A 31-year-old woman was admitted in a state of cardiogenic shock 6 months after she was diagnosed with nonischemic cardiomyopathy. Nearly 9 to 12 months ago, she had started experiencing fatigue and dyspnea while climbing stairs and was diagnosed with left ventricular systolic dysfunction a few months later. She had ejection fraction of 15% and dilated left ventricle of 6.8 cm and was started on medicines and evidence-based treatment. More recently, she developed intolerance toward her current carvedilol dose that had to be reduced as it caused hypotension and nausea. Currently, the patient was admitted with blood pressure of 88/62 mm Hg, heart rate of 105 beats per minute, S3 gallop on examination, elevated jugular venous distention to 6 cm above the clavicle, cool extremities, brain natriuretic peptide of 953 pg/mL, serum sodium of 134 mmol/L, and total bilirubin of 4 mg/dL. The physician started her on an inotrope upon admission. After diuresis, her right heart catheterization revealed elevated filling pressures (right atrial pressure of 15 mm Hg, wedge pressure of 36 mm Hg), pulmonary hypertension (mean pulmonary artery pressure of 49 mm Hg), and low cardiac index <1.8 on dobutamine 5 μg/kg/min. Echo now revealed progression of left ventricular dilation to 7.2 cm, moderate mitral regurgitation, and moderate right ventricular dysfunction in addition to left-sided failure. Due to advanced stage of the disease and clinical decline in patient’s condition, she was worked up for cardiac transplantation and listed with blood type O. Meanwhile, she continued to decline requiring 2 inotropes, and a repeat hemodynamic evaluation showed a high pulmonary vascular resistance of 4.5 Wood units. Her chances of receiving a cardiac transplant were also limited by both her blood type (type O) and worsening pulmonary hypertension. Besides, she could not tolerate attempts to wean her off the inotrope or pressor support, and continued to become more tachycardic. So a decision was made to implant ventricular assist device that would act as a bridge to cardiac transplantation by extending the life of the patient.
Heart failure is a complex clinical syndrome with increasing prevalence and incidence in developed and developing nations. Among adults in the United States, heart failure is now the leading etiology for inpatient admissions. Women represent half of these hospital admissions and heart failure accounts for approximately one-third of all deaths from cardiovascular disease in women.1,2,3 Although women bear a significant burden of heart failure mortality and morbidity, they are historically very poorly represented in clinical trials: prior to 2002, only one-fifth of patients enrolled in randomized controlled trials were women.4 Therefore a paucity of evidence exists regarding gender-specific differences in the diagnosis, treatment, and prognosis of heart failure.
Recent analysis revealed differential autosomal gene expression in men versus women with heart failure.5,6,7 Women overexpressed genes related to adrenergic and angiotensin signaling, cyclic nucleotide metabolism, and glucose transport (GATAD1, PDE6B, and SCLA12, respectively). Those genes upregulated in men with heart failure were associated with potassium channel/arrhythmia regulation, cellular homeostasis, and immune system regulation (KCNK1, PLEKHA8, and CD24, respectively). These initial genetic studies may provide an early foundation to explain the gender differences noted in etiology (eg, ischemic vs nonischemic secondary to hypertensive heart disease), presentation (eg, with age differences), clinical course, and response to treatment in heart failure—or personalized medicine based on sex-related heart failure management.
The prevalence of heart failure increases in both men and women as the population ages. However, the initial diagnosis of heart failure occurs later in women, and more women than men have heart failure after the age of 80.8 The most recent population data from the last decade reveal an incidence of 550,000 cases per year and approximately equal numbers of men and women with heart failure, overall affecting 3.1 million males and 2.6 million females.2 Women and men are admitted for inpatient care for acute exacerbations of heart failure at an almost equal rate, but women appear to have improved overall survival compared to men. One exception to the survival advantage in women versus men appears to lie in the specific subpopulation of patients with depressed left ventricular systolic function in the setting of coronary heart disease and ischemic cardiomyopathy; the Beta-Blocker Evaluation of Survival Trial (BEST) study suggested that survival is better for women with a nonischemic etiology versus those with ischemic etiology.9,10 In addition, in both the acute and chronic settings, women present more often with heart failure with preserved ejection fraction (HFPEF, defined as ejection fraction ≥50%) and often in the setting of multiple chronic medical conditions such as obesity, diabetes mellitus, sleep apnea, and hypertension.11,12 This increased incidence of HFPEF in women compared to men may at least partially account for the survival advantage in women due to the higher systolic ejection fraction and prevalence of nonischemic disease in HFPEF.13
Despite apparent overall survival advantages, women with heart failure present more often with symptoms of heart failure, poorer functional class, more significant physical examination findings consistent with heart failure (eg, jugular venous distension or S3), and increased diuretic requirements when compared to men.14 As per the ADHERE (Acute Decompensated Heart Failure National Registry) database, women were more hypertensive than men upon admission for acute heart failure exacerbations (systolic BP of 148 mm Hg vs 139.4 mm Hg, p <0.0001); despite a lower creatinine, women had a lower glomerular filtration rate of 51.3 mL/min/1.73 m2 vs 55.7 mL/min/1.73 m2 in men (p <0.0001).15 Gender differences in this registry support data that women are less likely to have an ischemic etiology and associated risk factors but are more likely to have hypertension. Population data also suggest that women with heart failure have poorer quality-of-life scores and a greater incidence of depression.16
Comorbid medical conditions upon presentation with heart failure also differ between women and men. While men are more likely to have chronic obstructive pulmonary disease, coronary heart disease (CAD), and peripheral vascular disease, women most often present in the setting of thyroid disease, valvular heart disease, and systemic hypertension15,17 (Tables 8-1 and 8-2).
Women are more likely to have
Women are less likely than men to have
Conflicting data: Diabetes & Anemia based on heart failure registry data |
| Women vs Men | |
|---|---|
Women are More Likely to Have | |
Diastolic heart failure or HFPEF Higher ejection fraction upon admission Older age on presentation for admission Hypertension as risk factor More hypertensive on admission (mean SBP) Nonischemic etiology of heart failure | 51% vs 28% 42% vs 32.9% 74.5 vs 70.1 years 76% vs 70% 148 vs 139 mm Hg |
Men are More Likely to Have | |
Coronary artery disease Ischemic etiology of heart failure | 51% vs 64% 19% vs 32% |
Utilization of Therapy and Outcomes Similar intravenous diuretic use Less vasoactive drug use in women Less procedure-oriented therapy in women Similar but underutilized oral evidence-based therapy in both Similar mean length of stay Similar adjusted in-hospital mortality | |
Diabetes mellitus and systemic hypertension have long been known risk factors for the development of heart failure in women, even in the absence of coronary heart disease.2
In terms of racial diversity associated with risk factors for heart disease, ethnicity has been underrepresented in clinical trials, similar to underrepresentation of women in general. Limited studies have focused on ethnic differences among women; more recently, as part of the Women’s Health Initiative, incident rates of heart failure hospitalization among different racial/ethnic groups were studied in postmenopausal women without self-reported heart failure, who were followed for an average of 7.8 years.18 Findings showed the highest incidence among black women (380 in 100,000 person-years) and lowest risk among Hispanic and Asian/Pacific Islander women (193 and 103 in 100,000 person-years, respectively). The effects of low income and diabetes mellitus, but not hypertension, explained the higher risk in black women; lower risk in Hispanic and Asian/Pacific Islander women persisted despite adjustment for socioeconomic status, age, and traditional risk factors. Such data emphasize the need for further evaluation of the effect of racial differences on the mechanism of heart failure among women.
Comorbid conditions are also associated with heart failure in women. Systemic hypertension is a significant risk factor and causative agent of heart failure in women.13,15 In particular, increased blood pressure is noted after menopause due to changes in arterial structure and function that increase stiffness of the vessels with age and hormonal changes. Hypertension has a higher prevalence in the elderly population, black patients, and women.19
Diabetes mellitus and obesity are also known etiologies of heart failure, which result in a significant burden on women with heart failure.20,21 In fact, glycemic control has been linked to the incidence of heart failure. Each 1% increase in hemoglobin A1C has been associated with an 8% increased risk of heart failure after adjustment for gender and other risk factors (race, education level, smoking, use of medical therapy) in a study of over 40,000 patients without a prior history of heart failure.20 A hemoglobin A1C of >10% relative to a hemoglobin A1C of <7% was associated with a 1.56-fold greater risk of heart failure. The risk of developing heart failure is increased by a factor of 4 to 5 times in diabetic women compared to nondiabetic women and twice that of diabetic men.7
Additionally, the endothelial dysfunction of diabetes has known pathological effects that can lead to the development of heart failure. Increased interstitial connective tissue and myocardial hypertrophy are caused by angiotensin II and endothelin, both derived from the endothelium, and could contribute to the higher left ventricular mass in those patients with both diabetes mellitus and systemic hypertension, compared to patients with hypertension alone. The significant correlation in women between heart failure and diabetes is also especially relevant given the higher occurrence of heart failure with preserved ejection fraction in women, where diabetes has been a more common risk factor for women compared to men.14
Obesity also plays a significant role in metabolic syndrome and comorbidities such as hypertension, type II diabetes mellitus, and sleep-disordered breathing; obesity alone is an independent etiology for the development of heart failure.21,22 Detrimental effects of fatty acids on the myocardium as well as toxic proteins released by adipose tissue contribute to structural alterations. Although this appears to be an equal risk factor for both women and men, the emerging obesity epidemic in developed nations warrants significant attention. More recent studies have mentioned the “obesity paradox” of heart failure, but this phenomenon refers to a protective effect of obesity in chronic, more advanced heart failure compared to the poorer prognosis associated with a leaner body mass in these patients, regardless of gender.23
Valvular heart disease is a well-known source of heart failure, and a significant number of women have valvular heart disease with approximately two-thirds of women discharged from the hospital in 1987 with mitral or aortic valve disease and more than half of valve replacements occurring in women.24 Mitral stenosis tends to have a higher predominance in women than men. Although rheumatic mitral stenosis, caused by rheumatic fever during childhood, has decreased recently in developed countries, this condition continues to be a significant burden in developing and underdeveloped countries. In developed countries, aortic stenosis in older populations is more common, due to calcific and degenerative processes. Valvular disease presents more commonly as a comorbid condition in women with heart failure compared to men with heart failure.
Pregnancy carries a potential risk based on the type of valvular heart disease. Mitral stenosis has the greatest risk of maternal cardiac complications whereas regurgitant lesions, asymptomatic aortic stenosis, and hypertrophic cardiomyopathy with mild-to-moderate left ventricular outflow obstruction are usually fairly well tolerated.25 Pregnancy is not recommended in Marfan syndrome with a dilated aortic root >4 cm, and a normal dimension aortic root in this population still carries a risk of dissection beyond that of a woman without connective tissue disease.
Coronary artery disease is the most common form of cardiovascular disease and a leading cause of death among men and women.26 Along with hypertension, ischemic heart disease accounts for the largest number of newly diagnosed cases of heart failure annually. Gender differences have been found among risk factors. Women have a higher prevalence of hypertension after age 55, more hypertriglyceridemia, greater mortality risk from diabetes, and higher total cholesterol after age 50. Women diagnosed with acute coronary syndrome are more likely to have noncritical CAD with the hypothesis that endothelial and microvascular dysfunctions play a role in symptoms and outcomes in these patients without obstructive disease. The WISE study (Women’s Ischemia Syndrome Evaluation) showed abnormal coronary flow reserve after intracoronary adenosine infusion in women and was associated with adverse cardiovascular outcomes.27 Estrogen seems to have a protective effect on the reaction to acute coronary ischemia in women by reducing apoptosis and, therefore, infarct expansion and remodeling after an acute myocardial infarction (MI).26 Women have a greater risk of developing heart failure post-MI, yet appear to have a long-term survival advantage compared to men in many studies, although this remains controversial since not all studies agree on this issue. Underrepresentation of women in clinical trials limits conclusions regarding gender differences. Figure 8-1 compares cardiac magnetic resonance imaging (MRI) in ischemic versus nonischemic etiology of heart failure.
FIGURE 8-1
Cardiac MRI in a woman with end-stage heart failure and severe LV dilation in case presentation (A), who presented with cardiogenic shock requiring multiple inotrope infusions and eventually mechanical circulatory support. Mild mid-wall fibrosis on late post-gadolinium imaging (B, yellow arrow) is consistent with nonischemic etiology of heart failure, which is more common in women with cardiomyopathy. (C) Note the difference when compared to an ischemic etiology of cardiomyopathy with transmural hyperenhancement on late post-gadolinium imaging (green arrows) in a 27-year-old woman with history of 2 left anterior descending artery stents, lupus anticoagulant with hypercoagulable state, and severe LV dysfunction, LVEF of 24%. MRI shows extensive, mostly transmural scar involving the septum and anterior wall consistent with nonviable myocardium in the LAD distribution.
All images from Ohio State University Medical Center noninvasive imaging laboratory.
Stress cardiomyopathy, or takotsubo cardiomyopathy, is a nonischemic cause of heart failure that occurs more often in women and, in particular, postmenopausal women28 (Figure 8-2). Severe left ventricular dysfunction, most often at the apex, is noted in the setting of preceding emotional, physical, or medical stress (eg, loss of a loved one, trauma, or significant infection); left ventricular function usually normalizes in most patients after a few weeks. Elevated biomarkers, such as brain natriuretic peptide (BNP) and troponin, as well as ST elevation on electrocardiogram are often noted, similar to a presentation of acute coronary syndrome and/or acute decompensated heart failure. The coronary angiogram, however, will reveal normal coronary arteries with no significant obstruction. The pathology of this condition is still not well understood, although an acute catecholamine release and possibly a localized acute inflammatory response are thought to play a role. The diagnosis of stress cardiomyopathy is one of exclusion and depends on multiple findings, including history, demographics, biomarker levels, electrocardiogram, echocardiogram or MRI, and cardiac catheterization results. Treatment includes standard heart failure therapies in addition to supportive care.
FIGURE 8-2
Cardiac MRI of woman who presented with chest pain, fatigue, and dyspnea with findings of apical ballooning of the left ventricle (arrows); overall LVEF 42%. No myocardial infarct scar or infiltrate and marked edema of mid and apical segments is visible on T2 imaging. This pattern along with apical ballooning and absence of scar is typical for takotsubo cardiomyopathy.
Women appear to be more susceptible to certain toxins known to damage the myocardium and result in cardiomyopathy. In particular, the cardiotoxic effect of chemotherapeutic agents is more often observed in women compared to men.29 It does not appear, however, that there is a difference in the duration of cardiotoxicity and resultant heart failure between genders. Cardiotoxicity may occur, at times acutely, within a few weeks of treatment or within a year to many years later. Risk factors also include type of drug, cumulative dose, schedule, coexisting cardiac disease, age >65 years, previous mediastinal radiation, and simultaneous use of other cardiotoxic drugs. For example, combination therapy of anthracyclines with trastuzumab, a monoclonal antibody against the human epidermal growth factor receptor-2 (HER2), enhances survival at the expense of augmented cardiotoxicity.30 The pathophysiology resulting in increased cardiomyopathy and heart failure in women is not well elucidated, but a proposed mechanism is related to cardiac damage because of free radicals.31 Concomitant treatment with dexrazoxane reduces the risk of cardiac toxicity through iron chelation and reduction in free radical production. Current strategies to minimize cardiotoxicity are focused on dose titration and altering treatment regimens to include dexrazoxane and liposomal anthracycline formulations to reduce free radicals.
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