Nonobstructive Coronary Artery Disease in Women: Risk Factors and Noninvasive Diagnostic Assessment

Keith C. Ferdinand, MD and Rohan Samson, MD

1 Tulane University Heart and Vascular Institute, Tulane University School of Medicine, 1430 Tulane Avenue, SL-8548,New Orleans, LA 70112, USA

Abstract Sex-specif c differences in the epidemiology and pathophysiology of coronary artery disease and ischemic heardt i sease are now well recognized. Women with angina more often have nonobstructive coronary artery disease( NOCAD) compared with men. This patient population carries a signif cant risk of future cardiovascular events that is not commonly appreciated, often leading to delayed diagnosis and treatment. While coronary microvascular dysfunction plays a central role in the pathophysiology of NOCAD in women, other mechanisms of myocardial ischemia are now recognized.Risk factors such as hypertension and obesity disparately affect women and are likely to account for a signif cant proportion of NOCAD in the coming years. Vascular inf ammation is an important pathophysiologic pathway in NOCAD and is a potential therapeutic tar get. Coronary CT angiography provides a comprehensive assessment of coronary anatomy and plaque morphology and is a reasonable screening test of choice for NOCAD.

Keywords: nonobstructive coronary artery disease; hypertension; obesity; inf ammation

Introduction

Although the rates of coronary heart disease (CHD)have reduced in the past decade, it continues to contribute signif cantly to overall morbidity and mortality in women worldwide.

While it is true that rates of CHD have declined in both sexes, the rates in females aged 55 years or younger have not [ 1]. The prevalence of CHD in adult American women between 2011 and 2014 was 7.5 million (5.3%) [ 2]. In 2015, CHD contributed to nearly 150,000 deaths in women, accounting for 43% all CHD-related deaths [ 2]. The epidemiology and pathophysiology of coronary artery disease(CAD) in women are unique when compared with those in men because of a number of factors, some that are still not well understood and are the focus of intense current investigation. Women have a higher burden of traditional risk factors such as hypertension and obesity and a higher prevalence of vascular inf ammation and microvascular dysfunction relative to men. We will f rst discuss the def nition and pathophysiology of nonobstructive CAD (NOCAD)and sex differences in coronary anatomy. The impact of traditional risk factors - namely, hypertension and obesity - on the coronary circulation and the atherosclerotic process and thereby in women with ischemia and NOCAD will be reviewed. Thereafter,evidence supporting the role of inf ammation as a novel risk factor and therapeutic target will be addressed. Lastly, current diagnostic approaches to NOCAD will be discussed.

NOCAD: Definition and Pathophysiology

CAD has traditionally been assessed by visual estimation of stenoses during invasive coronary angiography (CAG). This visual estimate is based on lumenography with enhancement of the contour of a vessel with use of contrast media. Obstructive CAD as assessed by CAG is arbitrarily def ned as at least one epicardial stenosis greater than or equal to 50% [ 3]. However, there has been considerable variation in the def nition of obstructive CAD.Coronary stenosis in the range of 50 - 70% during CAG was previously labeled as being signif cant or obstructive [ 4 - 6T h]. is visual assessment of epicardial coronary stenosis during CAG is therefore inaccurate for the assessment of lesion severity.Functional assessment of angiographically inter-mediate coronary stenosis between 40 and 70% via fractional f ow reserve and instantaneous wave free ratio is currently used to assess the clinical signif -cance and guide revascularization [ 7, 8].

Epicardial coronary artery stenoses not signif cant enough to warrant revascularization are deemed nonobstructive. Obstructive CAD has been def ned as at least one stenosis greater than or equal to 20% but less than 50% [ 3]. The current treatment paradigm is to relieve obstructive disease, and thus NOCAD has received less attention and has been inherently felt to be associated with a benign prognosis, although this is increasingly recognized as inaccurate [ 3 ]. The term “ nonobstructive coronary artery disease” (NOCAD) is now used to represent a rather heterogeneous spectrum of CAD and coronary disease that occurs in the absence of f owlimiting stenosis that implicates the involvement of microvascular circulation, the endothelium, and anatomical and functional differences in the coronary vasculature. This was previously described as ischemic heart disease without obstructive CAD,open artery ischemic heart disease, myocardial infarction with no coronary artery obstruction,coronary microvascular dysfunction (CMD), and microvascular angina. The term “ cardiac syndrome X” is no longer used.

NOCAD is highly prevalent in women under going CAG to evaluate ischemic symptoms, and nearly 70% women but only 30% of men unde rgoing CAG to evaluate stable angina had NOCAD [ 9 -1 1].A female preponderance for NOCAD is surprising considering that symptomatic women usually present 10 - 15 years later than their male counterparts and have a higher prevalence of risk factors such as diabetes mellitus, hypertension, dyslipidemia, and tobacco use. Myocardial ischemia due to mechanisms other than f ow-limiting epicardial stenosis such as endothelial dysfunction and microvascular dysfunction is more frequently observed in women. CMD, def ned as epicardial, microvascular endothelial, or nonendothelial dysfunction that causes ischemia, is usually identif ed as reduced coronary f ow reserve (CFR) [ 12], and has come to play a central role in attempts to describe sex differences in ischemia. Coronary vasomotor abnormalities are known to portend poor cardiovascular outcomes, especially in women [ 13 - 17W ]. hile data on sex differences in the prevalence of CMD have been conf icting, CMD remains a key player in the evaluation of NOCAD [ 18, 19]. Contrary to previous reports of a signif cantly higher prevalence of CMD in women, Sara et al. [ 18] reported a clinically insignif cant sex dif ference in CMD prevalence. In patients with chest pain and NOCAD,coronary blood f ow and CFR were evaluated with acetylcholine and adenosine, respectively. While female sex was not signif cantly associated with CMD on multivariable analysis, a higher propor-tion of women was noted in patients with abnormal CMD. Recently, however, during CMD evaluation with acetylcholine provocation testing, a pathological f nding was noted in 70% of women compared with only 43% of men [ 19]. The acetylcholine dose needed to elicit an abnormal response was much lower in women than in men. Further, in a recent study, excess cardiovascular risk in women compared with men was attributed to severely impaired CFR, but not obstructive CAD [ 20]. Lack of standardized protocols for invasive CMD evaluation could account for the disparate f ndings noted above.

While our current understanding of the pathophysiology of NOCAD is limited, several novel pathophysiological mechanisms of myocardial ischemia have now been described (Figure 1) [ 21].Vascular causes include endothelial dysfunction,hypercoagulable states, inf ammatory disorders(lupus, polyarteritis, etc.), spontaneous coronary artery dissection, and inf ammation/raref cation of the coronary microcirculation, while nonvascular causes include disorders of the cardiomyocytes(transcellular, intracellular, and mitochondrial) and the adventitia. The clinical implications of these novel mechanisms of ischemia are presently unclear and need to be evaluated further.

Sex Differences in Coronary Anatomy

Coronary circulation is signif cantly dif ferent in women compared with men. In women the coronary macrovasculature and the coronary microvasculature are both smaller in diameter with stiffer vessels than in men [ 22, 23]. Smaller epicardial vessel luminal areas in women compered with men have been consistently demonstrated, with the exception of the left main coronary artery, which was not affected by sex in the Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) study [ 24]. The difference in epicardial coronary artery diameter persists even after adjustment for body size or left ventricular mass [ 25].

Women have increased coronary microvasculature tone and are particularly prone to endothelial and smooth muscle dysfunction. Impaired CFR in response to adenosine occurs more frequently in women than in men and predicts future cardiovascular events [ 26]. Evaluation of the retinal arterial caliber, an indirect marker of myocardial blood f ow,also suggests an increased CMD prevalence and increased cardiovascular events in women [ 27, 28].A smaller retinal arterial caliber (representing lower hyperemic myocardial blood f ow) predicts incident coronary events in women but not in men [ 27, 28].Further, vasospastic vascular disorders such as coronary vasospasms, Raynaud phenomenon, and vasculitis occur more frequently in women [ 29].

Figure 1 Mechanisms for Nonobstructive Coronary Artery Disease (NOCAD) in Women.

Sex-specif c characteristics and differences in the coronary atherosclerotic process are being increasingly recognized in women with stable and/or acute coronary syndromes. Dif ferences include the “ spread-out” nature of atherosclerotic plaque buildup in women rather than focal manifestations of discrete lesions as seen by the Women’ s Ischemia Syndrome Evaluation (WISE) investigators in women presenting with ischemic symptoms and who underwent CAG [ 17]. Similarly, the mechanisms of plaque disruption in women with acute co-r onary syndromes show a sex predilection for plaque erosion versus plaque rupture. Culprit lesions in men predominantly display plaque rupture, thin-cap f broatheroma, and a high plaque burden [ 30 - 32].In women, plaque erosion appears to be unrelated to the presence of thin-cap f broatheroma or plaque burden [ 33 - 36N ]e. arly 50% of women with stable ischemic heart disease have atherosclerotic plaque features associated with acute coronary syndromes[ 37, 38]. Patterns of coronary artery remodeling in response to atherosclerosis may also differ between men and women. Evidence from subanalyses of the WISE study suggests that positive or compensatory remodeling of coronary arteries is prevalent in women with NOCAD [ 39, 40]. Positive remodeling is a well-recognized feature of the vulnerable plaque phenotype; vulnerable plaques have a lar ger lipid content, a necrotic core, and macrophage inf ltration and are more frequently associated with unstable coronary syndromes compared with plaques with negative remodeling [ 41 - 43 ].

Role of Risk Factors

Hypertension: A Major Modifiable CAD Risk Factor in Women

Nearly one in three adult women has hypertension,and approximately 20% of all deaths in women are related to hypertension [ 2, 44]. Hypertension is a major contributor to cardiovascular disease in both men and women, with a higher burden of CAD, heart failure, stroke, atrial f brillation, and chronic kidney disease in women than in men[ 45]. Hypertension is a much stronger risk factor for CAD in women than in men, in part because of the association of aging and postmenopausal status with hypertension, particularly in women older than 65 years. Sex hormones (namely, estrogens) have a direct ef fect on the vascular pathophysiology,and regulate vascular reactivity, angiogenesis, and atherosclerosis [ 46]. Estrogens modulate endothelial function and vascular tone by increasing the activity of endothelium-derived vasodilator factors while simultaneously decreasing the activity of vasoconstrictor factors such as endothelin 1, angiotensin-converting enzyme, and angiotensin I receptor [ 47]. Further, estrogen withdrawal results in an increase in peripheral sympathetic neuronal activity and circulating levels of norepinephrine, causing elevated blood pressure [ 48, 49]. The cardiovascular benef ts of hormone replacement in clinical studies has been inconsistent, however, and require further investigation [ 50 - 52 ].

Ethnic differences are also well recognized among women. The burden of myocardial infarction and fatal CAD is higher for African-American women than for other race/ethnic groups [ 53]. Data from Heron [ 54] demonstrate higher CAD death rates among African Americans than among whites, with a greater disproportional rate in African-American women than in white women, such that not only the CAD death rates but also the life expectancy of African-American women more signif cantly ref ect values seen in white men versus white women[ 54]. Among African-American men, CAD prevalence was lower than in white men (7.2 vs. 7.8%);however, this is reversed in women (7.0 vs. 4.6%).Despite the lower prevalence, the rates of death from CAD remain higher in African Americans than in the white population.

In the latest landmark trial, the Systolic Blood Pressure Intervention Trial (SPRINT), the proportion of women represented was less than ideal in consideration that elderly women are the predominant population of persons with isolated systolic hypertension [ 55, 56]. Only 28% of the entire SPRINT cohort were aged 75 years or older, and the upper limit was 80 years, limiting the ability to apply the mortality and morbidity benef ts of the SPRINT data to women [ 56]. Furthermore, younger women, who may have hypertensive disorders related to pregnancy and systemic autoimmune diseases, were not represented in SPRINT.

Obesity

Over the past several decades there has been an alarming rise in the rates of obesity worldwide[ 57]. In the United States, data from the National Health and Nutrition Examination Survey indicate that women have a higher prevalence of obesity compared with men [ 58]. Among women, non-Hispanic African-American women had the highest rate of obesity (55%), followed by Hispanic women (50%) [ 59]. Obesity and overweight are major risk factors for CHD and its associated risk factors such as hypertension [ 2]. Since obesity is a well-established risk factor for CAD, it is expected that the rates of CAD (and possibly in women) will increase over the next few decades [ 60]. Obesityassociated comorbidities such as hypertension, diabetes, dyslipidemia, and metabolic syndrome are all independent risk factors for CAD. Correlation between obesity and CAD was established early on in the Framingham Heart Study and Nurses’ Health Study cohorts [ 61 - 63]. The risk of CAD in the Nurses’ Health Study increased nearly threefold as BMI increased from less than 21 kg/m2to more than 29 kg/m2. In the Pathological Determinants of Atherosclerosis in Youth study, it was noted that obesity in adolescents and young adults acceler-ates the progression of CAD decades before clinical manifestation of CAD, and that a high BMI correlates with more complex CAD lesions [ 64].Abdominal obesity or visceral fat signif cantly contributes to a chronic, low-grade systemic and vascular inf ammation through the production proinf ammatory adipokines (leptin and resistin) and cytokines (interleukin [IL]-6, tumor necrosis factor [TNF]- α) [ 65, 66]. Compared with BMI, waisthip ratio is a stronger predictor of cardiovascular events and atherosclerotic burden, highlighting the role of regional fat distribution in promoting atherosclerosis [ 67 - 69T ]. here is also growing evidence that adipose-derived proinf ammatory substances and epicardial adipose tissue alter coronary vasomotor function and contribute to CMD[ 69, 70]. Eroglu et al. [ 71] evaluated the association between serum adiponectin, an adiposederived protein hormone, and CFR in women with normal coronary arteries. Lower adiponectin levels were associated with impaired CFR in women with normal epicardial coronary arteries, suggesting that hypoadiponectinemia may promote CMD in women. Further, in a recent study, Dou et al.[ 72] demonstrated that aging and obesity increase the expression of a vascular endothelial metalloproteinase, ADAM17, which regulates soluble TNF- α release in adipose tissue and contributes to the development of remote CMD in obese patients aged 69 years or older.

Inflammation: A New Pathway to Decreasing Cardiovascular Disease

The inf ammatory response to the presence of atherosclerosis is considered a hallmark and potential leading pathway to the identif cation and treatment of CAD [ 73, 74]. Sex-based variation in immune responses to atherosclerosis are being increasingly recognized [ 75]. Immune cells within atherosclerotic plaque express sex steroid hormone receptors and are thereby regulated by sex hormones, in particular, by estrogen [ 76]. Estrogen inhibits TNF, IL-1, and IL-6 by downregulating nuclear factor κ B [ 77 ]. Estrogen is also reported to decrease the levels of oxidized low-density lipoproteins and increase apolipoprotein E level, thereby promoting an antiatherosclerotic phenotype in macrophage [ 77]. Altered immune responses in women are not limited only to atherosclerosis; women are known to develop an exaggerated systemic antibody and autoantibody response to immunological stress and are thus predisposed to autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis [ 75]. High cardiovascular mortality rates have been observed in women with autoimmune disease [ 75 , 78 - 8 0 ].

Sex-based immune responses could result in unique biomarkers that could be used to monitor endothelial dysfunction and inf ammation in women. Sex-specif c inf ammatory biomarkers may improve the predictive ability of cardiovascular risk models and traditional risk factors that typically underestimate the risk in women [ 81, 82].Inf ammatory biomarkers such as high-sensitivity C-reactive protein (CRP), f brinogen, IL-6, matrix metalloproteinase 9 and E-selectin and markers of hemostasis such as f brinogen, D-dimer, and plasminogen activator inhibitor 1 were found to improve cardiovascular risk prediction in postmenopausal women [ 83]. Combination of the CRP level with the Framingham risk score increased the accuracy of cardiovascular risk prediction in women [ 84]. Other biomarkers, such as high-sensitivity troponin, natriuretic peptides, and other lipid measures such as the levels of lipoprotein A and lipoprotein-associated phospholipase A2, have also been evaluated to improve cardiovascular risk prediction [ 81 , 82 ].

T argeting inf ammation unrelated to lipid level lowering or blood pressure reduction led to decreased cardiovascular events in the recently concluded Canakinumab Anti-inf ammatory Thrombosis Outcome Study (CANT OS) [ 85]. In stable patients with previous myocardial infarction and a persistent proinf ammatory response(def ned as high-sensitivity CRP level of 2 mg/L or more), IL-1 β inhibition with a monoclonal antibody(canakinumab) reduced the risk of the primary end point of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death by 15% compared with placebo. The CANTOS results suggest that other anti-inf ammatory pathways such as those that alter inhibit inf ammosome function or downstream IL-6 signaling may also serve as atheroprotection targets. The clinical utility of ta rgeting inf ammation in women with NOCAD remains to be elucidated.

Diagnosis

The vast majority of investigations in patients with NOCAD have used CAG to assess epicardial coronary anatomy and invasive coronary vasoreactivity testing to evaluate patients for CMD. Several protocols for coronary vasoreactivity testing have been described [ 86]. However, their use as reported in the literature remains inconsistent, often yielding conf icting results regarding the prevalence, extent,and cause of CMD. While invasive testing has a low complication rate [ 86], a serious complication such as a coronary dissection or myocardial infarction can occur. Some authors have questioned the effectiveness of an invasive strategy for detection of CMD, since its presence or absence does not alter treatment of these patients, even though its presence does offer an explanation for their symptoms [ 87].Noninvasive techniques now offer a comprehensive assessment of epicardial coronary anatomy and coronary microvasculature and may soon replace CAG as the gold standard.

While CAG is the diagnostic gold standard, it visualizes only the lumen. Quantifying the degree of epicardial coronary obstruction by only measurement of the reduction of the lumen diameter can be misleading. Coronary computed tomography angiography (CCTA) is less prone to error in assessment of lesion severity compared with the lumenogram obtained with CAG and does not expose the patient to complications from an invasive procedure. In stable chest pain patients with a low burden of obstructive disease, CCT A provides better prognostic information than functional stress testing (i.e., exercise treadmill testing, nuclear stress test, or stress echocardiography) [ 88]. Compared with men, women derive a greater prognostic benef t from CCTA than from noninvasive testing [ 89].CCTA with or without calcium scoring and physiological testing is now the screening test of choice for CAD [ 90]. Current criteria to assess the severity of epicardial stenosis by CCTA are listed in Table 1[ 91]. NOCAD diagnosed by CCTA is def ned as less than 50% luminal narrowing in at least one coronary artery segment [ 92]. CCTA can accurately detect CAD and coronary plaque when compared with intravascular ultrasonography [ 93 , 94 ]. Further,there is robust correlation between CAD diagnosed by CCTA and cardiovascular event rates. NOCAD diagnosed by CCTA was associated with an increase risk of death in the CONFIRM registry [ 95]. Other large CCTA registries demonstrate an escalating risk of death with more vessels or coronary segments with NOCAD [ 96 - 98I n] . addition to angiography,CCTA can also provide a thorough assessment of plaque morphology and burden [ 99]. High-risk features of coronary plaque such as positive remodeling, low attenuation, or napkin-ring sign can be detected on CCTA [ 43, 100]. In a lar ge contemporary cohort of outpatients with stable chest pain,Ferencik et al. [ 101] recently demonstrated a 70%increase in the risk of future major adverse cardiac events (MACEs) in patients with high-risk plaque on CCTA, independent of obstructive disease. In patients with NOCAD, the high-risk plaque doubled the risk of MACEs. Further, the presence of highrisk plaque conferred the strongest predictive value for MACEs among patients with NOCAD and those with lower atherosclerosis burden such as women and young patients.

Table 1 Guideline-Recommended Grades of Epicardial Coronary Artery Disease (CAD) Based on Qualitative and Quantitative Assessment of Lesion Severity [ 91].

Sex-based dif ferences in plaque morphology have also been observed with a qualitative plaque assessment on CCTA [ 102]. Nonobstructive plaque in women was associated with death in women,an association not observed in men [ 103]. In the CONFIRM registry, NOCAD conferred a nearly two times higher risk of adverse cardiovascular events in women [ 102]. Dynamic CT can now be used to evaluate the intramyocardial blood volume and the microcirculation as well [ 104]. Modern CT scanners are able to accurately di fferentiate between attenuation dif ferences between the endocardium and epicardium. Recently, Kuhl et al. [ 105] demonstrated that in patients with NOCAD, a worsening CT-derived myocardial perfusion reserve from epicardium to the endocardium was suggestive of CMD. Computational modeling techniques evaluating f ow of contrast medium in epicardial vessels are also being used to estimate regional myocardial perfusion [ 106, 107]. As technology improves in the coming years, a reduction in radiation exposure and artifacts may promote a broader clinical application of CCTA.

Magnetic resonance (MR) techniques have also progressed rapidly in the past decade [ 108].Dobutamine and vasodilator stress MRI have superior accuracy in identifying CAD compared with single-photon emission CT (SPECT) [ 109,110]. The diagnostic yield and prognostic value of stress MRI is well established in women [ 111, 112].Increased spatial resolution and diagnostic accuracy coupled with lack of radiation exposure and body habitus limitations makes stress MRI particularly suited to evaluate ischemia in women [ 113]. Apart from perfusion imaging, MRI is also an excellent tool for myocardial blood f ow assessment. Good correlation has been established between blood f ow measured by MRI and microsphere-derived myocardial blood f ow in animal models [ 114].Hays et al. [ 115] demonstrated abnormal endothelial function with MR-based coronary blood f ow measurements in a predominantly female population with NOCAD compared with controls.Metabolic imaging is also feasible by MR spectroscopy using phosphorous-31. In women with chest pain but no epicardial CAD, a subset of patients was found to have a decrease in phosphocreatine to adenosine triphosphate ratio on hand grip exercise[ 116]. Abnormal hand-grip test f ndings on phosphorous-31 MR spectroscopy predicted cardiovascular events during a 3-year follow-up period [ 117].Coronary MR angiography is currently not used to evaluate CAD.

Unlike CCT A, positron-emission tomography(PET) does not directly assess coronary anatomy;however, it is an excellent tool to assess myocar-dial perfusion. Attenuation correction with PET/CT scanning reduces breast tissue attenuation, signif -cantly increasing the diagnostic accuracy compared with SPECT. Stress perfusion with PET has a higher diagnostic and prognostic capability than SPECT[ 118, 119]. In addition to perfusion imaging, PET has been widely studied for quantif cation of myocardial blood f ow and CFR. However, because of inconsistent def nition of NOCAD across various studies,f ow impairment in the coronary microvasculature in the absence of epicardial CAD has never been clearly established. Geltman et al. [ 120] showed that approximately 50% of patients with chest pain and NOCAD have an abnormal CFR, highlighting the heterogeneity in the pathophysiology of NOCAD patients [ 120]. Elevated CRP levels were associated with reduced PET-derived CFR in NOCAD patients,underscoring the role of inf ammation in this patient population [ 121]. PET has also been used to monitor changes in CFR following therapy in CMD patients.Patients treated with a sodium channel inhibitor,ranolazine, for 1 month showed signif cant improvement in PET-derived CFR [ 122].

Conclusion

The burden of ischemic heart disease and CAD is the leading cause of death in women as well as men. NOCAD in women has unique pathobiology, necessitating novel diagnostic and therapeutic approaches, beyond conventional vascular inter-ventions for stenotic lesions. Hypertension, exacerbated by increasing rates of obesity, is a highly prevalent and potent risk factor for cardiovascular events, especially in women. Specif c characteristics of coronary circulation in women, compared with men, and the presentation of CAD with microvascular disease strongly support newer diagnostic technologies to unmask myocardial ischemia.Diagnostic approaches using CT, MRI and PET are rapidly developing. Clinicians will need to recognize the emerging concepts of NOCAD in women to appropriately diagnose and treat this previously underrecognized patient population.

Conflict of Interest

The authors declare that they have no conf icts of interest.

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