Women with suspected ischemic heart disease

KEY POINTS

Heart disease remains the number one cause of death in women worldwide.
Compared with men, women with symptoms consistent with IHD often present without obstructive CAD on coronary angiography and have a higher prevalence of persistent angina, nonobstructive CAD, CMD, SCAD, stress-induced cardiomyopathy, and HFpEF.
Designed primarily for the identification of obstructive CAD, conventional diagnostic testing approaches for suspected IHD can lead to undertesting or overtesting in women without differentiating those truly at risk.
Increasingly, nuclear cardiology and multimodality cardiovascular imaging tools are being applied to better diagnose pathologic phenotypes prevalent in women, including ischemia with no obstructive CAD and CMD and to aid in the development of needed evidence-based strategies for their management.

Introduction

Diagnostic testing approaches for the evaluation of heart disease in women have historically paralleled those in men. Based on an assumption that stable ischemic heart disease (IHD) in women was the same as that in men except occurring about a decade later, conventional efforts focused on identification of obstructive epicardial coronary artery disease (CAD) as the principal etiology for symptoms such as chest pain and dyspnea, common in both women and men. We now recognize that several unique factors related to the presentation, diagnosis, and underlying pathophysiology of IHD in women necessitate a more tailored, evidence-based approach to their assessment of risk, complete with guidelines for sex-specific management strategies when appropriate. ^, Still, because most recommendations were derived predominantly from studies performed in men, the diagnostic utility and accuracy of testing in women can be undermined by lower predicted and observed probabilities of finding obstructive CAD. Currently, little high-quality data exist regarding optimal diagnostic strategies for the assessment of symptomatic women to establish or exclude a diagnosis of IHD.

Sex differences in ischemic heart disease

Epidemiology and risk factors

Despite this, heart disease remains the number one cause of death in women worldwide, and important sex differences in the rates of diagnosis, utilization of care, response to therapy, and clinical outcomes have been described. ^, Although these partly reflect that women outnumber men in the older populations at greatest risk for heart disease, women also often present with a higher burden of comorbidities and experience worse outcomes compared with men. Women relative to men have a higher prevalence of persistent angina, nonobstructive CAD, coronary microvascular dysfunction (CMD), spontaneous coronary artery dissection (SCAD), stress-induced cardiomyopathy, and heart failure with preserved ejection fraction (HFpEF). Cardiovascular risk factors, including diabetes mellitus (DM) and atrial fibrillation, are associated with higher rates of vascular complications in women versus men, and women account for a disproportionate burden of inflammatory diseases, such as rheumatoid arthritis, which have also been linked to increased cardiovascular morbidity. Women presenting with acute coronary syndromes experience higher mortality compared with men, ^, with lower utilization of cardiac device therapy, despite data showing increased benefit, and are referred for cardiac transplantation at later stages of heart failure.

As a result of a greater symptom burden and rate of functional disability in women, together with a lower prevalence of obstructive CAD by coronary angiography, the evaluation of IHD in women compared with men can present unique challenges to clinicians. The accuracy of standard noninvasive diagnostic testing for ischemia, such as stress testing with exercise electrocardiography (ECG), echocardiography, or semiquantitative nuclear myocardial perfusion imaging (MPI), can vary significantly when evaluated against a gold standard of identifying anatomic obstructive CAD. This is especially important for women, whose symptoms are less likely to be explained by findings on coronary angiography in both acute and chronic presentations of disease and whose abnormal stress tests in the absence of obstructive CAD are more likely to be interpreted as false-positives. ^, Nevertheless, women with angina and confirmed ischemia or myocardial infarction (MI) have increased mortality from heart disease. This chapter highlights how the recent clinical application of novel diagnostic tools in nuclear cardiology and multimodality cardiovascular imaging is leading to a paradigm change in how heart disease is diagnosed, ^, broadening the definitions of CAD and ischemia, respectively, to better reflect the pathologic phenotypes more prevalent in women.

Moving beyond obstructive coronary artery disease

Obstructive CAD, defined anatomically on coronary angiography as luminal narrowing of 70% or greater in the major epicardial arteries (or 50% or greater in the left main artery), is neither necessary nor sufficient to explain symptoms of IHD. Indeed, women present more frequently than men with symptoms of angina ^, ( Fig. 16.1 ) but are less likely to have anatomic obstructive CAD. In a contemporary cohort of 11,223 symptomatic patients (42% women) referred for nonurgent coronary angiography, one-third of men and two-thirds of women had no obstructive CAD, and these patients still experienced an elevated risk for major adverse cardiovascular events (MACEs). Among patients with stable angina who are found to have obstructive CAD, sex differences also exist in the extent and severity of disease, with women less likely than men to have obstructive multivessel disease. Sex differences in angiographic findings have been demonstrated not only in IHD but also in patients presenting with acute coronary syndromes, including unstable angina and MI. In autopsy evaluations of patients who died of ischemic heart disease, women demonstrated less extensive and less obstructive CAD than men, despite pathologic evidence of MI, with more evidence of plaque erosion than plaque rupture. Despite consistently documented lower angiographic disease burden and more often preserved left ventricular (LV) function compared with men, women with IHD have similar adverse outcomes ( Fig. 16.2 ). ^,

Fig. 16.1, Prevalence of angina pectoris by age and sex (NHANES, 2013–2016).

Fig. 16.2, Cardiovascular disease mortality trends for males and females (United States 1980–2017).

This paradox may be at least partly explained by the finding that a visually normal coronary angiogram does not necessarily indicate a normal coronary circulation ( Fig. 16.3 ). Beyond obstructive CAD, vascular dysfunction in the form of abnormal coronary reactivity often coexists with diffuse, nonobstructive atherosclerotic plaques and CMD. ^, ^, ^, Although invasive coronary angiography using visual assessments of epicardial coronary luminal patency remains a cornerstone of cardiovascular disease diagnosis, it has limited ability to identify diffuse atherosclerosis and small-vessel dysfunction. The addition of invasive fractional flow reserve, an assessment of the pressure drop across a focal epicardial stenosis, to coronary angiography has proven beneficial to identify lesion-specific ischemia and guide revascularization but may still underestimate the integrated contribution of diffuse atherosclerosis and small-vessel disease on myocardial ischemia. ^, Nonobstructive CAD and CMD have been implicated in adverse cardiovascular outcomes, including acute coronary syndromes, heart failure, and death from plaque erosion and impaired vasoreactivity with ensuing myocardial ischemia. ^, As a result, testing for IHD, especially in women, is now moving beyond testing for the presence or absence of obstructive epicardial CAD, which represents one of several possible contributors to myocardial ischemia. Over the last decade, the clinical integration of advanced diagnostic imaging tools is helping to redefine IHD and highlight the importance of nonobstructive CAD and CMD. Specifically, noninvasive approaches using coronary computed tomography angiography (CCTA), positron emission tomography (PET), and cardiac magnetic resonance (CMR) imaging have provided very sensitive assessments for the evaluation of anatomic atherosclerotic plaque, functional ischemia, and myocardial fibrosis, respectively.

Fig. 16.3, Illustration of the epicardial coronary arteries ( A , macrocirculation) and the full coronary circulation ( B , macro- and microcirculation).

Patient-centered clinical applications of imaging in women

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