Characteristic Symptoms in Women with Ischemic Heart Disease
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Purpose of Review
Advances in coronary imaging techniques have revealed that there are important sex differences in the pattern of ischemic heart disease. In this review, we aim to summarize our current knowledge and focus on the relation between a distinct symptom presentation in women and their underlying type of coronary artery disease.
Women in the age group 40–70 years more often have non-obstructive coronary artery disease (CAD) and coronary vasomotor disorders compared with the traditional obstructive CAD as seen in men. These differences in pathophysiology translate into another symptom presentation which we should rather call characteristic than atypical. Women at risk for coronary vasomotor disorders often have co-morbidities and an enhanced pro-inflammatory state, which leads the way to the appropriate diagnosis. Progress has been made with invasive testing to better discriminate between coronary spasm and microvascular dysfunction. Treatment options are still limited and often disappointing for this heterogeneous patient population.
Sex differences in ischemic heart disease truly exist and have been clearly defined over the past years. We should therefore approach female patients according to this acquired knowledge. The challenge for the coming years will be a more tailored diagnostic and therapeutic approach for symptomatic women at middle-age.
KeywordsAtherosclerosis Coronary spasm Ischemic heart disease Microvascular dysfunction Women
Female patients have historically been confusing for cardiologists. Being educated in treating obstructive coronary artery disease (CAD), its different pattern of symptoms and atherosclerosis have surprised so many. In the early 1990s of the last century, it was first assumed that women were discriminated in diagnostics and treatment of CAD [1, 2]. In addition, it was considered that gender issues in CAD were mainly driven by a different way in symptom expression and not by biological (sex) differences.
With the evolving knowledge gained by many percutaneous coronary intervention (PCI) research programs for acute coronary syndrome (ACS) and elective PCI over the past decades, we have learned that sex differences in ischemic heart disease (IHD) truly exist. Obstructive CAD occurs 7–10 years later in women than in men, and women have fewer focal stenotic lesions at all ages . They have a lower plaque burden with less vascular calcifications, a more diffuse pattern of atherosclerosis, and more often soft plaques and erosive lesions [4, 5, 6, 7]. Only a quarter of all included patients in PCI registries are women, reflecting their different pattern of disease [8••]. When having an ACS or an elective PCI, women are older with a higher clustering of traditional CVD risk factors. Coronary vasomotor disorders, such as coronary artery spasm (CAS) and endothelial dysfunction, represent a major cause of ischemic cardiac symptoms in middle-aged women.
Differences in underlying pathophysiology lead to a more distinct presentation of angina symptoms and warrant a more gender-sensitive, diagnostic, and therapeutic approach than the usual male-oriented pathway. As appropriate diagnoses are often lacking, this leads to an ongoing under-treatment and results in adverse outcomes in the long run. It is therefore not amazing that we observe a rise in the number of hospitalizations for ACS in younger women, even under 55 years of age [9•, 10•].
Ischemia with Non-obstructive Coronary Arteries
Women with symptoms of angina have twice as often ischemia with non-obstructive coronary arteries (INOCA) compared with men [3, 11]. Another often used term is NOCAD, meaning non-obstructive coronary artery disease. The over-emphasis of obstructive CAD over INOCA in our guidelines is one of the main reasons that women are still less well treated than men . When coronary stenosis is less than 50% at angiography, with a fractional flow reserve (FFR) ≥ 0.80, it is considered to be not significant. Non-obstructive CAD is often present in combination with coronary vasomotor disorders, such as spasm and endothelial dysfunction of the larger and smaller branches of the coronary tree [13, 14•]. In most symptomatic patients, intravascular ultrasound (IVUS) shows some signs of coronary atherosclerosis . However, IVUS is not routinely carried out in patients with INOCA, which may lead to the misdiagnosis of “clean arteries” and subsequent under-treatment of symptoms and risk factors. It has been demonstrated that INOCA is not a benign condition and that it has a higher 5-year event rate in symptomatic women compared with men, especially when signs of ischemia are present [16, 17]. Women with INOCA represent a very heterogeneous group, regarding the extent of atherosclerosis, the presence of risk factors, symptoms, and functional impairment.
Fluctuating Symptoms in Women with INOCA
The clinical evaluation of symptoms of angina pectoris in women is still considered along with the male standard of obstructive CAD. The combination of INOCA with vasomotor disorders frequently occurs in young and middle-aged women. Whereas typical symptoms of angina are more related to epicardial stenoses, the combination of INOCA with vasomotor dysfunction has other characteristics. Depending on the involvement of coronary spasm and endothelial dysfunction, chest pain may occur both at rest and during exercise and often varies over time. Symptoms fluctuate within days and weeks and may present in a crescendo/decrescendo pattern. The majority of patients feel unusually tired with a lack of energy. The traditional risk factors such as hypertension and dyslipidemia may serve as triggers for vascular dysfunction and coronary spasm. Stress-related factors are equally important risk factors and can also act as triggers for vascular dysfunction [18, 19•, 20]. Stressful circumstances and events often aggravate the duration and intensity of symptoms .
Classification of angina with female-specific aspects (♀)
Typical angina (definite)
Meets 3 of the following characteristics:
• Oppressive substernal chest discomfort
• Provoked by exertion or emotional stress
• Relieved by rest and/or nitrates within minutes
♀ Squeezing, tight, chest discomfort
♀ Radiation to chest, jaw(s), left armpit and/or left arm, neck, shoulders, and inter-scapular area
♀ May last longer than minutes
♀ Crescendo /decrescendo character (spasm)
♀ Dyspnea, anxiety, mental stress-related
♀ Extreme tiredness, also often after angina episode
Atypical angina (probable)
Meets 2 criteria
♀ Both typical and atypical symptoms in NOCAD
Non-anginal chest pain
Lacks or meets only one characteristic criterion
♀ Beware of cardiac anxiety disorder
Coronary Microvascular Dysfunction Type 1 Dominates in Women
Symptoms in patients with type 1 CMD overlap strongly with INOCA and share their fluctuating and often unpredictable character. Angina pectoris can occur both during exercise and spontaneous in the evening or at night. Affected patients often report to be extremely tired in the days after many activities.
Diagnosis and Management of Coronary Vasomotor Disorders
The Coronary Vasomotion Disorders International Study Group (COVADIS) has recently published two separate consensus statements on vasospastic angina and microvascular angina as guidance for coronary vasomotor disorders [33, 34••]. As the diagnosis cannot be established based on symptoms alone, additional non-invasive and invasive testing for ischemia are recommended. With positron emission tomography (PET) using ammonia, coronary flow reserve (CFR) can be measured. A CFR < 2.5 is considered to be abnormal and a CFR < 2.0 is associated with adverse cardiac outcomes . Despite, in many symptomatic patients, PET scans are not abnormal, presumably because vasospastic angina dominates over CMD.
Obstructive CAD can be ruled out with CT angiography when a coronary angiography has not been done previously. The best way to establish the diagnosis of vasomotor disorders is to perform invasive measures of the index of microvascular resistance (IMR) and CFR and to perform vasoreactivity testing with acetylcholine. This can be safely done by expert invasive cardiologists, using a standardized protocol [36, 37]. These invasive tests are important to discriminate between vasospasm of the epicardial coronary arteries and the coronary microvasculature. Abnormal test results are associated with adverse outcomes .
Treatment of coronary vasomotor disorders starts with lifestyle interventions and appropriate and adequate control of the traditional risk factors. The use of anti-platelet therapy is not routinely recommended, whereas statins are primarily indicated when lipid levels are elevated. Importantly, blood pressure should be more strictly treated than what the guidelines advice. In most patients, short-acting nitrates are helpful to relieve symptoms, but not at all times [12, 39]. Long-acting nitrates may even aggravate symptoms. Depending on the resting heart rate, high doses of calcium-antagonists can be given, preferably diltiazem, even combined with low doses selective beta-blockers. In patients with refractory angina, non-traditional treatment options can be beneficial. These include xanthine derivates, ivabradine, nicorandil, and ranolazine [12, 39, 40]. The use of postmenopausal hormone replacement therapy has no additional beneficial effect in women with CMD. As there is no standard treatment suited for every patient, it may take time to find the best individual options. Stress reduction programs with mindfulness and yoga can be helpful in symptom reduction.
Advances in coronary imaging and the increased attention to coronary vasomotor disorders over the past years are important reasons why female patients are now more into the spotlight. Progress has been made in better defining their characteristic symptoms with important diagnostic and therapeutic steps forward. However, many questions are still unresolved. More fine-tuning in diagnosis and therapy is needed to better serve each individual patient.
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Conflict of Interest
The author declares that she has no conflict of interest.
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- 1.Steingart, R.M., Packer M., Hamm P., Coglianese M.E., Gersh B., Geltman E.M., Sollano J., Katz S., Moyé L., Basta L.L., Lewis S.J., Gottlieb S.S., Bernstein V., McEwan P., Jacobson K., Brown E.J., Kukin M.L., Kantrowitz N.E., Pfeffer M.A., Sex differences in the management of coronary artery disease. Survival and Ventricular Enlargement Investigators. N Engl J Med, 1991. 325(4): p. 226–230.CrossRefGoogle Scholar
- 8.•• Chieffo A, et al. Percutaneous coronary and structural interventions in women: a position statement from the EAPCI Women Committee. EuroIntervention. 2018;14(11):e1227–35 This paper from the EAPCI Women Committee highlights the ongoing issues with the diagnosis and treatment of CAD in women. Differences in the pathophysiology between sexes are summarized, highlighting the need for greater awareness amongst healthcare professionals to enable the best evidence-based therapies for women and men.CrossRefGoogle Scholar
- 9.• Gabet A, et al. Acute coronary syndrome in women: rising hospitalizations in middle-aged French women, 2004-14. Eur Heart J. 2017;38(14):1060–5 This nationwide study showed substantial rising trends in STEMI annual incidence, especially among younger women. This increase could be attributed to increase in smoking and obesity. There is growing evidence of higher short-term mortality of CHD in women.CrossRefGoogle Scholar
- 10.• Arora S, et al. Twenty year trends and sex differences in young adults hospitalized with acute myocardial infarction. Circulation. 2019;139(8):1047–56 The proportion of AMI hospitalizations attributable to young patients increased from 1995 to 2014 and was especially pronounced among women. Compared with young men, young women presenting with AMI had a lower likelihood of receiving guideline-based AMI therapies.CrossRefGoogle Scholar
- 14.• Bairey Merz CN, Pepine CJ, Walsh MN, Fleg JL, Camici PG, Chilian WM, et al. Ischemia and no obstructive coronary artery disease (INOCA): developing evidence-based therapies and research agenda for the next decade. Circulation. 2017;135(11):1075–92 This document provides a summary of findings and recommendations for the development of an integrated approach for identifying and managing patients with ischemia with no obstructive coronary arteries and outlines knowledge gaps in the area.CrossRefGoogle Scholar
- 17.Gulati M, Cooper-DeHoff RM, McClure C, Johnson BD, Shaw LJ, Handberg EM, et al. Adverse cardiovascular outcomes in women with nonobstructive coronary artery disease: a report from the Women's Ischemia Syndrome Evaluation Study and the St James Women Take Heart Project. Arch Intern Med. 2009;169(9):843–50.CrossRefGoogle Scholar
- 18.Konst RE, et al. Different cardiovascular risk factors and psychosocial burden in symptomatic women with and without obstructive coronary artery disease. Eur J Prev Cardiol. 2018:2047487318814298.Google Scholar
- 19.• Kivimaki, M. and A. Steptoe, Effects of stress on the development and progression of cardiovascular disease. Nat Rev Cardiol, 2018. 15(4): p. 215–229. Expert review on the role of stress in cardiovascular disease. Stress has an important role as a disease trigger in individuals who already have a high atherosclerotic plaque burden, and as a determinant of prognosis and outcome in those with pre-existing cardiovascular or cerebrovascular disease. Google Scholar
- 25.•• Kaski JC, Crea F, Gersh BJ, Camici PG. Reappraisal of ischemic heart disease. Circulation. 2018;138(14):1463–80 Expert document on the importance of microvascular dysfunction in patients with ischemic heart disease. Structural and functional disturbances of the coronary microcirculation importantly contribute to obstructive and non-obstructive CAD.CrossRefGoogle Scholar
- 26.•• Faccini A, Kaski JC, Camici PG. Coronary microvascular dysfunction in chronic inflammatory rheumatoid diseases. Eur Heart J. 2016;37(23):1799–806 Inflammation can affect coronary microvascular function and contributes to the development of myocardial ischemia and cardiovascular events, even in the absence of obstructive epicardial coronary artery disease. The possible link between systemic inflammation and CMD may lead to an improvement in the treatment of CV involvement in chronic inflammatory disorders. Expert paper.CrossRefGoogle Scholar
- 28.•• Ford TJ, et al. Systemic microvascular dysfunction in microvascular and vasospastic angina. Eur Heart J. 2018;39(46):4086–97 Case–control study to investigate peripheral small artery changes in two distinct groups of INOCA—those with microvascular angina (MVA) and those with vasospastic angina (VSA). It was found that systemic microvascular abnormalities are common in patients with MVA and VSA. These mechanisms may involve ET-1 and were characterized by endothelial dysfunction and enhanced vasoconstriction.CrossRefGoogle Scholar
- 30.• Cornelius DC. Preeclampsia: from inflammation to immunoregulation. Clin med insights blood Disord. 2018;11:1179545X17752325 Expert paper on enhanced inflammation in women after preeclampsia (PE). PE is associated with chronic immune activation characterized by persistently higher levels of pro-inflammatory cytokines and diminished immunoregulatory factors. This immune imbalance promotes an inflammatory state during PE.CrossRefGoogle Scholar
- 31.• Zoet GA, Benschop L, Boersma E, Budde RPJ, Fauser BCJM, van der Graaf Y, et al. Prevalence of subclinical coronary artery disease assessed by coronary computed tomography angiography in 45- to 55-year-old women with a history of preeclampsia. Circulation. 2018;137(8):877–9 First paper to decribe a twofold higher risk of any CAC as sign of subclinical atherosclerosis in young women after preeclampsia.CrossRefGoogle Scholar
- 36.Wei J, Mehta PK, Johnson BD, Samuels B, Kar S, Anderson RD, et al. Safety of coronary reactivity testing in women with no obstructive coronary artery disease: results from the NHLBI-sponsored WISE (Women's Ischemia Syndrome Evaluation) study. JACC Cardiovasc Interv. 2012;5(6):646–53.CrossRefGoogle Scholar
- 37.Ong P, Athanasiadis A, Borgulya G, Vokshi I, Bastiaenen R, Kubik S, et al. Clinical usefulness, angiographic characteristics, and safety evaluation of intracoronary acetylcholine provocation testing among 921 consecutive white patients with unobstructed coronary arteries. Circulation. 2014;129(17):1723–30.CrossRefGoogle Scholar
- 40.Rambarat CA, Elgendy IY, Handberg EM, Bairey Merz CN, Wei J, Minissian MB, et al. Late sodium channel blockade improves angina and myocardial perfusion in patients with severe coronary microvascular dysfunction: Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction ancillary study. Int J Cardiol. 2019;276:8–13.CrossRefGoogle Scholar
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