Microvascular angina, INOCA, MINOCA: not as innocent as they seem
STELLA M. MACÍN1, HUGO R. RAMOS2, MARÍA L. ATENCIO3
On behalf of the Committe on Ischemic Heart Diisease. FAC.
1. Instituto de Cardiología JF Cabral. Corrientes. Facultad de Medicina Universidad Nacional del Nordeste, Corrientes. Argentina. 2. Instituto Modelo de Cardiología Privado S.R.L., Universidad Nacional de Córdoba, Facultad de Ciencias Médicas, Córdoba, Argentina. 3. Instituto del Corazón San Rafael. Hospital Español del Sur Mendocino. Mendoza, Argentina.
Recibido 24-SET-2019 – ACEPTADO -- 18-OCTUBRE-2019.
There are no conflicts of interest to disclose.
MINOCA is a syndrome characterized by symptoms suggesting normal ischemia and coronary arteries or with stenosis less than or equal to 50%, and INOCA by the presence of ischemia without obstructive coronary artery disease. It affects women more frequently, with a prevalence of 3.5 to 40%. It is multifactorial and may correspond to a) epicardial coronary abnormalities (atherosclerotic plaque rupture, ulceration, fissures, erosion or coronary dissection with non-obstructive coronary artery disease or without coronary heart disease): type 1 infarction; b) Imbalance between oxygen supply and demand (such as spasm and coronary embolism, type 2 infarction); c) Coronary endothelial dysfunction (epicardial coronary spasm or microvascular dysfunction, type 2 infarction), and d) Secondary to myocardial disorders without involvement of coronary arteries (myocarditis, cardiomyopathy, Takotsubo cardiomyopathy). Diagnosis is based on the clinical and ECG findings and elevated troponin values. Imaging has a determining role; thus, an angiography is necessary to start the diagnosis of accuracy and establish the cause, and to perform an evaluation of the coronary wall with IVUS or OCT, and when the lesions are moderate in many cases an FFR is necessary. PET provides a highly reliable evaluation of coronary microcirculation, myocardial perfusion, coronary blood flow and left ventricular function; but its high cost makes it not possible to use it routinely in our environment. Treatment should be aimed at correcting the cause; if there is ≤50% obstruction with evidence of atherosclerotic plaque rupture or erosion, the treatment will be that of an ACS.
Over a long time, the analysis on CAD has focused on the presence or absence of obstructive lesions at epicardial level, thus committing to a strictly anatomical preconception of the problem.
In recent years, questions have arisen that led us to propose different hypothesis, after which a change in paradigm is necessary, having to consider a multiple pathophysiology and variable dynamic in myocardial ischemia, not limiting it to just obstruction by atheromatous plaque.
Myocardial infarction (MI) with nonobstructive coronary arteries (MINOCA) is a syndrome characterized by clinical symptoms suggestive of ischemia and normal coronary arteries or with stenosis by angiography ≤50% [1,2].
Likewise, the presence of ischemia with nonobstructive coronary arteries is called INOCA [3,4].
Generally, the absence of characteristic signs or symptoms make its diagnosis difficult, as chest pain often is not differentiated from that caused by obstructive CAD [5,6]. Both men and women are affected; but women with this type of presentation are associated to unstable angina, appearing a decade later than in men [3,7-12]. Other factors include the duration of exposition to risk factors, inflammation and autoimmune diseases, as well as the possible genetic differences contributing to the expression of genes related to gender and its effects on cardiovascular function [12,13]. Coronary microvascular dysfunction is a predominant disorder in women, often perimenopausal or postmenopausal, with onset of symptoms between 40 and 50 years [6, 13-15].
Clinical criteria for the diagnosis of INOCA/MINOCA are [9,10,13,16,17]:
Symptoms of myocardial ischemia.
Objective evidence of ischemia (INOCA)/infarction (MINOCA): for instance, abnormal stress test or evidence of MI according to the fourth universal definition of infarction.
Absence of obstructive CAD or luminal epicardial stenosis ≤50% in invasive coronary angiography [6,10].
No alternative specific diagnosis (for example, sepsis, pulmonary embolism, myocarditis, etc.).
In patients meeting these criteria, additional tests include specialized noninvasive cardiac testing, or invasive coronary reactivity testing to confirm the diagnosis [13,18].
MINOCA has been described as myocardial necrosis in absence of significant coronary atherosclerosis in autopsies [3,4]. DeWood et al, found nonobstructive CAD by angiography in 5% of patients with MI . DeWood, Miller et al, detected in autopsies, absence of obstructive CAD in 6% of infarctions .
There is a great variability, with a range from 3.5 to 15%, attributable to population differences and heterogeneity in the definition . A study found that 40% of women and 8% of men had nonobstructive CAD and similar findings were observed in the CASS registry .
Retrospective studies on ACS, observed between 10 and 25% of women with normal coronary angiograms versus 6 to 10% in men [8,9,14].
A contemporary cohort reported a prevalence of 8.8% and between 10 and 25% in women and 6 to 10% in men that presented with non-ST elevation myocardial infarction (NSTEMI) [22,23].
Consequently, MINOCA is not a rare presentation of infarction, being observed more frequently in young women, of non-Caucasian ethnicity, with less traditional risk factors, and usually presenting with NSTEMI . Patients with MINOCA may have type 1 or 2 MI, according to the universal definition and remarkably it is not a benign syndrome, with a yearly mortality rate of 3.5% [13,22]; and its evolution could be compared to MI with atherosclerotic coronary lesions [1,10,23-26].
The mechanisms contributing to MINOCA are multifactorial and may operate in isolation or combined [9,10,25].
Patients are more prone to present the usual comorbidities, common in obstructive disease, such as diabetes, hypertension, smoking and heart failure .
Its possible etiologies could be grouped as follows: a) Secondary to epicardial coronary alterations (atherosclerotic plaque rupture, ulcers, fissures, erosion or coronary artery dissection with nonobstructive CAD or with no CAD): type 1 infarction; b) imbalance between oxygen output and demand (such as spasm and coronary embolism; type 2 infarction); c) coronary endothelial dysfunction (epicardial coronary spasm or microvascular dysfunction; type 2 infarction); and d) secondary to myocardial disorders with no implication on coronary arteries (myocarditis, cardiomyopathies, Takotsubo cardiomyopathy) .
Atherosclerotic plaque coronary disease: MINOCA comprises 5-20% of all type 1 infarctions, and studies with IVUS identified plaque rupture and erosion in more than 40% of patients [22,27-29].
With intracoronary images by OCT, it is possible to observe myonecrosis with plaque rupture and erosion with thrombosis and spasm, or a combination of these processes . MRI may show large areas of myocardial edema with or without small necrosis areas, or a smaller and properly defined area of late enhancement with gadolinium that is improving, suggesting compromise in a smaller vessel by atherothrombotic embolization [30,31].
Coronary artery dissection: It usually causes infarction by luminal obstruction and it may present with coronary intramural hematoma with no intimal tear, and in most cases, vascular dysplasia is present, with changes in the intima-media composition due to hormones [12,28,32].
Coronary spasm: It reflects hyperreactivity of vascular smooth muscle to endogenous vasospastic substances or exogenous agents such as cocaine or methamphetamines. MINOCA could be a de novo presentation for patients with vasospastic angina, or a temporary event in chronic forms of the disorder [8,9,12,14]. In a recent trial, provocation tests were positive in 46% of patients with MINOCA . Vasoreactivity test with a positive result predicts a worse outcome [12,25,33].
Other frequent causes:
Myocarditis, cardiomyopathies, Takotsubo, constitute around 50% of all cases of MINOCA. Currently, the consumption of sympathomimetic substances, such as cocaine or methamphetamines that may lead to MINOCA, is quite common [34-36].
In Figure 1, an algorithm is shown with the causes of MINOCA and tests to investigate the etiologies.
Figure 1. Algorithm of causes and test investigating for the etiologies of MINOCA.
Clinical symptoms, ECG and troponin establish a diagnosis of ACS, after which imaging tests have a determining role.
Invasive coronary angiography
By definition, MINOCA requires coronary arteries with no atherosclerotic disease or with <50% obstruction, so invasive coronary angiography (ICA) is necessary to start an accurate diagnostic work and establish the cause [16,27]. A meta-analysis gathered data on computed tomography coronary angiogram (CTCA), but current recommendations are based on ICA, so this is still the method of choice [17,37,38].
Because of arteries with <50% stenosis may have had a plaque accident or erosion with thrombosis or dissection, in the centers with the proper technology and expertise, it is advisable to perform an evaluation on the coronary wall with IVUS, OCT or CTCA as discussed below . In the lesions with stenosis near 50% or doubtful, it is advised to use FFR to estimate whether the lesion is hemodynamically significant or not; if FFR is ≤0.80, it is not considered to be MINOCA, but obstructive CAD; if the measured value is normal (>0.80), it is considered a positive diagnosis of MINOCA .
The evaluation of left ventriculogram is also important, considering that if ventricular dysfunction is segmentary and limited to specific coronary territories, it is very likely to be atherosclerotic obstructive coronary lesion, spasm or coronary embolism; instead, if motility alterations are more diffuse and do not follow a segmentary distribution, it is likely to be microvascular disease. In the first case, angiographic testing will be useful to detect the presence of thrombi or anomalies through IVUS, OCT or CTCA, or by testing to detect coronary spasm . In the second case, cardiac MRI with gadolinium, contrast echocardiogram, testing to measure coronary flow reserve with adenosine or IV dipyridamole, or intracoronary injection of acetylcholine or ergonovine .
Intravascular ultrasound and optical coherence tomography
IVUS is useful when placed on the proximal portions of epicardial vessels, searching for plaque rupture or ulceration, presence of thrombus, or spontaneous coronary artery dissection. Plaque alterations were identified by IVUS in 38% of patients, and ulceration in 10% [5,34,38,39].
OCT has ten times the resolution of IVUS, and may identify precisely plaques with a large lipid content and thin fibrous layer [34,40]. In Argentina, IVUS is more readily available than OCT.
Coronary vasoreactivity testing
Coronary spasm or microvascular disease tests are made invasively with coronary angiography. In the absence of evident anomalies such as dissection, plaque rupture, erosion, coronary embolism, Takotsubo, myocarditis, cardiomyopathy, type 2 MI by extracardiac cause, etc., acetylcholine or ergonovine tests are recommended. These have proven to be safer in experienced hands and contribute to the final diagnosis. Invasive vasoreactivity testing consists of administering acetylcholine or ergonovine during angiography in scaled doses, and one minute after the injection, a new coronary angiography is made, or when the patient presents chest pain or ECG changes. A test is considered positive for spasm when a focal or diffuse reduction in coronary diameter ≥90% occurs, in comparison to the basal state, which relaxes after the administration of nitroglycerin and reproduces the symptoms or ischemic changes in ECG. On the contrary, a result is considered microvascular spasm when angina and ischemic ST changes appear, with no spasm detected ≥90% in the epicardial arteries . Table 1
Table 1 . Guide of coronary reactivity tests.
(Based with modifications, on: Borja Ibáñez et al. Eur Heart J 2018; 39: 119-177).
Coronary microvascular dysfunction
Coronary macrovascular dysfunction
Abnormal intracoronary vasodilation with acetylcholine
Reduced coronary blood flow in response to intracoronary acetylcholine
Abnormal vasoreactivity to intracoronary nitroglycerin
Reduced coronary blood flow in response to intracoronary acetylcholine
Cardiac magnetic resonance imaging
Cardiac MRI is useful to detect myocarditis and cardiomyopathies or to confirm the diagnosis of MI or to functionally evaluate coronary flow; this is significant because a significant number of MINOCA occur due to the two first, and do not require secondary prevention or antiplatelet drugs, as when MI with atherosclerotic diseases is diagnosed [41,42].
Dastidar et al, showed in a group of 388 patients, that in 74% of patients, it was possible to reach a diagnosis by MRI: 25% had diagnosis of cardiomyopathy, 25% myocarditis and 25% infarction; while the rest were normal . Another study showed that in 87% of patients, a diagnosis was reached and the most frequent cause was myocarditis (37%), followed by Takotsubo cardiomayopathy (27%), MI (21%) and other etiologies (3%) . In most reports, cardiac MRI was performed from 2 to 37 days after ICA, and it allowed to reach a more accurate etiological diagnosis in 50-87% of cases. A protocol should be followed to enable a full evaluation, and currently one is being evaluated, the hypothesis of which would allow to diagnose at least 70% of cases. In general, it would be advisable to perform it 2-4 days after ICA, when ICA was not enough to reach a diagnosis [43-46].
Positron emission tomography
PET provides a highly reliable evaluation on coronary microcirculation, coronary blood flow and left ventricular function [37,46]. But due to its high cost and little availability, in our country as in others, this technique is still not widely used .
Computed tomography coronary angiography
CTCA allows to evaluate the presence of obstructions and also, coronary vascular wall. However, an accurate diagnosis still corresponds to invasive coronary angiography . It would be indicated to evaluate the coronary wall in <50% obstructions; although as in most of the other techniques there is still missing evidence to make recommendations and these are being studied. As iodinated contrast is used just as with coronary angiography, it would be advisable to perform CTCA around 30 days later to prevent contrast nephropathy [12,42,47].
In a systematic review, it was found that up to 14% of patients abnormal tests were detected with factor V Leiden, proteins C and S deficit, and factor XII deficit, so it would be advisable to perform screening tests in some patients.
Diagnostic algorithm of infarction with no obstructive atherosclerotic coronary disease. Figure 1 (with modifications, based on: Nicolli G, et al. Eur Heart J 2015;36(8): 475-81). ECG: Electrocardiogram; TTE: Transthoracic echo; IVUS: Intravascular ultrasound; OCT: Optical coherence tomography.
The prognosis of patients with MINOCA depends on the underlying cause and is currently under active investigation. Table 2
Table 2. MINOCA etiology
(Based with modifications on: Jacqueline E. Tamis-Holland et al. Circulation 2019; 139: 00-00).
Reduced troponin clearance
Increase in right pressures
CT angiography of pulmonary arteries. Angiographic MRI of pulmonary vessels.
Structural myocardial dysfunction
Cardiac Doppler echocardiography Cardiac MRI
CRP, cardiac MRI, color Doppler echocardiography
Coronary artery spasm
Provocation test with acetylcholine. Drugs screening: cocaine, methamphetamines.
Coronary flow reserve Provocation test with acetylcholine TIMI flow
Factor V Leiden
Protein C or S deficit
Factor XII deficit
Thrombophilia Diagnostic screening
Most of the studies have shown that patients with MINOCA have better results than those with infarction and obstructive coronary lesions. However, this finding is not consistent in all reports. In the VIRGO study, patients with MINOCA presented similar mortality rates at 1 month and 1 year compared with those with obstructive lesions [12,32,48].
In the SWEDEHEART registry, with a mean follow-up of 4.1 years, mortality was 13.4%, 7.1% suffered another myocardial infarction, 4.3% had ischemic stroke, 6.4% was admitted due to heart failure, and 3.6% presented bleeding [5,28,34].
Recently, a study with cardiac MRI showed that the patients with worse prognosis are those in whom cardiomyopathy is the disease causing MINOCA and those presenting with ST-elevation MI in ECG .
Predictors of adverse outcome
INOCA: Advanced age, hypertension, diabetes and smoking were associated to higher mortality; while gender, hypercholesterolemia, family history of premature CAD, or the chance of previous CAD were not .
MINOCA: Female gender and a younger age (mean age = 59 vs 64 years) were the only independent predictors [6,7,9,34,37].
The diagnosis of MINOCA allows for a proper risk stratification for future cardiovascular events; as well as the characterization to lead the therapy and improve the chance of therapeutic success [9,32,34].
In Figure 2, diagnostic algorithm for MINOCA (with modifications, based on: Agewall S et al. Eur Heart J 2016.)
Figure 2. Diagnostic algorithm for MINOCA
TREATMENT. Table 3
Table 3. Treatment of patients with angina, evidence of
ischemia and nonobstructive coronary lesions .
Coronary microvascular dysfunction
Anomalies in endothelial function.
Converting enzyme inhibitors
Enhanced external counterpulsation
Anomalies in non-endothelial function.
β-blockers and alpha and β-blockers
Optimization of energy-saving mechanisms in cardiomyocytes (beta-oxidation block, favoring glucose consumption above fatty acids).
Anomalies in muscle function (Prinzmetal angina)
Calcium channel blockers
Anomalies in nociception
Medication with low doses of tricyclic antidepressants
Spinal cord stimulation
Cognitive behavioral therapy
As in any pathology in INOCA or MINOCA, the cause should be treated; i.e. if there is <50% obstruction but evidence of atherosclerotic plaque rupture or erosion, the treatment should be that of ACS (aspirin, antiplatelet aggregation and statins) and may benefit from angiotensin-converting enzyme inhibitors (ACEI) [49,50].
Previous trials with statins and IVUS have documented that secondary prevention favorably influenced progression, or even regression of atherosclerosis in coronary arteries, as well as endothelial smooth muscle [10,16,34].
ACEIs improve tolerance to exercise and angina symptoms. In an auxiliary trial of the WISE, women using quinapril improved their angina symptoms [28,29,51].
Patients with essential hypertension presented a marked improvement after 12 months of treatment with perindopril, with regression of periarterial fibrosis verified in biopsy [52,46].
In coronary artery dissection, a conservative approach is preferred, because coronary intervention and stent placement tend to spread the dissection; while the results are acceptable with pharmacological treatment. Hospital survival and long-term survival are good; but there is 27% of recurrence of events in 5 years. In spite of a lack of evidence, beta blockers and antiplatelet therapy alone are considered in pharmacological treatment [27,29].
In the disorders with epicardial coronary spasm, the drugs of choice are calcium channel blockers; but other alternative drugs could be considered, such as nitrates, nicorandil, cilostazol and statins.
In microcirculation disorders, beta blockers and calcium channel blockers are to this moment, the drugs of choice even when in spite of not being effective, a scheme has been suggested based on numerous alternative drugs such as L-arginine, ranolazine, nitrates, ivabradine, ACEI, statins, xantines, dipyridamole, alpha blockers, imipramine or estrogens for selected patients [15,17].
Studies showed improvement in symptoms and ischemia with trimetazidine, a myocardial intracellular metabolic modulator; but more research is necessary in this field [53-56].
Patients with abnormal vasodilator reserve improve their symptoms with verapamil or nifedipine, with lower requirement of nitrates and better tolerance to exercise. Using nitrates may improve symptoms [26,46].
In patients with diagnosis by cardiac MRI of myocarditis, endomyocardial biopsy would be indicated, and the corresponding treatment according to the result. Likewise, when the diagnosis is dilated or hypertrophic cardiomyopathy, or Takotsubo, will be subsequently treated [16,17].
In thrombosis or coronary embolism, antiplatelet agents or anticoagulants are indicated, or specific therapies for coagulation disorders already mentioned above [16,17].
Ranolazine, aminofiline, imipramine, spinal cord stimulation, behavioral therapy and cardiac rehabilitation require controlled studies to establish their efficacy and safety [7,26,31,52,57].
Further, any therapy should include control of risk factors and modifications in lifestyle, optimization of body weight, suppression of smoking, fibers, fruits and vegetables consumption, and regular physical activity .
The prevalence of nonobstructive CAD is increasing and to the diagnosis of microvascular angina, the concepts of INOCA and MINOCA have been added, and currently, a comprehensive diagnostic strategy and risk stratification include imaging tests and possibly, assessment of vasoreactivity and coronary flow by invasive and noninvasive methods.
Coronary reserve tests could be useful in microvascular angina, and cardiac MRI has a central role for an accurate diagnosis in more than 2/3 of cases of INOCA and MINOCA.
Several studies have suggested benefits with some drugs, and new clinical trials will provide data based on evidence. Clinically, the diagnosis of MINOCA should be considered only in patients in whom the presentation suggests true infarction (meeting all conventional principles: positive ECG, characteristic pain and increased biomarkers), in whom the absence of obstructive coronary lesions or significantly anatomical lesions can be documented.
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