HOW TO TREAT 27 anginal symptoms. 64 With the same classical anginal symptoms, women are much less likely to have obstructive CAD and more likely to have CMD as a cause of their symptoms. INOCA has a wide range of clinical presentations, with symptoms varying over time, so do not automatically classify symptoms as non-cardiac in origin.
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HOW TO TREAT 27 anginal symptoms. 64 With the same classical anginal symptoms, women are much less likely to have obstructive CAD and more likely to have CMD as a cause of their symptoms. INOCA has a wide range of clinical presentations, with symptoms varying over time, so do not automatically classify symptoms as non-cardiac in origin.
Prognosis
INOCA and ANOCA are associated with impaired QoL, increased mortality and morbidity, higher hospital readmissions and repeated coronary
65, 66 angiograms. INOCA in women is associated with increased risk of MACE( including cardiovascular death, and MI) and a 10-fold increase in heart failure with preserved ejection fraction( HFpEF), late revascularisation or non-fatal stroke. 67-74 Patients who are older, have diabetes, hypertension or who smoke have worse outcomes and
32, 66 increased all-cause mortality.
While patients with obstructive CAD are at highest risk of MACE, non-obstructive CAD confers an intermediate prognosis with a MACE risk higher than those with minimal / no atherosclerosis. 75, 76 The annual risk of MI / death in a patient with non-obstructive CAD in three coronary arteries is similar to someone with single vessel CAD. 77 When MVA and VSA coexist, the prognosis is worse. 78
Patients with INOCA have more frequent angina, recurrent hospitalisations, worse QoL and physical limitations. 66-68 Women with INOCA continue to have chest pain at one and five years, more anxiety / depression and worse QoL.
44, 45, 79
Not all patients with ANOCA have ischaemia as a cause of their symptoms, thus making the diagnosis of CMD or endothelial dysfunction important.
Diagnosis
The evaluation of INOCA requires the exclusion of non-cardiac and non-ischaemic causes of chest pain and non-obstructive coronary arteries( see figure 5), plus clinical evidence of myocardial ischaemia( see box 2).
Evaluation of non-cardiac and non-ischaemic causes includes a comprehensive clinical history but may require endoscopy, oesophageal manometry, abdominal ultrasound and echocardiography.
Once a marker of myocardial ischaemia is demonstrated and there are no coronary lesions greater than 50 % on angiography, consider a diagnosis of INOCA. Confirmation of the diagnosis may include non-invasive tests( eg, stress PET / CMR [ cardiac magnetic resonance ]) or invasive coronary function testing to enhance diagnosis and risk stratification. 80 The choice of test depends on local availability and expertise; however, a comprehensive assessment of INOCA requires invasive functional coronary angiography with coronary reactivity testing with acetylcholine to diagnose spasm. Invasive testing for INOCA has been associated with improvement in angina and better QoL. 30
Non-invasive methods to detect ischaemia
Common non-invasive methods to detect ischaemia( stress echo, MIBI / myocardial perfusion imaging scans) rely on detection of large regional differences in left ventricular perfusion with or without wall motion
Obstructive CAD
Atherosclerotic CVD( ASCVD)
Figure 3. Chronic or stable IHD.
Traditional risk factors
• Hypertension
• Dyslipidaemia
• Diabetes
• Obesity
• Sedentary lifestyle
• Unhealthy diet
• Smoking
• Chronic kidney disease
• Family history
Figure 4. Risk factors for IHD in women.
Table 1. Diagnostic criteria for microvascular angina Criteria Evidence Diagnostic parameters
1 Symptoms of myocardial ischaemia
2 Absence of obstructive CAD( less than 50 % diameter reduction or FFR greater than 0.80)
3 Objective evidence of myocardial ischaemia
4 Evidence of impaired coronary microvascular function on coronary functional testing
abnormalities in epicardial perfusion territories. These are ineffective at detecting ischaemia affecting the whole left ventricle, such as in patients with CMD. As there is no technique that allows direct anatomical visualisation of the coronary microcirculation( see figure 6), assessment relies on non-invasive measurement of parameters that reflect functional status( eg, myocardial blood flow( MBF)/ coronary flow reserve [ CFR ]). Cardiac PET uses myocardial flow reserve( MFR); an MFR greater than 2.3 is favourable, an MFR less than 1.5 suggests CMD
Effort or rest angina Exertional dyspnoea
Coronary CTCA Invasive coronary angiography
Presence of reversible defect, abnormality or flow reserve on a functional imaging test
Impaired coronary flow reserve( CFR less than 2.0), invasive or non-invasively determined Abnormal coronary microvascular resistance indices( IMR 25 or greater) Coronary microvascular spasm( reproduction of symptoms, ischaemic ECG changes, but no epicardial spasm during acetylcholine testing)
FFR – fractional flow reserve; IMR – index of microcirculatory resistance
Source: Adapted from Kunadian V et al 2020 24
Chronic or stable IHD
Coronary microvascular dysfunction
Non-obstructive CAD
( INOCA)
Vasospasm
Sex specific risk factors
• Adverse pregnancy outcomes: gestational diabetes, hypertensive disorders of pregnancy, preterm delivery, small for gestational age
• Premature / early menopause
• Recurrent miscarriage / stillbirths
• Polycystic ovarian syndrome
• Systemic inflammatory and autoimmune disorders( affect women more)
• Breast cancer treatment
82, 83 and a risk of future cardiac events. Cardiac MRI uses myocardial perfusion reserve( MPR) to quantify MBF. MPR index of 1.5 or less is abnormal
83, 84 and low MPR correlates with CMD. These non-invasive tests have limited ability to evaluate vasospasm.
Invasive methods
Invasive coronary angiogram images the coronary artery lumen, while functional coronary angiography provides a pathophysiological assessment of the coronary circulation( see box 3).
Functional coronary angiography
Myocardial bridge
Under-recognised / non-traditional risk factors
• Psychological risk factors( depression, anxiety, loneliness, perceived stress)
• Abuse and intimate partner violence
• Socioeconomic deprivation
• Poor health literacy
• Environmental Risk factors( eg, air pollution)
• Cancer treatment
helps classify patients into INOCA endotypes— including CMD, epicardial vasospasm, or mixed( both CMD and vasospasm); helps guide treatment and is superior to angiography alone in improving angina burden
88, 89
( see figure 7).
Treatment of INOCA
Treatment of INOCA( see figure 8) includes non-pharmacologic measures( avoiding precipitants, cardiac rehabilitation, home based exercise programs, traditional risk factor management, meditation and stress reduction techniques) and pharmacologic management according to the‘ endotype.’
AVOIDING PRECIPITATING AND AGGRAVATING FACTORS Smoking is a key risk factor for vasospastic angina, cessation is strongly recommended. 91 Sympathomimetic agents( eg, recreational cocaine, methamphetamines, ecstasy), and therapeutically used sympathomimetic agents( eg, adrenaline, noradrenaline and methylphenidate), have been reported as precipitating coronary spasm. 92-96 Beta blockers can precipitate vasospastic angina but are used to improve angina in CMD. 97 Other drugs( eg, ergot alkaloids, serotonin uptake inhibitors and some chemotherapy agents) can precipitate vasospastic angina, as can general anaesthesia. 98-102
MENTAL STRESS This has been associated with epicardial coronary artery spasm, CMD, myocardial ischaemia in the
Adapted from Khandelwal A et al 2021 25 Adapted from Vogel B et al 2021 35
Box 2. Markers of ischaemia
• Typical angina pectoris(“ a strangling sensation in the chest”).
• Ischaemic ECG changes.
• Impaired myocardial perfusion on stress imaging.
• Stress-induced regional wall motion abnormalities.
• Abnormal hyperaemic coronary blood flow responses( ie, impaired coronary flow reserve).
Box 3. What is assessed by functional coronary angiography
• Whether equivocal coronary stenoses are functionally obstructive, via measurement of fractional flow reserve( FFR): an abnormal FFR is 0.80 or less.
• Whether CMD is present by measuring coronary flow reserve( CFR) and index of microcirculatory resistance( IMR):— An abnormal CFR is 2 or less.— IMR 25 or greater is suggestive of CMD.
85, 86
• Whether inducible coronary artery spasm is present on using intracoronary acetylcholine:— Epicardial vasospasm:
• Acetylcholine triggers reproducible chest pain, ischaemic ECG changes and greater than 90 % reduction in coronary artery diameter.
• Microvascular spasm is diagnosed when there is chest pain and ECG changes, but less than 90 % reduction in coronary artery diameter. 87
absence of CAD, and precipitation / aggravation of symptoms, so should be avoided. 103-05 INOCA has also been associated with anxiety and
106, 107 depression.
LIFESTYLE FACTORS Lifestyle measures to address risk factors, reduce symptoms and improve QoL are important and include exercise, stress management, yoga, meditation and dietary modification for weight loss. Take measures to address obesity. 24 Cardiac rehabilitation has been associated with improved functional capacity. 24 Aerobic exercise has been shown to reduce angina episodes in VSA. 108
TRADITIONAL RISK FACTORS Hypertension, dyslipidaemia, smoking and diabetes may all contribute to the pathology of CMD, vasospastic dysfunction and structural remodelling of the circulation. 24 Guideline-directed preventive pharmacological therapies to reduce CV risk factors is key, and intensification of preventive therapies in symptomatic patients with non-obstructive
24, 109
CAD is recommended.
Hypertensive microvasculature impairs myocardial perfusion and induces anginal symptoms. 110 Good BP control aims to prevent progression of microvascular changes and reduce the frequency and intensity of anginal symptoms. 111 Combination therapy can be used depending on the INOCA endotype( eg, ACE-I improve CFR in CMD and reduce angina frequency), and can be combined with PAGE 30