particularly important for women with diabetes because of the strong association of diabetes with hypertension, serum lipid disorders, and obesity.

Diabetes
Diabetes is a risk factor for premature atherosclerosis and atherosclerotic coronary artery disease.² Duration of diabetes is more strongly associated with risk than is severity of the disease.

Diabetes is approximately twice as potent a risk factor in women as it is in men and is a prominent risk factor even in women who are premenopausal and who are not hypertensive or hyperlipemic.³ Women with diabetes are about five times more likely to develop atherosclerotic coronary artery disease than are women without diabetes.

Diabetes leads to loss of the protection against atherosclerosis provided to women before menopause. All age- groups of women with diabetes have rates of atherosclerotic coronary artery disease similar to those of men with diabetes.⁴ Impaired estrogen binding in patients with diabetes⁵ might be related to the loss of the protection conferred by female gender.

While hypertension and lipid disorders are frequently associated with diabetes and may compound the atherogenic effects of these risk factors^4,6 these associations do not account for the high frequency of atherosclerosis in people with diabetes,⁷ including women with diabetes.⁸ The pathogenesis of atherosclerosis in patients with diabetes was reviewed by Stolar.⁹ Potential contributing factors include hyperinsulinemia, which may stimulate smooth muscle cells and fibroblasts and which may reduce fibrinolytic activity, elevated levels of growth hormone, and increased platelet adhesion and aggregation. It has not yet been definitively proved that strict control of blood glucose in patients with diabetes will reduce the likelihood of atherosclerotic coronary artery disease of the large epicardial vessels in contrast to the demonstrated benefits against the microvascular disease associated with diabetes.

Gender
Male gender is a risk factor for atherosclerosis, but menopause removes the protection conferred by female gender. Postmenopausal estrogen therapy appears to substantially restore the benefit of female gender. A recent meta-analysis of a large number of studies found that 24 of 26 studies overall reported reduced cardiovascular endpoints and that the combined decrease in cardiovascular risk was 44% for estrogen users.¹⁰ An analysis of all study data since 1970 reported in 1992 an estimated 35% reduction in cardiovascular risk for women who had ever used estrogen versus those who had never used estrogen.¹¹ A significant fraction of the protection conferred by estrogen appears to come from beneficial effects on low-density (LDL) and high-density lipoprotein (HDL) cholesterol.^12,13 Nevertheless, a residual protective effect of estrogen after correction for lipid levels led to the hypothesis of additional protective cardiovascular effects of estrogen.¹³ The majority of studies indicate continued protection with estrogen replacement therapy into advanced age.

Because estrogen therapy without progestins increases the risk of endometrial hyperplasia and neoplasia to a woman with an intact uterus, it has become routine to administer progestins with estrogens. The Post-menopausal Estrogen/Progestin Interventions Trial provided evidence that concomitant progestin therapy with estrogen reduces the increased risk of endometrial neoplasia associated with estrogen therapy alone. In addition, the estrogen and progestin combination therapy is associated with beneficial effects on lipid levels, although somewhat less so than with estrogen alone.¹⁴

The Women's Health Initiative Study is now under way to address whether hormone replacement therapy will reduce the incidence of coronary heart disease endpoints. This topic is reviewed in greater detail by Reis and associates.¹ Therefore, it would seem prudent for now to recommend hormone replacement therapy for all postmenopausal women with diabetes for whom there are no important contraindications to this therapy.

Dyslipidemias
Several dyslipidemias are well-identified risk factors for premature atherosclerosis and are discussed in numerous reviews, including those of Grundy¹⁵ and Farmer and Gotto.¹⁶ The weight of evidence for promotion of accelerated atherosclerosis is strong for high total cholesterol, high LDL cholesterol, and depressed HDL cholesterol. Clinical trials have consistently shown reductions in complications of coronary atherosclerotic heart disease with drug therapy to lower LDL cholesterol.

The importance of elevated very-low-density lipoprotein (VLDL) cholesterol and triglycerides, which reflect VLDL levels, as risk factors for premature atherosclerosis is less clear. Elevated triglycerides and VLDL cholesterol are often associated with low HDL. Elevated triglycerides are frequently observed with diabetes and renal failure, which are clearly associated with premature atherosclerosis. Along with other abnormalities, triglycerides and VLDL cholesterol are elevated in types IIB and III dyslipidemias, both of which are associated with premature atherosclerosis.

Many investigators are convinced that at least some forms of VLDL are atherogenic. While triglycerides do not accumulate in atherosclerotic plaques, patients with hypertriglyceridemia have increased small-density lipoproteins, intermediate-density lipoproteins (IDL), VLDL remnants, and chylomicron remnants, all of which are atherogenic.¹⁷ In the Framingham study, elevated VLDL cholesterol was an independent risk factor for coronary atherosclerosis in women and was a stronger predictor than it was in men.¹⁸ The Helsinki Heart Trial demonstrated lower cardiovascular mortality in men with elevated VLDL, elevated LDL, and de-pressed HDL when treated with gemfibrozil versus placebo.

Overproduction of VLDL, inappropriate lipolysis of VLDL triglycerides, low LDL receptor activity, low HDL levels, and occasionally type III hyperlipidemia have been reported to be associated with diabetes.^19-21 Poor glucose control is correlated with worsened hypertriglyceridemia in some patients with diabetes. Low HDL has been associated with high concentrations of glycosylated hemoglobin.²² Thus, many women with diabetes have elevated triglycerides and VLDL, often associated with low HDL. Not infrequently, these abnormalities are also associated with elevated LDL.

In women with diabetes and hyperlipidemia, a low atherogenic diet, maintenance of normal weight, good glucose control, and physical activity are obviously important. When drug therapy is warranted, bile acid binding resins and nicotinic acid are generally best avoided. Nicotinic acid may worsen glucose tolerance. Bile acid binding resins may worsen hypertriglyceridemia. Hormone replacement therapy could rationally be the first choice of pharmacological therapy in postmenopausal women with diabetes without significant elevation in triglycerides.

For premenopausal women with diabetes or when hormone replacement therapy is not an option for a postmenopausal woman, the nature of the hyperlipidemia should drive the choice of drug therapy. For a patient with low HDL and elevated triglycerides, VLDL, and LDL, treatment with a fibric acid derivative such as gemfibrozil could be considered and could be expected to substantially lower triglycerides and VLDL cholesterol and to lower LDL cholesterol by 10-20%.

An alternative regimen for women with diabetes when the triglycerides are not markedly elevated could be the recently introduced HMG CoA reductase inhibitor atorvastatin, which lowers triglycerides as well as LDL cholesterol. In the relatively uncommon case of a woman with diabetes with principally elevated LDL cholesterol, an HMG CoA reductase inhibitor would likely be the most prudent choice. In this case, it would seem prudent to follow the guidelines of the National Cholesterol Education Program expert panel and set the following goals for LDL cholesterol: <100 mg/dl for patients with known atherosclerosis; <130 mg/dl for patients with one additional risk factor for premature atherosclerosis; and<160 mg/dl for patients with no additional risk factors.²³

Hypertension
The frequency of hypertension is elevated in patients with diabetes.²⁴ The prevalence of hypertension is in-creased even in the absence of renal failure. The prevalence has been reported to be as high as 40-80% of people with diabetes.^25,26

The cause is likely multifactorial and may include abnormalities of the sympathetic nervous system, the renin-angiotensin system, volume status, sodium regulation, compliance of large vessels, and atherosclerotic renovascular disease.^25,27 The appearance of renal failure often worsens hypertension in patients with diabetes or causes the new onset of hypertension. The effect of hypertension is not only additive to diabetes in promoting atherosclerosis, but also accelerates diabetic microangiopathy.

Obviously, excellent control of blood pressure is crucial in the treatment of women with diabetes. Because of protective effects on the kidney, angiotensin-converting en-zyme (ACE) inhibitors are often an important part of the antihypertensive regimen, as they are in the treatment of women with diabetes who have hypertension and congestive heart failure.

Tobacco Smoking
Tobacco smoking is the single most potent risk factor for premature atherosclerosis, and there is no reason to think that it is otherwise for women with diabetes. The risk of atherosclerotic coronary artery disease is increased fourfold in women smokers. Smoking is associated with premature menopause and thus may further hasten the onset of atherosclerosis by early loss of estrogen's protective effects.

The current increased rate of tobacco smoking among adolescent women raises the prospect of an increase in the rate of smokers in the next generation of women with diabetes. It goes without saying that health-care workers should do everything in their power to influence and help women with diabetes to avoid tobacco smoking.

ISCHEMIC HEART DISEASE IN WOMEN WITH DIABETES
Pathology
Hemodynamically significant arteriosclerotic narrowing of a coronary artery is the underlying pathology of more than 90% of all patients with ischemic heart disease. Nevertheless, it is important to note some alternative causes, especially: 1) a long list of diseases that can cause nonatherosclerotic coronary artery disease (which will not be discussed in this review); 2) Syndrome X or microvascular angina; and 3) Prinzmetal's (variant) angina in the presence of arteriographically normal coronary arteries.

Microvascular Angina (Cardiac Syndrome X)
Cardiac Syndrome X, a term used widely in Europe, or microvascular angina, the term used more widely in the United States, is the disorder in which a patient has classical exertional angina pectoris with objective evidence for myocardial ischemia with arteriographically normal coronary arteries. It is believed that this is principally the result of failure of normal autoregulation at the level of the coronary arterioles, hence the term "microvascular angina."

Microvascular angina is more common in women than in men. It generally has a favorable prognosis,^29-31 but progression to cardiomyopathy and congestive heart failure sometimes occurs. Some women with microvascular angina may be dismissed as having noncardiac discomfort, even though there is objective evidence for ischemia. This should be avoided because these patients respond to administration of organic nitrates and calcium-channel blocking agents.

Prinzmetal's (Variant) Angina
Prinzmetal's (variant) angina usually occurs with a hemodynamically significant coronary artery stenosis (see below), but occasionally occurs in the absence of arteriosclerosis. Severe, occlusive spasm causes the ischemia. Prinzmetal's angina is more common in women than men.³² While the coronary arteries of these patients may be normal to arteriographic interrogation, the sites of spasm have been reported to have evidence of atherosclerosis by intravascular ultrasound examinations.³³

Endothelial dysfunction and the resulting deficient nitric oxide (endo-thelial-derived relaxing factor) production at the site of an atherosclerotic plaque is likely an important mechanism.³⁴ In this situation, normally vasodilating physiological stimuli may paradoxically lead to vasoconstriction. Mild to moderate degrees of vasoconstriction are common in atherosclerotic coronary arteries (see below), but the reasons for severe occlusive spasm in Prinzmetal's angina are not clear.

Patients with Prinzmetal's angina with arteriographically normal coronary arteries respond well to nitrates and calcium-channel blockers. The prognosis is generally good, but recurrent episodes and myocardial infarction (MI) have been reported.

Chronic Myocardial Ischemia With Atherosclerotic Coronary Artery Stenoses
Typical and "atypical" angina pectoris. The principal manifestation of chronic myocardial ischemia is typical exertional angina pectoris. This is principally a problem of myocardial oxygen demand exceeding the available oxygen supply delivered by the coronary arteries. The myocardium has exceptionally high myocardial oxygen needs. Oxygen extraction by the heart in the basal state is very nearly maximal. Accordingly, in-creased coronary blood flow is essential for increased demand.

The major determinants of myocardial oxygen demand (MvO₂) are heart rate, myocardial wall tension, and cardiac contractility. Myocardial ischemia occurs when an increase in myocardial oxygen demand cannot be adequately met by a limited supply as the result of insufficient coronary blood flow.

Coronary blood flow is a function of the coronary artery perfusion pressure and the resistance to the flow of blood in the coronary bed. Coronary resistance can be thought of as occurring at three levels: the so-called R1, R2, and R3 coronary resistance vessels. R1 is defined as the epicardial coronary arteries and the large intra-myocardial vessels. In health, these vessels impart minimal resistance. The R2 resistance vessels are the arterioles and the pre-arteriolar arteries. This is where the majority of coronary artery resistance occurs in health. In the basal state, the arterioles and the pre-arteriolar arteries are tonically constricted. With exertion, resistance can usually decline three- to fivefold. The R3 resistance is the contribution by the myocardial wall tension resulting from myocardial contraction. The tension is greatest in the subendocardium.

With the onset of exercise, diastolic blood pressure changes very little. The principal mechanism for an increase in blood flow to the heart during exercise is a greatly decreased resistance of the R2 resistance vessels.

When there are hemodynamically significant coronary artery stenoses, the nature of coronary resistance is changed, with greatly increased resistance in the epicardial vessels (the R1 vessels). Arteriolar and pre-arteriolar resistance decreases, but in so doing, coronary blood flow reserve is diminished. When there are critical coronary lesions, 85-90% or more coronary artery diameter stenosis, the coronary flow reserve is reduced to practically zero.

When a patient with hemodynamically significant coronary lesions exercises, the resistance at the epicardial vessel level stays about the same or is minimally decreased from its raised baseline levels. The R2 resistance vessels decrease to the most limited degree possible, but after that is exhausted, myocardial ischemia occurs as myocardial oxygen demand exceeds the supply. Because R3 resistance tends to increase with the increased contractility of exertion, and because the R3 resistance can no longer be offset by a decline in R2 resistance, there tends to be greater myocardial ischemia in the subendocardium than is present in the subepicardial regions.

The predominant initial presentation in women with atherosclerotic coronary artery disease is typical angina, whereas the predominant initial presentation in men is acute MI. Nevertheless, only about 60% of women with typical angina pectoris have coronary atherosclerosis as demonstrated by arteriography, whereas about 90% of men do. This may be due, at least in part, to the higher frequency of microvascular angina and Prinzmetal's angina in women, as discussed above.

The description of typical angina pectoris was developed centuries ago principally from interviews with men. Women with atherosclerotic coronary artery disease are more apt than men to present with "atypical angina," chest discomfort that is suggestive of but atypical for angina (at least in men), which can interfere with the diagnosis of atherosclerotic coronary artery disease in women.

Stress testing, likewise, was originally developed mostly based upon experiences in men. The differences between the genders in presentation, disease prevalence, and pathophysiological mechanisms for chest discomfort contribute to the substantial differences between the genders in the sensitivity and specificity of exercise testing for hemodynamically significant coronary artery disease. In the Coronary Artery Surgery Study, there was a 12% false-positive rate for men, but a 54% false-positive rate for women. The sensitivity was 57% in women, but 72% in men.³⁵ While cardiac perfusion imaging with stress testing improves the sensitivity and specificity greatly in women,^36-40 photon attenuation by breast tissue in women poses a greater confounding problem in interpretation of the images than in men.

Using coronary arteriography and coronary revascularization procedures as the reference points, women are less aggressively managed for diagnosis and treatment of atherosclerotic coronary artery disease than are men.⁴¹ The lack of awareness of coronary artery disease in women, the lower prevalence and generally lesser severity of coronary atherosclerosis in women than in men, the differences in presentation with chest pain, and the problems with stress testing noted above probably all contribute to the less aggressive approach in women. Other factors influencing the different approaches for women versus men may include: 1) women are nearly a decade older than their male counterparts on average (although this is not true for women with diabetes); 2) the women (in substantial part because of the toll of diabetes) are sicker overall; and 3) cardiac revascularization procedures have greater risks for women than for men (see below).

With a few exceptions, women with diabetes and coronary atherosclerosis should receive antianginal therapy and revascularization procedures similar to those performed for men and women without diabetes. Traditional pharmacological therapy of aspirin, organic nitrates, beta-adrenergic blockers, calcium-channel blockers, and other agents to control hypertension should be employed as they would be in patients without diabetes, with two exceptions. The first is the realization that beta-adrenergic-blocking therapy may slightly complicate management of hyperglycemia and mask the symptoms of hypoglycemia. Nevertheless, because beta-adrenergic blockers are so vital to the pharmacological therapy of chronic myocardial ischemia, the majority of women with diabetes should receive beta-blocker therapy with close attention to these two possible adverse effects. The second exception is the realization that organic nitrate therapy may be more difficult in diabetic women with atherosclerotic coronary artery disease and a diabetic dysautonomia (see below) and postural hypotension.

In establishing the risk-to-benefit ratio of revascularization procedures (angioplasty and coronary artery bypass graft surgery) for women with diabetes, we must take into account that both procedures pose a greater risk for women than for men.^42-45 The benefits for women, however, appear to be similar to those afforded to men.

Coronary artery bypass graft surgery has consistently been found to be approximately twice as risky in women than in men in regards to operative mortality. Many surgeons believe that the smaller body size, smaller hearts, and smaller coronary arteries of women compared with men account for much of the greater risk of bypass graft surgery in women. Bypass graft surgery is more difficult and is more likely to be associated with graft closure for smaller bypassed vessels. Also, women who undergo bypass graft surgery tend to be several years older than men who have the procedure and to have a higher prevalence of diabetes than such men. The presence of diabetes slightly increases the operative mortality and morbidity, as it does with any major surgery. Nevertheless, when the risk-to-benefit ratio appears to be favorable, bypass surgery when indicated should be offered as readily to women with diabetes as it would be to patients without diabetes.

It must also be recognized that the risk-to-benefit ratio for coronary angioplasty procedures in women with diabetes women is not the same as for nondiabetic men.^46-53 As with bypass graft surgery, women coming to coronary angioplasty procedures tend to be older and to have a greater frequency of diabetes than men. In general, the in-hospital mortality rate for angioplasty has been reported to be at least twice as high for women as for men. Women also have been found to have more angina pectoris in the long-term follow-up period than do men.

As with bypass graft surgery, it is believed that the smaller coronary and peripheral arteries of women, the greater technical difficulties associated with angioplasty, and the greater likelihood of restenosis or closure of the vessel in question account for much of the difference between men and women undergoing coronary angioplasty procedures.

Patients with diabetes undergoing coronary angioplasty procedures for a single coronary artery have similar benefits to patients without diabetes, but this is not the case for multivessel coronary angioplasty procedures. The recently completed large BARI (Bypass Angioplasty Revasculari-zation Investigation) study confirmed observations of several earlier studies in their comparison of bypass graft surgery with angioplasty procedures for patients with multiple hemodynamically significant coronary sten-oses. The data showed a remarkable difference favoring bypass graft surgery over angioplasty, and a clinical alert was sent out.⁵⁴ Therefore, women with diabetes and multiple flow-limiting coronary stenoses who have indications for coronary revascularization should generally be treated with bypass graft surgery rather than with coronary angioplasty.

Diabetic women with a single flow-limiting coronary artery stenosis who have indications for a revascularization procedure and for whom the risk-to-benefit ratio is good can be referred to coronary angioplasty procedures with confidence.

Vasoconstrictive components to chronic myocardial ischemia. There may be an abnormal vasoconstrictive contribution to the pathophysiology of chronic myocardial ischemia in some patients. This phenomenon has sometimes been termed "mixed angina pectoris." This abnormal coronary vasoconstriction, which is often seen at the level of the epicardial vessels and the large intramyocardial vessels, is due to endothelial dysfunction as a result of the arteriosclerotic process and is often thought to be an important component of diurnal shifts in ischemic threshold, angina with emotional upsets, and angina upon exposure to the cold.

The pathophysiology of Prinz-metal's variant angina, noted above, is thought to be severe, occlusive epicardial vasospasm, usually at the site of an atherosclerotic plaque. It is that phenomenon in which a patient has brief but severe angina pectoris at rest or minimal activity and has associated transient ST-segment elevation on the electrocardiogram.

As noted above, epicardial vasoconstriction is more common in women than in men. In mixed angina pectoris or Prinzmetal's angina in women with diabetes, the treatment regimen should emphasize organic nitrates and calcium-channel blockers. Because beta-blockers and central and peripheral sympatholytic agents may worsen vasoconstrictive angina, these agents should be de-emphasized or avoided when possible in the treatment regimen for women with diabetes.

Silent Myocardial Ischemia
Occasionally chronic myocardial ischemia is not associated with any discomfort. This has been termed "silent myocardial ischemia." Often, patients with typical angina have some episodes of painful ischemia and some episodes of painless ischemia. In a few patients, silent painless ischemia predominates. Because of the frequency of diabetic dysautonomia, it is widely held that silent ischemia (and also silent MIs) are more common in people with diabetes than in those without, but this has never been definitively proved. Nevertheless, it is prudent in caring for women with diabetes to keep in mind the possibility of silent ischemia. When silent myocardial ischemia is documented, it should be treated similarly to myocardial ischemia associated with angina pectoris.

Syndromes of Acute Myocardial Ischemia
The underlying pathophysiology of syndromes of acute myocardial ischemia (acute MI and unstable angina) is the sudden total or near-total occlusion of a coronary artery. In more than 90% of cases, this is the result of the deterioration of an atherosclerotic plaque with marked plaque ulceration, fissuring, hemorrhage, or rupture. It is also associated with retraction of the fibrous cap over the atherosclerotic plaque and retraction of the normal endothelial cell lining of the artery in the region of the deteriorating plaque. Furthermore, the endothelial cells in the vicinity of the deteriorating plaque become dysfunctional, promoting paradoxical vasoconstriction and perhaps becoming coagulant neutral or procoagulant instead of their normal anticoagulant state. The deteriorating plaque is associated with varying degrees of platelet plugging, thrombosis, and abnormal vasoconstriction. Platelet adhesion and aggregation is enhanced in the diabetic state and thus may enhance this process. Transient limitations in coronary blood flow result. This process may wax and wane for hours, days, or even weeks, and accounts for the development of MI following the syndrome of unstable angina in many patients.

The eventual outcome of this process determines the clinical syndrome: unstable angina, non-Q-wave (subendocardial) MI, or Q-wave (transmural) MI. If the process is kept in check by the normal governing processes of thrombosis and thrombolysis, and if total or near-total occlusion of the involved coronary artery does not occur or is very brief, the unstable plaque may heal and the patient will escape with only unstable angina pectoris. If the artery becomes totally or nearly totally occluded long enough to cause myocardial necrosis, but the time of occlusion is relatively short or if some flow persists, the patient may sustain a non-Q-wave MI. If occlusion is total and persistent, a Q-wave infarction is apt to occur. Occasionally, coronary spasm, occurring either spontaneously (Prinz-metal's angina) or as a result of drugs (especially cocaine) is the principal underlying physiological problem, whether in the presence or absence of atherosclerotic coronary heart disease.

The syndromes of acute myocardial ischemia are more common in patients with diabetes than in those without.^55,56 People with diabetes have a worse short- and long-term prognosis than do people without diabetes. The incidence of mortality and complications such as congestive heart failure, cardiogenic shock, arrhythmias, myocardial rupture, and recurrent infarction are elevated in those with diabetes versus those without. Overall, the mortality and complication rates in people with diabetes are approximately 1.5 to 2 times higher than those in people without diabetes.^56-65

Some of the elevated mortality and complication rates in people with diabetes reflects the high number of women in the diabetes group. Women, compared with men, have poorer mortality and complication outlooks.^66-70 For example, in the huge megatrials of thrombolytic therapy versus placebo, the nearly 2,000 women in the control group of the International Study of Infarct Survival-2 (ISIS-2) trial had a mortality of 17.5% compared with 12.0% for men.⁶⁶ In the Gruppo Italiano per Lo Studio Della Stretochinasi Nell'Infarto Miocardio (GISSI-I) trial, the group of more than 1,000 women had a mortality rate of 22.6% compared to 10.6% for men.⁶⁷ Older age and a greater number of women with diabetes than men with diabetes accounts for some, but not all, of the greater mortality risk.

Clinical trial data with interventions have consistently found that the highest-risk subgroups in their populations have the greatest absolute benefit. As noted above, women with atherosclerotic heart disease, including those with syndromes of acute ischemia, tend to be treated less aggressively than are men with pharmacological therapy and revascularization procedures. Yet ample clinical trial data suggest that the benefits of interventions are equally helpful in women as in men.

Randomized, prospective clinical trials of aspirin, anticoagulant, beta-adrenergic blocker, thrombolytic, and ACE-inhibitor therapies have all been found to be beneficial interventions following MI in well-selected patients. The protective benefits in women from all of these pharmacological interventions are no less than the benefits found in men. In the ISIS-2 trial, vascular death in women was reduced by aspirin therapy versus placebo from 15.8 to 13.2% compared to a reduction in men from 10.6 to 8.2%.⁶⁶ In the Bronx Municipal Hospital Study of anticoagulants versus placebo after MI, death in women was reduced from 31 to 14.9% compared to a reduction from 11.0 to 10.3% in men.⁷¹ Esymann and Douglas re-viewed clinical trials of thrombolytic therapy versus placebo in women compared with men.⁷² Overall, more than 7,000 women were included in these trials, and the benefits of thrombolysis in women were no less than the benefits in men. Beta-blocker therapy in women is of equal or even greater benefit than in men.^73-75 The huge GISSI-3 trial found equivalent beneficial effects of ACE-inhibitor therapy in women as in men.⁷⁶

Syndromes of acute myocardial ischemia often destabilize glucose control in patients with diabetes.⁷⁷ There is evidence that people with diabetes who have better glucose control have better outcomes after syndromes of acute myocardial ischemia than do patients with poor glucose control.

Clinicians should treat women with diabetes similarly to nondiabetic men, including being as aggressive with interventions as they would be with nondiabetic men, with just a few cautions. Because women with diabetes constitute a high-risk group after syndromes of acute myocardial ischemia, one can expect to have more absolute benefit with useful interventions than in a lower-risk group. As is the case in the treatment of chronic myocardial ischemia (see above), an occasional patient may be a less-than-ideal candidate for organic nitrate therapy because of postural hypotension. An occasional patient may not be able to tolerate a beta-blocker, but this reservation should not be exaggerated.

Women with diabetes appear to be as protected after MI by coronary revascularization procedures as are women without diabetes.⁷⁹ The risk-to-benefit ratio for revascularization procedures must be calculated given the higher risks associated with these procedures in women, as discussed above. Coronary arteriography can usually be carried out with an acceptably low risk in women with diabetes, but those patients with renal failure have a higher risk of postcatheterization worsening of their renal disease and should be managed accordingly.

CONGESTIVE HEART FAILURE AND DIABETIC CARDIOMYOPATHIES
The Framingham Study found that the risk of developing heart failure is greatly increased in people with diabetes compared with those without diabetes, even after excluding atherosclerotic coronary heart disease and rheumatic heart disease from the analysis and even after correcting for age, blood pressure, body weight, and cholesterol.⁷⁷ The risk for heart failure in women with diabetes in this study was approximately twice as high as it was for men and 4-5 times as high as in a nondiabetic population.⁷³

Many patients with diabetes have heart failure because of atherosclerotic coronary artery disease, myocardial ischemia, and MIs. It is likely that atherosclerotic coronary artery disease accounts for a substantial portion of the heart failure seen in people with diabetes. Some experts believe that coronary artery disease accounts for virtually all heart failure in people with diabetes.⁸⁰ Nevertheless, the clinical evidence cited above and considerable pathological and experimental data, while sometimes complex and controversial, are generally supportive of the existence of a diabetic cardiomyopathy or, more likely, cardiomyopathies.

A cardiomyopathy as the result of hypertension is well known. The addition of diabetes to hypertension has been reported to accelerate and augment this process, causing what has been termed a "diabetic-hypertensive cardiomyopathy."³¹ A similar interaction, which closely parallels the clinical phenomenon, has been described in diabetic rats.^82-84

It has been proposed that the microvascular process similar to that causing retinal and kidney disease in people with diabetes may also occur in the heart and cause a cardiomyopathy, but this proposal remains controversial and uncertain.^85-89

Uncontrolled diabetes may directly affect myocardial biochemistry. A number of biochemical abnormalities have been reported, including shifts in cardiac myosin ATPase from a faster to a slower form,⁹⁰ reduction in calcium binding of isolated sarcoplasmic reticulum,⁹¹ and abnormalities of Ca²⁺-ATPase and Na⁺, K⁺-ATPase.^92-93

Interstitial infiltration of the heart with periodic acid-Schiff-positive material, fibrous tissue, glycoproteins, triglycerides, and cholesterol has been reported, raising the possibility of another mechanism for a diabetic cardiomyopathy, especially in patients with chronically poor glucose control.⁹⁴

A cardiomyopathy in infants born to mothers with diabetes has been reported. It is characterized by cardiomegaly or heart failure or both. Echocardiographic observations consistent with both dilated cardiomyopathy and hypertrophic cardiomyopathy with or without obstruction have been seen. These changes often resolve within 72 hours of birth.^95-96

Occasionally, the dysautonomia (see below) sometimes observed in people with diabetes can contribute to a cardiomyopathic presentation.

The hemodynamic changes ob-served in people with diabetes and cardiomyopathy have been reported in a number of clinical and experimental animal studies. In humans, there are extensive noninvasive and cardiac catheterization laboratory data. These data have been reviewed by Fleischer, Fein, and Sormenblick.⁹⁷ The findings from these studies are consistent with cardiomyopathic disorders characterized by either a disorder principally of ventricular filling (diastolic dysfunction) or a disorder of both ventricular contraction and filling (systolic and diastolic dysfunction). Either disorder can lead to signs and symptoms of congestive heart failure.

The burden of congestive heart failure for women with diabetes is enormous, and the potential rewards for good management are equally enormous. To prevent or mitigate congestive heart failure, the management of women with diabetes requires risk-factor testing and modification to limit atherosclerotic coronary artery disease with careful control of hypertension, excellent glucose regulation, and careful treatment of atherosclerotic coronary artery disease to minimize ischemia and limit the extent of MIs. Treatment of hypertension and congestive heart failure should include ACE-inhibitor therapy when feasible because of its potential triple benefit for hypertension, heart failure, and diabetic kidney disease.

DIABETIC DYSAUTONOMIA
Dysautonomias are observed in people with diabetes much more frequently than in those without diabetes. Defects in both parasympathetic and sympathetic function have been identified. The defects in parasympathetic innervation tend to occur more frequently and earlier than do defects in sympathetic innervation. Defects in parasympathetic innervation are characterized by increased resting heart rate and decreased heart rate variability with respiration. Defects in sympathetic innervation are characterized by inadequate heart-rate response to physiological stimuli.

A higher-than-expected incidence of QT-interval prolongation in people with diabetes may be due to autonomic nervous system imbalance and may predispose such patients to a higher risk for ventricular arrhythmias.^95-103 Postural hypotension, reflecting the effects of dysautonomia on the heart and peripheral vessels, is also more frequent in people with diabetes than in those without, especially those who require prolonged bed rest or treatment with antihypertensive agents, diuretics, and organic nitrates. The development of renal failure in a patient with diabetes may further worsen the dysautonomia.

While it is attractive to postulate an important role for diabetic dysautonomias in silent myocardial ischemia and silent MIs, the evidence currently available to support such a hypothesis is insufficient.

It is not clear whether strict glucose control will prevent the development of diabetic dysautonomias. The treatment of women with diabetes who have diabetic dysautonomia is currently similar to the treatment of dysautonomias in general.

References

¹Reis SE, Zell KA, Holubkov R: Women's hearts are different. Curr Prob Obstet Gynecol and Fertil 1997. In press

²Garcia MJ, McNamara PM, Gordon T, Kannell WB: Sixteen year follow-up study: morbidity and mortality in diabetics in the Framingham population. Diabetes 23:105-11, 1976.

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Thomas C. Smitherman, MD, is a professor of medicine and medical director of the Cardiac Care and Intervention Unit and the Cardiac Pavilion at the University of Pittsburgh Medical Center. Steven E. Reis, MD, is an assistant professor of medicine and associate medical director of the Cardiac Intensive Care and Intervention Unit and the Cardiac Pavilion and medical director of the Ladies Hospital Aid Society Women's Heart Center at the University of Pittsburgh Medical Center in Pittsburgh, Pa.

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