Challenges in Heart Disease in Women

Cardiac disease is one of the leading causes of death for women in the United States, killing one in three women in 2018.¹ A number of differences exist between men and women in cardiac imaging. Women on average have smaller coronary artery size, left ventricle (LV) chamber size, and greater chest wall attenuation.^2,3 The reduced coronary artery size may decrease the non-assessable coronary segments, especially in the mid- to distal coronary vessels. Small LV size and breast tissue may decrease the diagnostic performance of myocardial perfusion imaging (MPI). Breast attenuation particularly affects the anterior wall interpretation in the left anterior descending territory.

Radiation Exposure

Increased cardiovascular imaging use over the past two decades has increased radiation doses from cardiac imaging, particularly coronary computed tomography (CT). Radiation exposure to breast tissue remains an important concern. Hurwitz et al. have predicted that single coronary CT angiogram increases lifetime excess relative risk for breast cancer of 1.4-2.6% and 0.2 and 0.4% in women aged 25 and 55 years, respectively.⁴ Breast tissue is a non-target organ for coronary CT, and the majority of the breast tissue lies in z axis. Recent studies suggest that cranial displacement decreases breast skin entrance dose.⁵

Pregnancy

Although undertaken less commonly, pregnancy poses some challenges in cardiac imaging. The biggest risks are radiation exposure and contrast exposure in case of cardiac CT, especially for the fetus.⁶ Radiation exposure has two types of effects: stochastic and deterministic.⁶ The linear no-threshold model applies to stochastic effects, implying that there is no threshold below which the radiation damage does not occur. In contrast, deterministic effects are predictable due to threshold-exceeding radiation doses that cause multi-cellular damage. Regarding the stochastic effects, probabilistic models suggest an exposure of 50 mGy, which doubles relative risk of childhood carcinogenesis from 0.1 to 0.2%.⁵ In relation to deterministic effects, a threshold of 150 mGy is traditionally used, beyond which a patient should be assessed for intervention, including the possibility of pregnancy termination.⁶ Notably, however, fetal exposure is well below 50 mGy for all cardiac imaging modalities.

For magnetic resonance imaging (MRI), the present data have not conclusively documented any deleterious effect on developing fetus.⁷ Methods to reduce duration of the scan should be used, such as gradient echocardiography pulse sequence, increasing repetition time, and decreasing flip angle and echocardiography train length for fast spin echo pulse.⁶

Intravenous iodinated and gadolinium-based contrast agents may cross the placenta to enter the fetal circulation and are classified as US Food and Drug Administration Category B and C agents, respectively.⁷ Fetal teratogenic or mutagenic effects in humans have not been reported with either type of contrast medium. However, well-controlled human studies are lacking. After birth, newborns with a history of in-utero iodinated contrast agent exposure should undergo screening for hypothyroidism, a routine process in industrialized countries. For newborns with a history of in-utero gadolinium exposure, no special screening is required.⁷

Sex-Based Differences in Presentation and Pathogenesis of Ischemic Heart Disease

Although mortality from ischemic heart disease (IHD) has declined since 1980, disease mortality remains higher in women than men, and the decline in disease mortality from IHD has been greater for men than women. Reasons for increased female mortality from IHD are multifactorial, potentially attributable to older age at initial presentation, (women are approximately 10 years older than men at initial presentation), atypical symptoms, post-menopausal estrogen depletion, and possible underutilization of medical services.⁸

There is growing evidence that coronary microvascular disease, with or without obstructive coronary artery disease (CAD), contributes to the pathophysiology of IHD in women. The link between microvascular disease and coronary atherosclerosis is incompletely understood, but microvascular disease partly explains the adverse outcomes in women despite a lower prevalence of obstructive CAD. In this regard, imaging modalities that provide quantification of myocardial blood flow MBF and/or coronary flow reserve (CFR), which are surrogate markers of microvascular function, may help identify at-risk patients.⁸

Table 1

Challenges	Details	Imaging Implications
Sex-based differences in anatomy and physiology	Smaller coronary diameter Smaller LV chamber Digitalis-like effect of estrogen	CT angiography: Inaccessibility to coronary segments especially mid- to distal segments. Radionuclide MPI: Reduced accuracy due to breast attenuation and LV size.
Radiation	Radiation exposure to breast tissue Radiation risk in pregnancy	Consider non-ionizing modalities like echocardiography or MRI, especially in younger women. Use cranial breast displacement and organ based dose modulation.
Pregnancy	Maternal and fetal radiation exposure Maternal and fetal contrast exposure	Consider non-ionizing modalities like echocardiography and MRI. Use intravenous contrast only when necessary.
Sex based differences in pathogenesis	Atypical presentation Older age at presentation Microvascular dysfunction	Imaging work-up maybe delayed due to older presentation. Decreased exercise capacity in older women may decrease sensitivity of stress testing. Quantification of MBF and CFR may identify microvascular dysfunction.

Noninvasive Testing of CAD in Women

In light of the potential sex-based differences in pathophysiology and clinical presentation of IHD in women, there have been recent efforts to incorporate sex-specific evidence and adopt female-specific diagnostic paradigms for the workup of IHD.⁸ Tests for the noninvasive detection of IHD are discussed below, with a focus on differences in women and men.

Exercise Electrocardiography

Exercise electrocardiography (ECG), which traditionally relies on the detection of ST-segment deviations during exercise, is usually the initial test for symptomatic, intermediate-risk women who are able to exercise.⁸

Reasons for the decreased diagnostic accuracy in women are not fully understood but may include reduced exercise capacity, chest wall attenuation, and digitalis-like effects of estrogen, which may potentiate ST-segment ECG changes.³ In this regard, combining multiple parameters obtained during exercise ECG testing, such as what can be done with the Duke Treadmill Score, may improve accuracy and risk stratification in women.

Despite the relatively low positive predictive value of traditional exercise ECG testing, its high negative predictive value (approximately 80% in men and women) is valuable in ruling out obstructive CAD and predicting event-free survival, provided maximum exercise capacity is reached. Consequently, the American Heart Association recommends that a pretest evaluation for exercise capacity be made in symptomatic women with suspected IHD. For women with adequate exercise capacity and a normal resting ECG, exercise ECG remains the initial recommended test.⁸

Stress Imaging

Stress imaging with echocardiography or radionuclide MPI (single-photon emission computed tomography [SPECT] or positron emission tomography [PET]) is recommended for the initial evaluation of symptomatic women at intermediate to high risk for CAD who have resting ECG ST-segment abnormalities, poor exercise capacity, or abnormal (intermediate to high risk) exercise ECG.^9-12

Stress Echocardiography

Echocardiography allows visual assessment and localization of systolic dysfunction, stress- induced wall motion abnormalities, and myocardial scarring. Additionally, echocardiography may help identify causes of angina unrelated to CAD, such as valvular disease, aortic dissection or aneurysm, pulmonary hypertension, and pericardial disease. Although few studies have compared the performance of stress echocardiography to detect CAD between the sexes, diagnostic accuracy is regarded as comparable in women and men.⁸ Echocardiography also offers the advantage of using no ionizing radiation, conferring a potential preference in pregnant and young women.

SPECT MPI has been reported to have sex-specific challenges in women, such as reduced LV size and breast attenuation, that may confer reduced accuracy to detect CAD.³ However, with contemporary gating and attenuation-correction techniques, performance in women is comparable to stress echocardiography and is also comparable to that in men.

Compared with SPECT MPI, PET MPI affords higher spatial resolution and reduced artifact. Although studies evaluating the diagnostic performance of PET MPI in women are not as numerous as for SPECT MPI, recent evidence suggests improved accuracy over SPECT MPI to detect CAD in women. Improved performance is partly due to decreased soft tissue attenuation experienced by high-energy PET. PET agents also have a shorter half-life, conferring lower radiation exposure.⁹

Another benefit of PET MPI is the ability to quantify rest and stress MBF and CFR (defined as the ratio of stress to rest MBF). Quantitative measurements of MBF and CFR obtained by means of sequential PET acquisition may augment the detection of microvascular disease and ischemia, where a CFR of less than 2.0 is suggestive of vascular dysfunction.¹⁰

Cardiac MRI

The role of cardiac MRI in evaluating ischemic and non-ischemic diseases has expanded. The absence of ionizing radiation, superior contrast and spatial resolution, and quantification of MBF provide potential advantages, especially in young and pregnant women.¹¹

Coronary CT Angiography

With the advent of multi-detector spiral CT, dual-energy CT, and improved gating and decreased radiation dosing techniques, the use of coronary CT scan has become more widespread.

Calcium scoring helps predict the likelihood of obstructive CAD; absence of calcium does not rule out possibility of plaque. Studies suggest that the accuracy of coronary CT angiography is similar in men and women to diagnose obstructive CAD.⁸

CT MPI with dual energy or dynamic acquisition, as well as CT-derived fractional flow reserve, have the potential to increase the diagnostic accuracy of coronary CT angiography. Although these techniques are not incorporated into mainstream cardiology, their potential to obtain simultaneous anatomic and functional assessment may facilitate better patient risk stratification.

Table 2

Test	Sensitivity (%)		Specificity (%)
	Men	Women	Men	Women
Exercise ECG	61	68	70	77
Stress Echocardiography	79	76	83	88
SPECT MPI	84	89	79	71
PET MPI	81	81	86	89
Cardiac MRI	89	86	84	83
Coronary CT Angiography	90	96	89

Non-Ischemic Cardiomyopathy

Non-ischemic cardiomyopathies are, in general, more prevalent in men, but certain cardiomyopathies like stress-induced cardiomyopathy, sarcoid, and certain inflammatory cardiomyopathies are more prevalent in women.

Stress-Induced Cardiomyopathy

Women account for 86-95% of the cases with the mean age of 61-72 years. Pathogenesis is poorly understood, but proposed causes include coronary spasm, micro-vascular dysfunction, catecholamine toxicity, or neurogenic stunning. Echocardiography, MRI, or ventriculography aid the diagnosis. There is transient LV apical ballooning with hypokinesis and hypercontractile LV base. Late gadolinium enhancement when used as a tool to identify myocardial scarring following an acute myocardial infarction is absent in most patients, thereby helping to differentiate other forms of cardiomyopathies from myocardial infarction.¹³

Sarcoidosis

Sarcoidosis has incidence of 5-39 per 100,000 patients, with female preponderance. Clinically, cardiac involvement is seen in 5% of cases. Diagnostic testing involves gallium 67 scintigraphy, MRI, and cardiac PET.

Imaging findings show wall thinning or hypertrophy on echocardiography, non-coronary wall motion abnormality, and ventricular aneurysm. Right ventricular involvement and pericardial involvement can also occur. Cardiac MRI shows delayed enhancement in non-coronary distribution, particularly in mid-myocardium or epicardium. Fluorodeoxyglucose PET is also very sensitive and shows enhancement in the area of active inflammation and can also be used to monitor treatment with immune modulators.¹⁴

Chronic Inflammatory Diseases

There is increased evidence regarding the presence of inflammatory diseases like rheumatoid arthritis and systemic lupus erythematosus and presence of premature CAD. Pathogenesis of accelerated atherosclerosis is not well understood and is thought to be due to both traditional and non-traditional risk factors. In addition to atherosclerosis, they can also lead to systolic and diastolic dysfunction, dilated cardiomyopathy, and pericardial effusions. Echocardiography and MRI can also often show systolic dysfunction and increased volumes.

Heart Disease in Pregnancy

Cardiovascular disease occurs in 1-4% of pregnancies and is the leading cause of maternal mortality in United States. Pregnancy induces many physiological changes, and incomplete hemodynamic adaptation may lead to adverse outcomes.

A complication seen sometimes during pregnancy or immediately postpartum is peripartum cardiomyopathy, with incidence varying widely between 1 case per 1,300 and 1 case per 15,000.

Peripartum cardiomyopathy is a dilated cardiomyopathy occurring in last month up to 5 months postpartum. Echocardiographic features include global LV hypokinesis with reduced ejection fraction and LV dilation without hypertrophy. MRI is complementary to assess volumes and ejection fraction.

Conclusion

Women with heart disease compose a unique population with many important imaging and diagnostic considerations. It is prudent for clinicians and cardiologists to be aware of the sex-specific differences in the presentation, pathogenesis, diagnostic testing, and imaging evaluation of these patients.

References

1. Xu J, Murphy SL, Kochanek KD, Bastian BA. Deaths: Final Data for 2013. Natl Vital Stat Rep 2016:64:1-119.
2. Solimene MC. Coronary heart disease in women: a challenge for the 21st century. Clinics (Sao Paulo) 2010;65:99-106.
3. Nevsky G, Jacobs JE, Lim RP, Donnino R, Babb JS, Srichai MB. Sex-specific normalized reference values of heart and great vessel dimensions in cardiac CT angiography. AJR Am J Roentgenol 2011;196:788-94.
4. Hurwitz LM, Reiman RE, Yoshizumi TT, et al. Radiation dose from contemporary cardiothoracic multidetector CT protocols with an anthropomorphic female phantom: implications for cancer induction. Radiology 2007;245:742-50.
5. Vadvala H, Kim P, Mayrhofer T, et al. Coronary CTA using scout-based automated tube potential and current selection algorithm, with breast displacement results in lower radiation exposure in females compared to males. Cardiovasc Diagn Ther 2014;4:470-9.
6. Litmanovich DE, Tack D, Lee KS, Shahrzad M, Bankier AA. Cardiothoracic imaging in the pregnant patient. J Thorac Imaging 2014;29:38-49.
7. Expert Panel on MR Safety, Kanal E, Barkovich AJ, et al. ACR guidance document on MR safe practices: 2013. J Magn Reson Imaging 2013;37:501-30.
8. Mieres JH, Gulati M, Bairey Merz N, et al. Role of noninvasive testing in the clinical evaluation of women with suspected ischemic heart disease: a consensus statement from the American Heart Association. Circulation 2014;130:350-79.
9. Iskandar A, Limone B, Parker MW, et al. Gender differences in the diagnostic accuracy of SPECT myocardial perfusion imaging: a bivariate meta-analysis. J Nucl Cardiol 2013;20:53-63.
10. Murthy VL, Naya M, Taqueti VR, et al. Effects of sex on coronary microvascular dysfunction and cardiac outcomes. Circulation 2014;129:2518-27.
11. Greenwood JP, Motwani M, Maredia N, et al. Comparison of cardiovascular magnetic resonance and single-photon emission computed tomography in women with suspected coronary artery disease from the Clinical Evaluation of Magnetic Resonance Imaging in Coronary Heart Disease (CE-MARC) Trial. Circulation 2014;129:1129-38.
12. Tsang JC, Min JK, Lin FY, Shaw LJ, Budoff MJ. Sex comparison of diagnostic accuracy of 64-multidetector row coronary computed tomographic angiography: results from the multicenter ACCURACY trial. J Cardiovasc Comput Tomogr 2012;6:246-51.
13. O'Donnell DH, Abbara S, Chaithiraphan V, et al. Cardiac MR imaging of nonischemic cardiomyopathies: imaging protocols and spectra of appearances. Radiology 2012;262: 403-22.
14. Miyagawa M, Yokoyama R, Nishiyama Y, Ogimoto A, Higaki J, Mochizuki T. Positron emission tomography-computed tomography for imaging of inflammatory cardiovascular diseases. Circ J 2014;78:1302-10.

Keywords: American Heart Association, Aneurysm, Aneurysm, Dissecting, Arthritis, Rheumatoid, Atherosclerosis, Biomarkers, Breast Neoplasms, Calcium, Carcinogenesis, Cardiomyopathies, Cardiomyopathy, Dilated, Catecholamines, Cicatrix, Coronary Angiography, Magnetic Resonance Angiography, Coronary Artery Disease, Digitalis, Dilatation, Disease-Free Survival, Echocardiography, Stress, Echocardiography, Electrocardiography, Estrogens, Exercise Test, Female, Fetus, Gadolinium, Gallium, Half-Life, Heart Diseases, Heart Ventricles, Hypertension, Pulmonary, Hypertrophy, Hypothyroidism, Incidence, Infant, Newborn, Inflammation, Lupus Erythematosus, Systemic, Magnetic Resonance Imaging, Maternal Mortality, Models, Statistical, Mutagens, Myocardial Infarction, Myocardial Ischemia, Myocardial Perfusion Imaging, Myocardium, Pericardial Effusion, Pericardium, Peripartum Period, Placenta, Positron-Emission Tomography, Postmenopause, Postpartum Period, Pregnancy, Prevalence, Radiation Dosage, Radiation, Ionizing, Radioisotopes, Radionuclide Imaging, Risk, Risk Factors, Sarcoidosis, Spasm, Stroke Volume, Thoracic Wall, Tomography, Tomography, X-Ray Computed, Tomography, Spiral Computed, Tomography, Emission-Computed, Single-Photon, United States Food and Drug Administration

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