Dr Rachel Bastiaenen, PhD, St George's Hospital London, UK

Recognition of ischaemic heart disease (IHD) is frequently delayed in women. In part this relates to differences in the underlying pathophysiology. Whereas symptoms in men are commonly due to flow-limiting atherosclerotic coronary artery disease (CAD), women are more likely to present with non-obstructive CAD (with a tendency to plaque erosion and thrombus) and coronary microvascular dysfunction (CMD). There are emerging data that demonstrate more extensive non-obstructive CAD is associated with an increased rate of major adverse cardiovascular (MACE) events, but our understanding of this is limited by gaps in current knowledge.

The Women’s Ischaemia Syndrome Evaluation (WISE) study examined symptomatic women referred clinically for coronary angiography. 540 women (62%) had suspected ischaemia but no angiographic evidence of obstructive CAD (defined as no stenosis ≥50%).(1) These were compared with age and sex matched controls. At 5 years the annualized event rates (first occurrence of death, nonfatal myocardial infarction (MI), nonfatal stroke or heart failure hospitalisation) were 16.0% in WISE women with non-obstructive CAD (stenosis in any coronary artery 1-49%), 7.9% in WISE women with normal coronary arteries (stenosis 0% in all coronary arteries) and 2.5% in asymptomatic controls after adjusting for baseline CAD risk factors (p=0.002). At 10 years cardiovascular death or MI had occurred in 6.7%, 12.8% and 25.9% of WISE women with no CAD, non-obstructive CAD and obstructive CAD respectively (p<0.001).(2) The authors conclude that amongst women with symptoms and signs of ischaemia, non-obstructive CAD is common and associated with adverse outcomes.

Limitations of the WISE data largely relate to the study design: absence of men, small sample size and selection bias at the referring centres. However, multiple larger studies in Canada, USA and Europe, have replicated the high prevalence of non-obstructive CAD in angina patients and the adverse prognosis in women. It appears that, contrary to common perception, excluding obstructive CAD by angiography in stable angina patients (particularly women), does not ensure a benign prognosis. Further research is needed to better understand the pathophysiology, treatments and outcomes for non-obstructive CAD.

References

  1. Gulati M, Cooper-DeHoff RM, McClure C, 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;169:843–50.
  2. Sharaf B, Wood T, Shaw L, et al. Adverse outcomes among women presenting with signs and symptoms of ischemia and no obstructive coronary artery disease: findings from the National Heart, Lung, and Blood Institute-sponsored Women’s Ischemia Syndrome Evaluation (WISE) angiographic core laboratory. Am Heart J 2013;166:134–41.
Cardio Debate Expert Comments

In the recent PROMISE trial comparing an anatomical versus functional strategy in patients with stable angina and comprising more than 10,000 patients, only approximately 10% of patients with angina underwent invasive angiography and ultimately only 5% were revascularized1. This leaves more than 90% of patients with angina without obstructive CAD to explain their symptoms.

The issue of non-obstructive angina is an important one and the impact of the disease is huge. An estimated 6.7% of the population have angina, increasing further with age and more commonly seen in women than in men.  Angina is the most common manifestation of heart disease in women. Guidelines recommend non-invasive testing in the majority of patients with angina before referral to invasive angiography. This means that the majority of patients do not – and should not– reach invasive angiography. Yet our knowledge on prognosis of these patients is mainly based on the minority that reaches angiography.

The prognosis of patients with angina in terms of CVD events has been shown to be more similar to patients with obstructive CAD than to the back-ground population, as noted by Dr Bastiaenen. The impact on quality of life, anxiety and depression due to continued and unexplained chest pain is just as dire 2;3, as is the likelihood of repeated angiographies showing no obstructive CAD .

The impaired prognosis may be related to coronary microvascular dysfunction. Unfortunately, microvascular dysfunction is not easily diagnosed non-invasively and only few centers routinely assess microvascular function during angiography. Results of stress tests and symptom characteristics seem of little help in identifying coronary microvascular dysfunction4. Thus, more studies addressing the issue are needed and these should increasingly involve the majority of patients with angina who do not reach angiography.

References

  1. Douglas PS, Hoffmann U, Patel MR, Mark DB, Al-Khalidi HR, Cavanaugh B et al. Outcomes of anatomical versus functional testing for coronary artery disease. N Engl J Med 2015; 372(14):1291-1300.
  2. Jespersen L, Abildstrom SZ, Hvelplund A, Prescott E. Persistent angina: highly prevalent and associated with long-term anxiety, depression, low physical functioning, and quality of life in stable angina pectoris. Clin Res Cardiol 2013; 102(8):571-581.
  3. Jespersen L, Abildstrom SZ, Hvelplund A, Madsen JK, Galatius S, Pedersen F et al. Burden of hospital admission and repeat angiography in angina pectoris patients with and without coronary artery disease: a registry-based cohort study. PLoS One 2014; 9(4):e93170.
  4. Sara JD, Widmer RJ, Matsuzawa Y, Lennon RJ, Lerman LO, Lerman A. Prevalence of Coronary Microvascular Dysfunction Among Patients With Chest Pain and Nonobstructive Coronary Artery Disease. JACC Cardiovasc Interv 2015; 8(11):1445-1453.
 

The increasingly acknowledged concept of non-obstructive coronary artery disease (CAD) comprises signs and symptoms suggestive of atherosclerotic epicardial artery stenosis but with lumen reduction of coronary arteries of <50 percent and at least one vessel wall abnormality of ≥20 percent. 1 Patients with nonobstructive CAD are a heterogeneous population. Most individuals with nonobstructive CAD show some signs of atherosclerotic plaque. Although it is diagnosed in women in the majority of cases it is not a disease exclusive to female gender: up to 65 percent of women with suspected CAD and about one third of men have nonobstructive CAD on angiography for stable angina.2 About 10 percent of patients admitted with symptoms of acute coronary syndrome and myocardial infarction have nonobstructive CAD, more than half of them are women.3 The pathophysiology most likely underlying the disease is endothelial dysfunction and microvascular impairment. Major adverse cardiovascular events are not negligible in the group of symptomatic individuals with nonobstructive CAD independent of gender and prognosis is not benign.4

The recognition of non-obstructive CAD as a serious disease leads to the dilemma that we need to act but do not have guidelines to help us with the diagnosis and treatment of the disease. Broadly applied, uniform criteria for the definite diagnosis of the disease have not been established. The WISE (Women’s Ischemic Syndrome Evaluation) undertook the first large effort to define the disease by standardized quantitative measurement methods and core lab readings of angiography results in women. However, the best way of diagnosing nonobstructive CAD has not been identified. Fractional flow reserve and intravascular ultrasound can help to exclude epicardial obstruction that is not detected on the angiogram. Endothelial function testing using intracoronary acetylcholine and microvascular resistance testing with adenosine may help identify vascular dysfunction. Current therapeutic options are limited to symptom relief. Therefore, in addition to a better understanding of the underlying disease in men and women, innovative methods for diagnosis and therapy of non-obstructive CAD are required and need focused research efforts.

References

  1. Pepine CJ, Ferdinand KC, Shaw LJ, Light-McGroary KA, Shah RU, Gulati M, Duvernoy C, Walsh MN, Bairey Merz CN. Emergence of Nonobstructive Coronary Artery Disease: A Woman's Problem and Need for Change in Definition on Angiography. J Am Coll Cardiol2015;66:1918-1933.
  2. Jespersen L, Hvelplund A, Abildstrom SZ, Pedersen F, Galatius S, Madsen JK, Jorgensen E, Kelbaek H, Prescott E. Stable angina pectoris with no obstructive coronary artery disease is associated with increased risks of major adverse cardiovascular events. Eur Heart J 2012;33:734-744.
  3. De Ferrari GM, Fox KA, White JA, Giugliano RP, Tricoci P, Reynolds HR, Hochman JS, Gibson CM, Theroux P, Harrington RA, Van de Werf F, White HD, Califf RM, Newby LK. Outcomes among non-ST-segment elevation acute coronary syndromes patients with no angiographically obstructive coronary artery disease: observations from 37,101 patients. Eur Heart J Acute Cardiovasc Care 2014;3:37-45.
  4. Murthy VL, Naya M, Taqueti VR, Foster CR, Gaber M, Hainer J, Dorbala S, Blankstein R, Rimoldi O, Camici PG, Di Carli MF. Effects of sex on coronary microvascular dysfunction and cardiac outcomes. Circulation 2014;129:2518-2527.
 

Dr Bastiaenen’s cardionote makes important points in relation to the problem of angina pectoris in women and highlights findings in the recently published Women’s Ischaemia Syndrome Evaluation (WISE) study (1). Differences in clinical presentation and “entrenched views” among cardiologists regarding prevalence of ischaemic heart disease (IHD) in women, contribute to delays in diagnosis and treatment of angina in the female population. Furthermore, the absence of obstructive coronary artery disease in women undergoing cardiac catheterisation for the assessment of chest pain leads, in most cases, to the diagnosis of “non-cardiac chest pain” with patients being discharged without specific treatments.

Current data indicate that extensive non-obstructive CAD is associated with an increased rate of major adverse cardiovascular (MACE) events, and -very importantly- a reduced coronary blood flow reserve in patients with angina despite angiographically normal coronary arteries is also associated with adverse clinical outcomes. Indeed, results of the WISE study –as described by Dr Bastiaenen – showed that in women with symptoms and signs of ischaemia, non-obstructive CAD is common and associated with adverse outcomes thus suggesting that contrary to common perception, in stable angina patients –both men and women- the absence of obstructive coronary artery disease does not guarantee a benign prognosis. Chest pain in these patients is very often the expression of myocardial ischaemia triggered by coronary microvascular dysfunction, i.e. lack of appropriate vasodilatory responses or microvascular spasm, as demonstrated by our studies recently (2-4). There is an important message here for physicians dealing with individuals suffering from angina without obstructive coronary artery disease and the message is that the cause (and mechanisms) for the patients’ symptoms need to be investigated as appropriate, as effective treatments are available for microvascular angina that can improve symptoms and quality of life in a large proportion of patients.

References

  1. WISE – Lourdes please enter the reference that Rachel provided for her comment on this study
  2. Coronary microvascular spasm triggers transient ischemic left ventricular diastolic abnormalities in patients with chest pain and angiographically normal coronary arteries. Arrebola-Moreno AL, Arrebola JP, Moral-Ruiz A, Ramirez-Hernandez JA, Melgares-Moreno R, Kaski JC. Atherosclerosis. 2014;236:207-14. doi: 10.1016/j.atherosclerosis.2014.07.009. Epub 2014 Jul 18.
  3. Clinical usefulness, angiographic characteristics, and safety evaluation of intracoronary acetylcholine provocation testing among 921 consecutive white patients with unobstructed coronary arteries. Ong P, Athanasiadis A, Borgulya G, Vokshi I, Bastiaenen R, Kubik S, Hill S, Schäufele T, Mahrholdt H, Kaski JC, Sechtem U. Circulation. 2014.129:1723-30. doi: 10.1161/CIRCULATIONAHA.113.004096. Epub 2014 Feb 26
  4. High prevalence of a pathological response to acetylcholine testing in patients with stable angina pectoris and unobstructed coronary arteries. The ACOVA Study (Abnormal COronary VAsomotion in patients with stable angina and unobstructed coronary arteries). Ong P, Athanasiadis A, Borgulya G, Mahrholdt H, Kaski JC, Sechtem U.  J Am Coll Cardiol. 2012; 59:655-62. doi: 10.1016/j.jacc.2011.11.015