Cardiovascular Disease in Women Part 2

Clinical Manifestations

Whereas MI and sudden cardiac death are the more common presentations in men with CAD, angina pectoris is the main initial and subsequent presenting symptom of CAD in women.

Compared with men, women with angina are more likely to be older and to have hypertension, diabetes, and heart failure. They are less likely than men to have a history of either MI or percutaneous coronary intervention.57-59

When women present with symptoms of CAD, they are less likely to have typical or classic symptoms of heart disease and more likely to have atypical symptoms, particularly abdominal, neck, and shoulder pain. Older and diabetic women have a higher frequency of dyspnea and fatigue. Other ischemic symptoms in women are sleep disturbance, indigestion, and anxiety.

Laboratory Testing

Because women at all ages are less likely to have obstructive CAD, the pretest probability of CAD is lower in women with chest pain presenting for a diagnostic evaluation. Therefore, false positive results with exercise ECGs are more common in women than in men60-62; this also means that a negative result on exercise ECG in a woman has high predictive accuracy for the absence of clinically significant CAD.

Table 3 Major Risk Factor Interventions for Cardiovascular Disease in Women⁴²

Intervention	Comment (Evidence Rating)
Blood pressure normalization	Lifestyle: encourage optimal BP of < 120/80 mm Hg (class I, level B) Drugs: treat when BP a 140/90 mm Hg, or lower in patients with target-organ damage or diabetes; thi-azide diuretics should be part of initial regimen in most patients unless contraindicated (class I, level A)
Lipid normalization—nonpharmacologic	Encourage lifestyle approaches to maintain optimal levels: LDL < 100 mg/dl, HDL > 50 mg/dl, triglycerides < 150 mg/dl, non-HDL cholesterol < 130 mg/dl (class I, level B) Diet: in woman at high risk or with elevated LDL, reduce saturated fat intake to < 7% of calories, cholesterol to < 200 mg/day; reduce trans-fatty acid intake (class I, level B)
Lipid normalization—pharmacologic	High-risk patients: LDL-lowering therapy—preferably a statin—plus lifestyle therapy in women with LDL a 100 mg/dl (class I, level A); statin therapy in women with LDL < 100 mg/dl, unless contraindi-cated (class I, level B); niacin or fibrate therapy for women with low HDL or elevated non-HDL (class I, level B)
	Intermediate-risk patients : LDL-lowering therapy (preferably a statin) if LDL a 130 mg/dl despite lifestyle therapy (class I, level A); niacin or fibrate therapy for women with low HDL or elevated non-HDL after LDL goal reached (class IIa, level B)
	Low-risk patients: consider LDL-lowering therapy in women with one or no risk factors when LDL a 190 mg/dl or in women with multiple risk factors when LDL a 160 mg/dl (class IIa, level B); consider niacin or fibrate therapy in women with low HDL or elevated non-HDL after LDL goal reached (class IIa, level B)
Diabetes treatment	Use lifestyle and pharmacotherapy to achieve glycosylated hemoglobin < 7% (class I, level B)

BP—blood pressure

HDL—high-density lipoprotein cholesterol

LDL—low-density lipoprotein cholesterol

Table 4 Preventive Drug Interventions for Cardiovascular Disease in Women⁴²

Drug	Comment (Evidence Rating)
Aspirin	High-risk patients: 75-162 mg/day, unless contraindicated; clopidogrel in aspirin-intolerant patients (class I, level A)
	Intermediate-risk patients: consider 75-162 mg/day, if blood pressure is controlled and benefit is likely to outweigh risk of GI side effects (class IIa, level B)
	Low-risk patients: Routine aspirin use not recommended (class III, level B)
	Patients with chronic or paroxysmal atrial fibrillation: 325 mg/day, for stroke prevention when warfarin is contraindicated or stroke risk is low (< 1%/yr) (class I, level A)
Beta blockers	Unless contraindicated, should be used indefinitely in all women who have had an MI or who have ischemic syndromes (class I, level A)
ACE inhibitors	Unless contraindicated, should be used in women at high risk (class I, level A)
ARBs	In high-risk women with clinical evidence of heart failure or an LVEF < 40% who are intolerant to ACE inhibitors (class I, level B)
Warfarin	Treatment to INR of 2.0-3.0; for stroke prevention in women with chronic or paroxysmal atrial fibrillation, unless they are considered at low risk for stroke (< 1%/yr) or at high risk for bleeding (class I, level A)

ACE—angiotensin-converting enzyme

ARBs—angiotensin receptor blockers

GI—gastrointestinal

INR—international normalized ratio

LVEF—left ventricular ejection fraction

MI—myocardial infarction

The use of exercise echocardiography and single-photon emission computed tomography (SPECT) imaging has been promoted in women, but data on the utility of these tests in this setting are limited. In a cross-sectional study of the accuracy of exercise SPECT imaging with thallium-201, the sensitivity of exercise thallium SPECT imaging was lower in women than in men. Specificities were similar in men and women. A systematic review of SPECT versus exercise echocardiography showed that although the sensitivity of exercise SPECT was high (87%), its specificity was low (64%), resulting in a low likelihood ratio (1.9) for both men and women.63

Myocardial perfusion imaging improves the diagnostic accuracy of exercise testing; technetium-99m sestamibi SPECT imaging offers particular benefit. Stress echocardiography in women with adequate echocardiographic images displays sensitivity and specificity comparable to those in men. The most cost-effective diagnostic strategy is a sequential approach to testing tailored to patient risk and symptoms.

The most cost-effective diagnostic strategy is a sequential approach to exercise testing that is tailored to the patient’s coronary risk factors and symptoms. According to the ACC/AHA practice guidelines for exercise testing, a woman’s pretest likelihood for CAD may be crudely defined on the basis of age and the presence and characteristics of symptoms [see Table 5]; testing has the largest potential effect on diagnostic outcome in women at intermediate risk.64 In addition, symptomatic women who have diabetes mellitus or multiple risk factors (i.e., the metabolic syndrome) are at increased risk for CAD and should be considered for testing.

Acute Coronary Syndromes

Although women with acute coronary syndromes (i.e., unstable angina, non-ST segment elevation MI, and ST elevation MI) are more likely to present with nausea and vomiting and indigestion than men, typical symptoms are the strongest predictors of acute coronary syndromes in women [see I:X Unstable Angina and Non-ST Segment Elevation Myocardial Infarction]. In the Myocardial Infarction Triage and Intervention Registry, the clinical presentation of MI was indistinguishable by sex, with comparable numbers of women and men having typical and atypical pain presentations.65 However, in the Worcester Heart Study, more women than men had a history of angina pectoris before their initial MI.66-70 In addition, women with acute coronary syndromes are more likely to have a higher Killip class, tachycardia, atrioventricular block, and pulmonary rales on presentation; complications such as shock, heart failure, recurrent chest pain, cardiac rupture, and stroke are more common in women.

Time to presentation may differ between men and women. In the first Global Utilization of Streptokinase and Tissue Plas-minogen Activator for Occluded Arteries (GUSTO-I) trial, median time from onset of chest pain to admission was longer for women than for men.71 Initial studies suggested that women were more likely to have unstable angina than to have documented acute MI.72,73 Women with MI are less likely than men to have ST segment elevation MI. Compared with men with MI, women with MI tend to be older; are more likely to have diabetes and hypertension and to have had heart failure; and are less likely to have had an MI.

Treatment

There is currently no evidence that acute coronary syndromes should be treated differently in women than in men, and current therapeutic guidelines do not make recommendations based on gender. A number of randomized, controlled clinical trials of MI therapies—including antiplatelet drugs, beta blockers, calcium channel blockers, fibrinolytic drugs, and ACE inhibitors—confirm comparable reductions in mortality for women and men. Unfortunately, the use of these therapies after acute coronary syndromes is less common in women than in men. For example, in the GUSTO-I study, median time from onset of chest pain to thrombolysis was longer for women than for men. In addition, women are less likely than men to be treated aggressively. They are half as likely to be considered for acute catheterization, angioplasty, thrombolysis, or coronary artery bypass grafting.71 Women are also less likely to be referred for cardiac rehabilitation after a cardiovascular event. The inequitable application of treatment guidelines may result in poorer outcomes for women.

Table 5 Pretest Probability of Coronary Artery Disease in Women⁶⁴

Age	Typical or Definite Angina Pectoris	Atypical or Probable Angina Pectoris	Nonanginal Chest Pain	Asymptomatic
30-39	Intermediate	Very low	Very low	Very low
40-49	Intermediate	Low	Very low	Very low
50-59	Intermediate	Intermediate	Low	Very low
60-69	High	Intermediate	Intermediate	Low
a 70	High	Intermediate	Intermediate	Low

Prognosis

Women with ST segment elevation MI have a higher mortality than men of the same age, whereas women with non-ST segment elevation MI have outcomes similar to those of men. Some of the differences in outcome may be explained by differences in disease burden or severity of MI on presentation.

In the second National Registry of Myocardial Infarction (NRMI-2), younger women with MI (< 70 years) had higher death rates during hospitalization than their male counter-parts.13 Only at older age was there gender parity, and in the very oldest age group (over 80 years), women had better outcomes. Whether these mortality differences reflect the contribution of gender per se or of residual confounders and treatment differences remains to be determined.13,74-77 Certainly, increasing the use of proven standard therapies offers significant potential to improve clinical outcomes and increase survival in women with suspected acute MI.

Race also affects prognosis: African-American women have a higher mortality from CAD than white women. In the United States, the age-adjusted CAD mortality is 25% to 50% higher for African-American women than for white women; in particular, the mortality from MI is twice as high in African-American women.78

Heart Failure in Women

Epidemiology

Each year, more than one million women have heart failure in the United States and approximately 100,000 die of this disease. Men and women differ with respect to the risk, causes, and prognosis of heart failure.79-81 The majority of deaths attributable to heart failure occur in women, even though women with heart failure have a lower risk of death than men.82

Risk factors

Risk factors for development of heart failure differ by sex. Hypertension and diabetes mellitus have a greater role in women, with diabetes disproportionately increasing the risk of heart failure in women.5,83-86 Women may also be more likely to develop heart failure after MI.84 An excess number of cases of heart failure and pulmonary edema in women after revascularization was reported both in the Coronary Artery Surgery Study (CASS) and in the Bypass Angioplasty Revascularization Investigation (BARI), despite left ventricular ejection fractions (LVEFs) that were equivalent to those or better than those in men.87,88

Pathophysiology

Although chronic heart failure from left ventricular systolic impairment is well characterized, less is known regarding heart failure with preserved left ventricular systolic function. From 30% to 50% of all patients with chronic heart failure have preserved left ventricular systolic function, and most of these patients are women, are elderly, and have hypertension. Patients with chronic heart failure and preserved left ventricular systolic function appear to have pathophysiologic derangements that are similar to, but less severe than, those with impaired systolic function.89-92

Diagnosis

Irrespective of gender, heart failure has a wide spectrum of potential clinical presentations. The majority of patients have signs and symptoms of pulmonary congestion, including dyspnea, or-thopnea, and paroxysmal nocturnal dyspnea. Others do not have congestive symptoms but instead have manifestations of low cardiac output, including fatigue, effort intolerance, cachexia, and renal hypoperfusion. Clinically, the New York Heart Association (NYHA) functional classification can be utilized to assess the severity of functional limitations and correlates well with prognosis in both men and women [see Table 6]. In addition, the ACC/AHA have issued guidelines to promote earlier identification of heart failure in patients at risk [see I:II Heart Failure].

Clinical Manifestations

Women with heart failure have more symptoms than men with similar LVEFs, are older, and are more likely to have hypertension, diabetes mellitus, and preserved systolic function.79 Patients with heart failure and intact ventricular systolic function, predominantly women, experience dyspnea and fatigue, exercise intolerance, and resultant impaired life quality.

Laboratory Testing

In general, the evaluation of new-onset heart failure in women is similar to that in men [see 1:IIHeart Failure].

Treatment

Pharmacologic Therapy

Although a significant body of evidence supports the use of angiotensin-converting enzyme (ACE) inhibitors, diuretics, and beta blockers in patients with reduced systolic function, few women were included in these studies, and data regarding the benefits of these therapies in women remain conflicting.

ACE inhibitors Afterload reduction and neurohormonal modulation with ACE inhibitors lower mortality; improve heart failure symptoms, exercise tolerance, and LVEF; and reduce emergency room visits and hospitalizations. In a meta-analysis of gender-stratified data for all seven major studies that assessed the impact of ACE inhibitors on mortality, however, the authors conclude that women with symptomatic left ventricular systolic dysfunction probably benefit from ACE inhibitors but that treatment with ACE inhibitors may not reduce mortality in women with asymptomatic left ventricular systolic dysfunction (pooled relative risk, 0.96; 95% confidence interval [CI], 0.75 to 1.22) [see Figure 2].93

Table 6 New York Heart Association Classification of Heart Failure

NYHA Class	Comment (Evidence Rating)
I	No symptom limitation with ordinary physical activity
II	Ordinary physical activity somewhat limited by dyspnea (e.g., long-distance walking, climbing two flights of stairs)
III	Exercise limited by dyspnea at mild work loads (e.g., short-distance walking, climbing one flight of stairs)
IV	Dyspnea at rest or with very little exertion

Angiotensin receptor blockers Gender-specific analyses of angiotensin receptor blockers (ARBs) in heart failure have not been performed. In clinical trials, ARBs were superior to placebo but not better than ACE inhibitors in improving mortality. ARBs improve morbidity when given along with ACE inhibitors; they are recommended as second-line therapy in patients who cannot tolerant ACE inhibitors because of cough or angioedema.94 They should not be substituted for ACE inhibitors in cases of hy-perkalemia or renal dysfunction. ARBs may be useful for the treatment of diastolic heart failure.

Beta blockers Three beta blockers—carvedilol, metoprolol succinate, and bisoprolol—have been shown to increase survival in patients with heart failure.95-99 Metoprolol tartrate has not been approved by the Food and Drug Administration for heart failure and was less effective than carvedilol in preventing sudden death in the Carvedilol Or Metoprolol European Trial.100

Although the addition of beta blockers to a treatment regimen of diuretics, ACE inhibitors, and digoxin has been recommended to improve clinical outcomes and decrease mortality and hospi-talizations, questions have arisen regarding the benefit in women. However, a meta-analysis of the five major mortality studies of beta-blocker treatment in heart failure showed lower mortality in women (risk ratio in women, 0.63 [95% CI, 0.44 to 0.91]; risk ratio in men, 0.66 [95% CI, 0.59 to 0.75]; HR in women, 0.75 [95% CI, 0.51 to 1.09]; and HR in men, 0.68 [95% CI, 0.51 to 0.89].93

Despite gender-related differences in outcomes, current guidelines from the Heart Failure Society of America (HFSA) and the ACC/AHA recommend the use of beta blockers for NYHA classes I through III heart failure, irrespective of gender. Beta blockers are also indicated in NYHA class IV patients who are euvolemic—again, irrespective of gender.

Digoxin HFSA and ACC/AHA guidelines recommend digoxin for patients with left ventricular systolic dysfunction who remain symptomatic despite standard medical therapy, particularly if they are in atrial fibrillation. No distinctions are made for gender. Significant gender differences have been reported in response to digoxin for the management of heart failure, however. In the 6,800-patient Digitalis Investigation Group study, for example, women who were randomized to digoxin had a higher rate of death (33.1%) than women who were randomized to placebo (28.9%). In contrast, men who received digoxin or placebo had similar death rates. In the multivariable analysis, digoxin was associated with significantly higher risk of mortality in women (HR, 1.23; 95% CI, 1.02 to 1.47), but it had no significant effect on mortality in men (P = 0.014; HR, 0.93; 95% CI, 0.85 to 1.02).101 This study suggests that digoxin therapy is associated with an increased risk of death from any cause in women with heart failure and depressed left ventricular systolic function.

Diuretics and aldosterone antagonists Diuretics and aldo-sterone antagonists (e.g., spironolactone) in the treatment of heart failure are used similarly in men and women [see 1:II Heart Failure].

Heart Failure with Preserved Ventricular Systolic Function

Most large clinical trials of heart failure management strategies have involved patients with a decreased LVEF. Older patients with heart failure, among whom women predominate, are more likely to have preserved ventricular systolic function, a problem not addressed in these major treatment trials.11,102-104 The few heart failure trials in patients with preserved ventricular systolic function have failed to produce conclusive evidence for optimal pharmacologic management. Because no clinical trial evidence is consistent, the ACC/AHA guidelines recommend a pathophysiologic approach to treatment that consists of measures to control blood pressure and tachycardia, to decrease cen-tral blood volume, and to alleviate myocardial ischemia.

Figure 2 Efficacy of angiotensin-converting enzyme inhibitors in the management of left ventricular systolic dysfunction according to sex.

Prognosis

Research on gender and heart failure prognosis has shown inconsistent results.105-109 Epidemiologic data from the Framingham cohort suggest that the prognosis in women is better than that in men.83 In contrast, Bourassa and colleagues demonstrated a poor prognosis in older women with heart failure.82

Differences in survival may reflect differences in etiology.105,110 An Italian study found that women were more likely than men to have a nonischemic cause of their heart failure, and LVEF was higher in nonischemic women than nonischemic men; the survival advantage in women was in part attributed to better left ventricular function and in part to the primary etiology of heart failure.111 In a United States study, survival was significantly better in women than in men when heart failure was from nonis-chemic causes; but when the principal etiology was ischemic heart disease, men and women had similar survival rates.105

Pathophysiology also affects prognosis in heart failure. Although mortality is significantly greater in patients with chronic heart failure who have impaired left ventricular systolic function than in those with preserved systolic function, even patients with preserved systolic function—most of whom are women— have a 25% 5-year mortality.