PART III - ISCHEMIA AND MYOCARDIAL INFARCTION WITHOUT OBSTRUCTIVE CORONARY ARTERY DISEASE
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PART III

Ischemia and myocardial infarction without obstructive coronary artery disease

Alaide Chieffo1, Valeria Paradies2, Alessandro Beneduce1, Javier Escaned3
1Interventional Cardiology Unit, San Raffaele Scientific Institute, Milan, Italy.
2Department of Cardiology Unit, Maasstad Hospital, Rotterdam, Netherlands.
3Department of Cardiology, Hospital Clinico San Carlos, Instituto de Investigación Sanitaria San Carlos & Universidad Complutense de Madrid, Madrid, Spain

Summary

Myocardial ischemia may be caused not only by flow-limiting obstructions in the epicardial vessels, but also by a variety of non-obstructive mechanisms leading to a mismatch between myocardial oxygen demand and blood flow supply. This explains why a large proportion (up to 70%) of patients undergoing coronary angiography because of angina and demonstrated myocardial ischaemia do not have coronary artery disease with obstructive lesions.[1] Furthermore, myocardial infarction (MI) in the absence of obstructive coronary artery disease (MINOCA) can be found in ≈5% to 6% of all patients with acute infarction who are referred for coronary angiography.[2]

The pathogenesis of ischemia with no obstructive coronary arteries (INOCA) relies on two distinctive mechanisms (alone or in combination with coronary artery disease) which subsequently define different endotypes: coronary microvascular dysfunction (CMD) and epicardial vasospasm. CMD occurs in the context of structural microcirculatory remodeling or microvascular spasm caused by arteriolar dysregulation. Epicardial vasospasm is the epiphenomenon of enhanced vessel reactivity. Clinical manifestations of INOCA comprise a wide range of symptoms that are often misdiagnosed. The working diagnosis of INOCA include examination of clinical context, ischemia detection and documentation of non-obstructive coronary artery disease (CAD). Currently available non-invasive imaging are valid options to detect INOCA but suffer from several limitations. The direct assessment of coronary microcirculatory responses to vasodilatory stimuli and the assessment of vasomotor disorders represent advantages of interventional diagnostic procedures. Hemodynamic relevance of intermediate coronary artery stenoses as well as endothelium-independent mechanisms of CMD can be assessed during guidewire testing. The administration of vasoreactivity-inducing stimuli investigate the endothelium-dependent mechanisms of CMD and epicardial vasomotor tone disorders. Interventional diagnostic procedures, including guidewire testing and vasoreactivity testing can differentiate between different INOCA endotypes and may guide a tailored-therapy approach.

The therapeutic treatment of this patient subset is challenged by the wide spectrum of clinical manifestation, the different endotypes and the lack of randomized clinical trials (RCTs). The role of cardiovascular risk factors in the context of INOCA and MINOCA has not been well defined, but in many instances there seem to be a relationship with some of the vascular dysfunction endotypes which highlights the importance of adequate risk factor control as the first step in treatment. While standard pharmacological anti-ischemic treatment often leads to disappointing results, a tailored therapy guided by the results of invasive testing has been shown to improve patient’s symptoms and quality of life. A combination of first-line drugs including nitrates, betablockers or calcium channel blockers and second-line drugs such as nicorandil, ranolazine, ivabradine and trimetazidine can be considered.

Likewise, the pathogenesis of MINOCA represent a conundrum for clinicians. The underlying mechanism ranges from functional alterations at the level of epicardial coronary arteries to microvascular dysfunction. Epicardial vessel may represent the locus of plaque rupture and erosion causing MI throughout distal embolization, or superimposed vasospasm. Intense epicardial vasoconstriction as well as spontaneous coronary dissection (SCAD) may cause increase of myocardial biomarkers in the absence of CAD.

The diagnosis of MINOCA is made in the context of no coronary artery stenosis ≥ 50%, increase of cardial biomarkers and the absence of a specific alternate diagnosis for the clinical presentation. The working diagnosis includes the evaluation of the clinical context and a multimodality assessment of MINOCA etiology. The management of this subset of patients should rely on a target therapy based on specific etiologies and secondary prevention to reduce the burden of recurrent events.

Both INOCA and MINOCA patients suffer from a not benign condition and are at higher risk of mortality, rehospitalization, disability and angina burden at follow-up as compared to the general population without cardiovascular disease. More evidence-based diagnostic and therapeutic strategies are needed to improve quality of life and prognosis and to reduce healthcare-related costs in this patient population.

Definition and epidemiology of INOCA and MINOCA

Cardiac ischaemia caused by vascular dysfunction in the setting of non-obstructive coronary atherosclerosis has been defined INOCA. In this condition, the mismatch between blood supply and myocardial oxygen demands may be caused by structural or vasomotor disorders at a microcirculatory level and/or epicardial coronary artery spasm. At least 10% to 30% of patients presenting with signs or symptoms of angina have no significant coronary artery disease (CAD) on invasive coronary angiography. [3, 4] Recent studies have shown that this prevalence may go up to 70%. [5, 6] Potential explanations for the apparent increasing prevalence of stable INOCA include more sensitive diagnostics, including advanced cardiac imaging and high‐sensitive troponins.

The association between traditional cardiovascular risk factors and INOCA is not well established. Diabetes is not frequently found in this category of patients, while hypertension and dyslipidaemia are relatively more prevalent. [7, 8] Smoking habits has been associated with coronary microvascular dysfunction (CMD). [9]

In all studies, there is a strong female preponderance for the condition. Compared with men, women have a higher incidence of signs and symptoms of myocardial ischemia, yet 30% to 50% of women who undergo coronary angiography do not have obstructive CAD. [10, 11, 12]

Myocardial infarction in the absence of obstructive coronary artery disease (MINOCA) is diagnosed in patients with features of acute myocardial infarction (AMI) with non-obstructive coronary arteries on angiography. The diagnosis can be made in case of no coronary artery stenosis ≥ 50% in any potential infarct-related artery, in the absence of a specific alternate diagnosis for the clinical presentation.

The prevalence of MINOCA in large AMI registries ranges from 5% and 25%, depending on the population examined. [13]

MINOCA patient characteristics differ from those of other AMI and Chronic Coronary Syndrome (CCS). MINOCA subjects are younger, are more often female, and tend to have fewer traditional cardiovascular risk factors. In the Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients (VIRGO) study, women were disproportionately represented and had 5-fold higher odds of presenting with MINOCA than men. [14] The prevalence of traditional CAD risk factors and clinical features also varies among patients with MINOCA versus AMI with obstructive CAD coronary artery disease. All traditional cardiovascular risk factors are less frequent in MINOCA than in their counterparts with CAD; however consistent data have been observed only for dyslipidaemia. [15, 16, 17, 18]

Pathogenesis of INOCA

Myocardial ischemia can result from a large variety of conditions ultimately leading to an imbalance between myocardial oxygen demand and blood flow supply. Structural and functional abnormalities affecting either or both the epicardial and microvascular compartments of the coronary circulation may impair coronary blood flow (CBF) in the absence of obstructive CAD. Extravascular factors, including increased intramyocardial or intracavitary pressure and reduced diastolic time, may also contribute to myocardial ischemia of non-obstructive origin. Of note, all these mechanisms can coexist in patients with epicardial atherosclerosis, underscoring the relevance of a comprehensive approach to understand the multifactorial pathophysiology of chronic coronary syndrome (CCS). [19, 20, 21, 22, 23, 24, 25, 26]

In the setting of INOCA, two distinctive mechanisms play a central role in defining different endotypes.[1, 5, 27, 28]

Coronary Microvascular Dysfunction – Microvascular angina

The term coronary microvascular dysfunction (CMD) encompasses multiple mechanisms affecting the key functions of the microvasculature in various clinical settings: (i) in the absence of coronary or valvular heart disease, (ii) in the presence of myocardial or valvular heart diseases, (iii) in the presence of obstructive CAD, or (iv) in the context of percutaneous coronary interventions.[19]

Focusing on patients without flow-limiting coronary artery disease, myocardial ischemia can result from different dysfunction pathways in the microcirculatory domain, including structural microcirculatory remodeling or functional arteriolar dysregulation. Both these mechanisms can coexist and their relative importance may vary in different clinical conditions and patient subsets.[19, 20, 21, 22, 23, 24, 25, 26]

1) Structural microcirculatory remodelling is caused by arteriolar thickening, decrease in capillary density, or both, leading to reduced microcirculatory conductance and increased blood flow resistance.[29] This phenomenon can be observed in association to cardiovascular risk factors that cause atherosclerosis, left ventricular hypertrophy, myocardial diseases, or cardiac allograft vasculopathy.[23] It involves the whole myocardium, creating ischemia with a patchy or diffuse distribution.[26] The hemodynamic correlates of structural microcirculatory remodelling in response to a non-endothelium-dependent vasodilator, such as adenosine, are (i) a reduced coronary flow reserve (CFR) and (ii) an increase in minimal hyperaemic microcirculatory resistance.[1] Notably, structural remodelling can also lead to functional dysregulation, enhancing arteriolar sensitivity to vasoconstricting stimuli.[1]

2) Functional arteriolar dysregulation is related to endothelial dysfunction, determining impaired vasorelaxation or paradoxical vasoconstriction of medium and large size arterioles in response to endothelium-dependent vasodilating stimuli and hypersensitivity to vasoconstricting agents.[23] The hemodynamic correlates of this phenomenon can be observed during intracoronary acetylcholine infusion: (i) limited vasodilatory response to the drug (<1.5 times resting flow), (ii) significant reduction in blood flow without epicardial spasm, hinting at arteriolar spasm and (iii) diffuse narrowing of distal epicardial vessels.[1] The diagnosis of microvascular spasm is performed when ischemic ECG changes associated with chest pain occur during acetylcholine testing in the absence of epicardial vessel spasm. The term microvascular angina (MVA) is used to describe the clinical manifestation of myocardial ischemia caused by structural or vasomotor abnormalities affecting the coronary microcirculation.[30]

Epicardial Coronary Artery Spasm – Vasospastic angina

Epicardial coronary artery spasm is a vasomotor disorder originating mainly from vascular smooth muscle hyperreactivity, with endothelial cells dysfunction playing a lesser role than at an arteriolar level. In vasospastic angina a vasoconstrictor stimulus triggers the development of a dynamic flow-limiting stenosis, ultimately producing acute myocardial ischemia and chest pain.[21, 24, 31] Among triggering stimuli, smoking, drugs, blood pressure peaks, exposure to cold, emotional stress or hyperventilation are frequently encountered.[21, 24, 31] Coronary vasospasm can also result from mast cells activation and release of inflammatory cytokines in the context of allergic reactions (Kounis syndrome) or from abnormal vessel response to drug-eluting stents implanted in adjacent coronary segments.[32, 33] Epicardial coronary spasm can be detected during intracoronary acetylcholine infusion, with two main patterns: (i) focal or (ii) diffuse epicardial spasm.[1, 34] Vasospastic angina (VSA) is the clinical manifestation of ischemia caused by epicardial coronary artery spasm.[31]

FOCUS BOX 1
  • In the setting of INOCA two distinctive mechanisms play a central role (alone or in combination with CAD), defining different endotypes: CMD and epicardial vasospasm.
  • In INOCA the main mechanisms of CMD are structural microcirculatory remodelling or vasomotor disorders caused by arteriolar dysregulation, the latter much related to endothelial dysfunction. The clinical manifestation of CMD in INOCA is MVA.
  • Epicardial vasospasm originates from enhanced vessel reactivity to vasoconstrictor stimuli. The clinical manifestation of CMD is VSA.

Working Diagnosis of INOCA

In patients with angina symptoms, the diagnosis of INOCA relies on ischemia detection and documentation of non-obstructive CAD. Clinical presentation, physical examination, ECG and non-invasive functional or anatomical imaging tests represent essential steps in the diagnostic workup. However, a full diagnostic assessment of INOCA currently requires an interventional diagnostic procedure (IDP) to provide information on epicardial coronary artery atherosclerosis, structural microcirculatory remodelling, microvascular spasm or epicardial vessel vasospasm, defining the spectrum of endotypes: (i) microvascular angina of structural or vasomotor origin, (ii) vasospastic angina, (iii) mixed angina, (iv) non-cardiac chest pain, and (v) non-flow-limiting CAD.[1]

Clinical presentation

Patients with INOCA present with a wide range of symptoms that are often misdiagnosed as of non-cardiac origin, leading to under-investigation and under-treatment of this condition, with consequent patient dismay and depression.[35, 36]

These symptoms include the classical anginal chest pain, as well as other angina-equivalent symptoms, encompassing dyspnea, fatigue, weakness, back pain, dyspepsia, nausea, vomiting or even sleep disturbances. Importantly, clinical presentation exhibits sex variation and symptom burden may vary over time.[1, 5, 27, 37]

Microvascular angina

Patients with MVA typically present with exercise-related angina, evidence of ischemia at non-invasive tests and no obstructive coronary artery stenoses at coronary computed tomography or invasive coronary angiography. As a result of the coexistence of structural and functional microvascular abnormalities, these patients often present a mixed pattern of angina, with occasional angina episodes at rest, especially in associated with exposure to cold.[11, 12] An updated standardization of MVA diagnostic criteria has been provided by the Coronary Vasomotion Disorders International Study Group (COVADIS) group ( Table 1).[30]

Vasospastic angina

In patients with VSA, anginal symptoms occur predominantly at rest, with maintained effort tolerance. Usually, symptoms follow a circadian pattern, with more episodes at night and in the early morning hours.[11, 12] An updated standardization of VSA diagnostic criteria has been provided by the COVADIS group ( Table 2).[31]

Non-invasive testing for INOCA

According to ESC CCS 2019 guidelines, non-invasive imaging testing should be the first-line assessment in the vast majority of patients presenting with angina symptoms.[5] In patients with non-obstructive CAD on coronary computed tomography angiography (CCTA) eventually presenting ischemia on functional imaging testing, INOCA can be the cause of symptoms.

The application of currently available non-invasive imaging testing modalities to detect ischemia caused by CMD or vasomotor disorders is affected by several limitations: (i) inability to directly visualize coronary microcirculation, (ii) ischemia detection through identification of regional perfusion or wall-motion abnormalities (not useful when CMD affects uniformly all myocardial territories) and (iii) inability to test for vasomotor disorders.[10] Therefore, non-invasive assessment of coronary microcirculation can only explore non-endothelial dependent mechanisms and relies on CFR and CBF measurement.[28] CFR is calculated as the ratio of hyperaemic blood flow in response to the administration of an endothelium-independent vasodilator (adenosine, dipyridamole, regadenoson) divided by resting blood flow. CFR and CBF can be accurately quantified by positron emission tomography (PET) using different tracers, but this technique is limited by costs and availability. Cardiac magnetic resonance (CMR) myocardial perfusion reserve index can provide semi-quantitative information which however lacks clinical validation in this context. Transthoracic pulsed-wave Doppler echocardiography (TTE-DE) of the left anterior descending artery (LAD) can evaluate CFR through the assessment of coronary flow velocity reserve.[5, 27]

It should be acknowledged that myocardial perfusion measurements alone lack the sensitivity to discriminate the relative contribution of epicardial and microvascular disease to ischemia and need to be integrated with anatomical information regarding epicardial coronary arteries. Computed tomography (CT) perfusion imaging and CT-derived CFR could overcome this limitation, offering the advantage to combine anatomic and functional assessment, but require further validation and evidence from clinical trials.[38]

Current ESC guidelines recommend the use of transthoracic echocardiography Doppler of the LAD, CMR or PET for non-invasive assessment of CFR and CMD (Class IIb, Level of evidence B). However, a comprehensive assessment of these patients currently requires invasive testing.[5]

Invasive testing for INOCA

The Coronary Microvascular Angina (CorMicA) trial provided evidence that routine management guided by an IDP and stratified therapy reduces angina burden and improves quality of life in patients with INOCA.[39, 40] An IDP proceeds through different steps to provide a comprehensive assessment of patients with suspected INOCA. This approach combines anatomical epicardial coronary artery assessment (invasive coronary angiography), evaluation of intermediate coronary artery stenoses (FFR or non-hyperaemic indexes), detection of endothelium-independent CMD (CFR and IMR) or endothelium-dependent CMD (microvascular response to acetylcholine), and identification of vasospastic disorders (epicardial artery response to acetylcholine).[1, 28] ( Figure 1)

To ensure optimal IDP result, vasoactive drugs (calcium channel blockers and long-acting nitrates) should be withheld for at least 24 hours before the procedure. Intravenous unfractionated heparin should be administered (50-70 UI/kg) to achieve optimal anticoagulation (activated clotting time of 250 seconds) before arterial instrumentation.[1, 28, 41] Generally, the LAD is the preferred artery for functional testing due to the large subtended myocardial mass and coronary dominance, while additional studies in other coronary arteries may be considered if the initial tests are negative and the clinical suspicion is high.[1, 28, 41] According to EAPCI consensus document on INOCA, following the acquisition of coronary angiogram, IDP should proceed with diagnostic guidewire assessment and then, as appropriate, with acetylcholine testing, as the assessment of resting coronary physiology could be affected by enhanced sympathetic tone in case vasospasm should occur during acetylcholine infusion.[1, 28] IDP is considered safe when performed by experienced operators.[28, 42, 43] The risks of an IDP are those of coronary instrumentation with a guidewire and adverse physiological reactions.[28] In the CorMicA trial, IDPs were feasible in 99% of cases, and no serious adverse events occurred.[39] Coronary reactivity testing may induce transient atrial fibrillation or bradycardia that typically resolve after acetylcholine infusion discontinuation.[28, 39]

Invasive coronary angiography

Invasive coronary angiography (ICA) is the first step of any IDP. It can diagnose obstructive atherosclerosis in patients directly referred for invasive testing due to high pre-test probability of CAD (>85%) and can provide functional assessment of intermediate (50-80%) coronary artery stenoses eventually detected by CCTA in patients presenting without non-invasive ischemia testing by addition of diagnostic guidewire testing.[5] Care should be applied to select the appropriate angiographic projection to avoid foreshortening of the target vessel and significant vessel overlapping.[28] Furthermore, ICA can provide semi-quantitative assessment of coronary blood flow. Thrombolysis in myocardial infarction (TIMI) frame count >27 (image acquisition at 30 frames/s) after administration of glyceryl trinitrate (GTN) suggests impaired resting flow (slow-flow phenomenon), pointing to CMD due to microvascular remodelling.[44]

Importantly, during ICA additional information can be obtained to identify patients with myocardial bridging and those in whom an increase in endocavitary pressure secondary to heart failure or valvular heart disease plays a role in determining subendocardial ischemia by direct measuring left ventricular end diastolic pressure (LVEDP).[45]

Diagnostic guidewire testing

Diagnostic guidewire testing provides information about hemodynamic relevance of intermediate grade epicardial coronary artery stenoses, as well as endothelium independent-mechanisms of CMD.[1, 28] The 2019 ESC CCS guidelines recommend the use of guidewire-based CFR and/or microcirculatory resistance measurements in patients with persistent angina symptoms but coronary arteries that are either angiographically normal or have moderate non-flow-limiting stenoses (Class IIa, Level of Evidence B).[5]

Diagnostic options include coronary thermodilution using a pressure-temperature sensor guidewire (PressureWire XTM, Abbott Vascular, Santa Clara, CA, USA), or Doppler technique (ComboWire XT or Flowire, Philips Volcano Corporation, San Diego, CA, USA). Administration of adenosine either by intravenous infusion (140 mcg/kg/min for 2 to 3 min) or intracoronary bolus injections (up to 200 mcg) is required to achieve endothelium-independent vasodilatation and induce steady-state hyperaemia. Thermodilution measurements require additional saline bolus injections (3 ml) at room temperature at rest and during maximal hyperaemia. When thermodilution measurements are performed, the guide catheter should be stable, coaxially engaged without pressure damping and the position of the guidewire should be stable in the distal third of the vessel to reduce variability in saline transit time. As Doppler wires are less flexible and steerable than workhorse coronary guidewires, a buddy wire or a microcatheter may be occasionally needed to safely advance them into the target artery.[28]

During this step of the IDP, hemodynamic relevance of intermediate coronary artery stenoses can be assessed using FFR which is obtained as the ratio of mean distal coronary pressure to mean aortic pressure at maximal hyperemia.[46] A positive result indicating a flow-limiting stenosis is defined as FFR ≤0.80 or as resting non-hyperaemic pressure ratio ≤0.89.[5, 28, 47, 49]

Endothelium-independent mechanisms of CMD can be explored using coronary flow reserve (CFR) and microcirculatory resistance.[10]

Coronary flow reserve can be calculated using thermodilution as the ratio of resting mean transit time divided by hyperaemic mean transit time.[49, 50] Most studies evaluating the prognostic value of thermodilution-based CFR have used a cut-off value of 2.0.[51, 52] Alternatively, CFR can be calculated using Doppler technique as the ratio of hyperaemic flow velocity by resting flow velocity.[53] Studies showing a prognostic relevance of CFR as assessed by Doppler have used a CFR cut-off of 2.5 or lower.[54, 55]

Microcirculatory resistance can be obtained by combination of pressure and flow measurements. The index of microvascular resistance (IMR) is calculated as the product of distal coronary pressure at maximal hyperaemia by the hyperaemic mean transit time.[56] An increased IMR ≥25 has been shown representative of CMD.[57] The hyperaemic myocardial velocity resistance (HMR) index is a Doppler-based measurement calculated as the ratio of intracoronary pressure by hyperaemic flow velocity. Although recent studies have suggested a cut-off of ≥2.5 mmHg/cm/s to predict CMD, further investigations are required to determine the optimal HMR cut-off value.[58, 59] ( Figure 3.png" data-toggle="modal" data-target="#popup-media" class="media-link" data-media_id="4689" data-folder="pcr-textbook" data-chapterid="363"> Figure 2)

Importantly, the binary thresholds of continuous data should be viewed within the context of each patient: a CFR between 2.0 and 2.5 may be considered a “grey zone,” as is also the case for FFR between 0.75 and 0.82. CFR, IMR, non-hyperaemic pressure ratio, and FFR have prognostic significance across the diagnostic range of their values.[1]

Vasoreactivity testing

Vasoreactivity testing explores endothelium-dependent mechanisms of CMD and epicardial vasomotor tone disorders.[1, 1, 1, 1, 1] The most established approach for coronary vasoreactivity testing is by intracoronary infusion of acetylcholine, although other substances like ergonovine have been proposed.[28, 60] The 2019 ESC CCS guidelines recommend the use of intracoronary acetylcholine with ECG monitoring to assess microvascular or epicardial spasm.[5]

A standard approach involves sequential intracoronary infusion of acetylcholine at concentrations approximating 0.182, 1.82, and 18.2 mcg/ml (10-6, 10-5, and 10-4 mol/l, respectively) at 1 ml/min for 2 min using a mechanical pump.[1, 28, 39] An alternative option to facilitate ease of adoption include manual infusion of 2, 20, 100, and 200 mcg over 20-30 s.[28] Given the higher potential of acetylcholine to induce bradycardia when injected in the right coronary artery, it is generally considered safer to administer a half dose (i.e., 50 mcg instead of 100 mcg) when testing in that vessel.[28] Acetylcholine infusion is generally performed through the guiding catheter, while selective infusion using a dedicated microcatheter is generally not required as it can increase procedural time and complication risk.[28] Intracoronary administration of nitrates is typically used to revert vasospasm.[1, 28]. Continuous measurements of Doppler blood flow velocity over the acetylcholine testing may inform on the responses of the coronary microcirculation to incremental doses of the drug. [41]

Patient’s symptoms, ECG and coronary angiogram should be carefully assessed during vasoreactivity testing. A diagnosis of MVA or VSA is made according to established criteria.[31] Microvascular spasm can be identified by anginal symptoms and ECG ischemic changes, sometimes with transient flow reduction (TIMI flow grade ≤2), in the absence of epicardial coronary artery spasm. Epicardial coronary artery spasm diagnosis additionally requires ≥90% reduction of epicardial coronary artery with either focal or diffuse pattern.

FOCUS BOX 2
  • Non-invasive imaging techniques (TTE-DE, CMR, PET) are valid options to detect myocardial ischemia in patients without obstructive CAD.
  • Interventional diagnostic procedures including guidewire testing and vasoreactivity testing should be implemented to differentiate between different INOCA endotypes: MVA, VSA, mixed angina and non-cardiac chest pain.

Contemporary treatment of INOCA

The optimal management of INOCA is still controversial and represents an unmet need due to the lack of large, randomized studies involving homogenous patient groups, and the difficult to provide evidence-based recommendations in this context. A contemporary approach should be patient-focused, multidisciplinary and based on different lines of intervention.[1, 9, 27] Key objectives of INOCA treatment should be: (i) to improve or abolish myocardial ischemia addressing its mechanisms, (2) to improve quality of life, (3) to improve prognosis, and tackling mechanisms associated with impaired clinical outcomes.[1] ( Figure 3)

Lifestyle factors

Considering the high prevalence of coronary atherosclerosis and endothelial dysfunction, all patients with INOCA should receive a tailored counselling on behaviours implementing healthy lifestyle behaviours to address risk factors, reduce symptom burden, improve quality of life and decrease the risk of subsequent cardiovascular events and mortality.[1, 27, 61] General recommendations are comparable to those provided in ESC cardiovascular disease prevention guidelines.[62] Healthy diet, physical activity, healthy weight maintenance, smoking cessation, and stress management are important goals of lifestyle intervention and can be pursued taking advantage of nutrition experts, nurse practitioners, physiotherapists, and psychologists.[1]

Risk factors management

Traditional cardiovascular risk factors, including hypertension, dyslipidaemia, smoking and diabetes may all contribute to the development of structural microvascular remodelling and vasomotor disorders.[19, 23] Although the majority of patients with CMD have endothelial dysfunction with angiographically normal coronary arteries, intravascular ultrasound studies have demonstrated a significant atherosclerotic plaque burden in this setting.[62, 63] Therefore, the use of antiplatelets agents as aspirin in patients with INOCA has been advocated in ACC/AHA CCS guidelines.[65] Statins exhibit pleiotropic properties beyond their lipid-lowering effect, encompassing vascular inflammation reduction, improvement in endothelial function and CFR in patients with non-obstructive CAD.[66–68] Blood pressure management has been shown to prevent the progression of microvascular changes and to reduce the burden of anginal symptoms.[69] The selection of blood pressure medications, alone or in combination, relies on the predominant mechanism of angina symptoms (MVA or VSA).[1] Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) have been shown to improve exercise tolerance and anginal symptoms.[70] Regression of perivascular fibrosis and increase CFR in patients with CMD have been observed in patients treated with ACEi.[71, 72] A combination of ACEi and statin therapy (ramipril plus atorvastatin) has been showed to improve endothelial function and quality of life compared to placebo in a small randomized trial.[75] The ongoing WARRIOR (Women’s Ischemia Trial to Reduce Events in Non-Obstructive Coronary Artery Disease) multicenter randomized study will investigate the effects of intensive statin and ACEi/ARB therapy compared to usual care on major adverse cardiovascular events (MACE) in symptomatic women with INOCA. In patients with diabetes, the addition of the mineralocorticoid receptor antagonist spironolactone has been demonstrated to improve microvascular function.[74]

Antianginal medications

Treatment of anginal symptoms in patients with INOCA is challenging and standard pharmacological anti-ischemic treatment often leads to disappointing results.[75] Antianginal drug therapy should follow a stepwise strategy, according to 2019 ESC CCS guidelines.[1, 5] First-line drugs include nitrates, betablockers or calcium channel blockers, while second-line drugs encompass nicorandil, ranolazine, ivabradine and trimetazidine. A combination of first-line and second-line drugs can be considered.[1, 5]

Short-acting and long-acting nitrates can be used to reduce anginal symptoms in patients with MVA, although data regarding their effects on microvascular dysfunction and actual efficacy are limited, and benefits are often limited by side effects.[76]

Betablockers (particularly those with vasodilator effects, such as nebivolol and carvedilol) can improve symptoms and exercise tolerance in patients with MVA.[77, 78]

Calcium channel blockers (either verapamil and diltiazem or amlodipine) are considered the first-line agents in patients with microvascular or epicardial vasomotor disorders.[1]

In the recent CorMicA (CORonary MICrovascular Angina) trial it was tested whether routine management guided by an IDP and stratified therapy could improve angina and quality of life in patients with INOCA.[39] Patients with non-obstructive CAD were randomized at coronary angiogram 1:1 to the intervention group (IDP stratified medical therapy) or the control group (standard care, IDP sham procedure). The IDP consisted of guidewire-based assessment of FFR, CFR, and IMR, followed by vasoreactivity testing with acetylcholine. Patients in the intervention group were classified into four endotypes (MVA, VSA, mixed MVA/VSA and normal coronary artery function), based on the results of invasive testing, and received different targeted treatments. Non-obstructive CAD was detected in 53.7%. of the patients and 151 patients were randomized. Compared to those in the control group, patients in the intervention group had a mean improvement of 11.7 U in the Seattle Angina Questionnaire summary score at 6 months (95% CI: 5.0 to 18.4; p=0.001). In addition, the intervention led to improvements in mean quality-of-life (EQ-5D index 0.10 U; 95% CI: 0.01 to 0.18; p=0.024) and visual analogue (14.5 U; 95% CI: 7.8 to 21.3; p<0.001) scores.[39]

Nicorandil, a potassium channel activator with nitrate-like actions, has been reported to have beneficial actions in patients with MVA.[79] Ranolazine, a late sodium current inhibitor has been shown to improve symptoms and CFR in patients with MVA, especially in those with markedly reduced CFR.[80, 81, 82] Ivabradine reduces myocardial oxygen demand through its effects on heart rate but little information exists regarding its efficacy in MVA.[81] Trimetazidine, a metabolic modulator of myocardial cells, effectively improved symptoms and exercise capacity in patients with MVA.[83, 84]

The rho-kinase inhibitor Fasudil has been shown effective in preventing ischemia by reducing vascular smooth cells hypercontractility in a small study on18 patients with VSA undergoing acetylcholine testing, and is currently under investigation also in patients with MVA.[85, 86]

The currently ongoing PRIZE (Precision Medicine With Zibotentan in Microvascular Angina) trial will explore the role of zibotentan, an oral endothelin-A receptor antagonist that could provide benefits in CMD by opposing the increase in vasoconstrictor response of coronary microcirculation to endothelin.

The use of low-dose tricyclic antidepressants, such as imipramine, may be helpful to reduce symptoms burden, owing to their norepinephrine uptake modulation and anticholinergic effect that can cause analgesia, although potentially affected by several side effects.[86–88] Similarly, aminophylline, a non-selective adenosine receptor antagonist has been proposed to reduce anginal symptoms owing to its effects on nociception.[89, 90] Currently, there is no available evidence-based approach to address nociception in INOCA patients.[1, 23, 27]

In up to 25% of INOCA patients, anginal symptoms result refractory to classical pharmacological treatment options and might benefit from alternative non-pharmacological treatments, such as enhanced external counterpulsation, spinal cord stimulation or cognitive behavioural therapy.[92, 93, 94]

FOCUS BOX 3
  • A patient-centered comprehensive approach to the management of INOCA is warranted to address prognosis and quality of life.
  • Counselling on lifestyle and risk factors management should be offered.
  • A tailored therapy guided by IDP and stratified by INOCA endotype can improve patient’s symptoms and quality of life.

Prognosis of INOCA

Current evidence indicates that INOCA is not a benign condition, as these patients have impaired quality of life, higher risk of disability and higher incidence of MACE including death, non-fatal myocardial infarction, heart failure, re-hospitalization and repeated coronary angiography for recurrent angina.[95, 96, 97, 98, 99, 100, 101, 102] The social and economic burden of INOCA is worsened by the poor awareness of this condition among treating physicians, which often leads to incorrect interpretation of patient’s symptoms, avoidance of further diagnostic evaluation and inadequate treatment.[103]

The incidence of all-cause death and non-fatal myocardial infarction has been shown higher in patients with non-obstructive CAD as compared to those with angiographically normal coronary arteries. When ischemia is documented through the demonstration of CMD or endothelial dysfunction, the prognosis is further impaired. Epicardial vasospasm is associated with major adverse events including sudden cardiac death, acute myocardial infarction and syncope which may unfortunately occur before the diagnosis is established.

Almost two thirds of women undergoing clinically indicated coronary angiography for suspected ischemic heart disease in the original cohort of the WISE study were diagnosed with INOCA.[84, 85] The risk of MACE (death, non-fatal myocardial infarction, non-fatal stroke and heart failure hospitalization) in these subjects exceeded 2.5% yearly by 5 years, and was mirrored by elevated rates of clinically-driven hospital re-admission and repeated coronary angiography.[98, 99] Invasively assessed CFR <2.32 was the best predictor of adverse outcomes, with a 5-year MACE rate of 27% versus 9.3% for women with a CFR ≥2.32 (p=0.01).[100] Chest pain persisting at 1-year follow-up also predicted MACE among these patients. Of note, women with INOCA are 4-times more likely than men to be re-admitted within 180 days for acute coronary syndrome or anginal chest pain.[97] The long-term analysis of the WISE study demonstrated higher rates of 10-year cardiovascular death or myocardial infarction (12.8% vs 6.7%) in women with INOCA as compared with those with normal coronary circulation.[97]. For the time being, there are no studies demonstrating reduction in major adverse cardiac events after stratified medical treatment for INOCA. In part, this may be due to the fact that INOCA may be an epiphenomenon of more profound changes in myocardial structure, like loss of capillary density or myocardial fibrosis, which may not be reversible and have prognostic implications. As existing primary and secondary prevention risk assessment tools do not appear to predict MACE risk in INOCA patients, further investigation is needed to develop specific risk-assessment tools in these patients.[104]

FOCUS BOX 4
  • INOCA is not a benign condition, affecting patient’s quality of life, causing disability and carrying a higher risk of MACE.
  • Specific risk-assessment tools are warranted to better stratify this heterogenous population.

Pathogenesis of MINOCA

Myocardial infraction without obstructive coronary artery disease (MINOCA) is a heterogeneous entity comprising multiple causes.

From a diagnostic perspective, MINOCA is defined as a myocardial infarction (MI) with elevated cardiac biomarkers, typically cardiac troponin >99th percentile of the upper reference level. Table 3 provides the current criteria for the MINOCA definition. A typical rise or fall in the troponin levels indicate myocyte insult but is not disease specific and can follow either ischaemic or non-ischaemic mechanisms. The “Fourth Universal Definition of Myocardial Infarction” by the Joint European Society of Cardiology/American College of Cardiology/American Heart Association/World Heart Federation Task Force for the Universal Definition of Myocardial Infarction recently redefined the concept of myocardial injury [105]. Despite sharing the same hallmark for troponin increase, myocardial infarction and myocardial injury substantially differs in pathogenesis, the first being caused by ischemic and the second by non-ischemic mechanisms. With the revised concept of MI, the diagnosis of MINOCA is reserved for patients in whom there is an ischemic basis for their clinical presentation. Non-cardiac causes for troponin rise should be ruled out and these include but are not limited to sepsis, pulmonary embolism, cardiac contusion, aortic dissection. Myocardial disorders, including myocarditis, Takotsubo cardiomyopathy (TTS), and other cardiomyopathies, have been historically included in the MINOCA definition but subsequently excluded. According to the 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation, TTS and myocarditis are now by consensus not enlisted as potential causes of MINOCA. [106]

The underlying pathogenesis of MINOCA ranges from functional alterations at the level of epicardial coronary arteries to microvascular dysfunction.

Atherosclerosis

This incorporates a heterogeneous group of underlying causes that may involve both plaque rupture, erosion or thromboembolism as a cause of MINOCA.

Plaque rupture occurs frequently in the context of thin-cap fibroatheroma (TFCA), when the overlying thin fibrotic cap discontinuity exposes a large lipid pool to the coronary lumen. [107] Plaque erosion is defined by endothelial discontinuity without signs of cap rupture. Both can ultimately result in thrombus formation and consequent partial or total occlusion of the vessel, superimposed coronary spasm or transient thrombosis with complete spontaneous resolution.

Depending on the modality of assessment, the prevalence of plaque rupture and erosion in MINOCA patients, can be observed in up to 35% and 30%, respectively. [108]

Coronary thromboembolism

Thromboembolism may be the consequence of plaque rupture/erosion or arise from systemic arterial thrombi. Coronary emboli may also occur in the context of hereditary or acquired thrombotic disorders or other predisposing factors.

Hereditary thrombophilia disorders include Factor V Leiden thrombophilia, elevated factor VIII/von Willebrand factor, Protein S and C deficiencies. Acquired hypercoagulable status comprises atrial fibrillation, valvular heart disease, cardiac tumors, auto-immune disorders, myeloproliferative neoplasms. In MINOCA patients, the prevalence of hereditary thrombofilic disorders has been reported to be 14%, the most commonly observed was factor V Leiden, followed by protein C or S deficiency [15]

Vasospasm

As discussed before, coronary artery spasm is defined as intense epicardial vasoconstriction with compromised myocardial blood flow. The consensus from the Coronary Vasomotion Disorders International Study Group (COVADIS) symposium defined a 90% diameter stenosis as the angiographic threshold to diagnose inducible spasm. [109] Coronary vasospasm may occur in the context of epicardial atherosclerosis or microvasculair dysfunction either spontaneously or in response to vasoconstrictor stimuli. MINOCA can be the first clinical event for patients with vasospastic angina, or an interim event in the context of recurrent episodes of angina as a chronic disorder.

Provocative spasm testing has demonstrated inducible spasm in 27% of patients with MINOCA confirming vasospasm as a relevant pathogenetic mechanism in this subset of patients. [15] Nevertheless, coronary artery spasm may be found in up to 95% of MINOCA patients, depending on spasm definition, the ethnic origin of patients, and the stimuli used to unmask spasm. [110]

Spontaneous coronary artery dissection

Spontaneous coronary artery dissection (SCAD) may be responsible for luminal obstruction but also for MI without obstructive coronary disease. The angiographic images of a SCAD can vary from a near-normal coronary artery to contrast staining with multiple radiolucent lumens, tapering of the vessel or diffuse stenosis of varying severity.

The pathogenesis of SCAD is still unclear but may result from an underlying vasculopathy. Fibromuscular dysplasia is present in other vascular beds in the majority of cases of SCAD when screening is performed. [111] Changes in the intima-media composition due to hormones, pregnancy, and delivery have also been implicated as triggers. However, most dissections occur in the absence of atherosclerotic disease.

Beside the established higher prevalence in young women, its real incidence is controversial due to under-or misdiagnosis. [112]

SCAD diagnosis can be determined in about 1% of all ACS and up to 35% of ACS among young women. [112, 113, 114]

Microvascular mechanisms

Coronary microvasculature represents the main site of regulation of myocardial blood flow and accounts for ≈70% of the coronary resistance in the absence of obstructive CAD.

The definition of impaired microvascular system is based on the presence of all four following criteria: (1) Symptoms of myocardial ischemia, (2) Absence of obstructive CAD (3) Objective evidence of myocardial ischemia with documented ECG changes during chest pain or stress-induced chest pain and (4) evidence of impaired microvascular function based on impaired coronary flow reserve, reproduction of symptoms during acetylcholine test, impaired microvascular resistance indexes, impaired coronary blood flow, as measured with a corrected Thrombolysis in Myocardial Infarction (TIMI) frame count.

Functional alterations at the level of coronary microcirculation represent a frequent, but often unrecognized, cause of MINOCA. As for epicardial vasospasm, MINOCA can be considered the unstable counterpart of chronic microvascular angina.

Previous studies showed that about 25% of patients with MINOCA have evidence of microvascular spasm. [115]

Alternative diagnosis

Type 2 AMI is defined as myocardial cell necrosis due to supply–demand mismatch, characterized by significant increase and/or decrease in troponins with at least one value above the 99th percentile of a normal reference population, in the absence of evidence for coronary plaque rupture and in addition to at least one of the other criteria for AMI.

Potential causes are pulmonary embolism, hypertensive crisis, tachyarrhythmias, sepsis, severe anaemia, and cardiac contusion, among others and should be considered as alternative diagnosis of MINOCA.

FOCUS BOX 5
  • MINOCA represents a heterogeneous clinical conundrum with several aetiologies.
  • After ruling out alternative cardiac and extracardiac causes of myocardial injury, the potential underlying mechanism of MINOCA ranges from epicardial to microvascular disorders.

Working Diagnosis of MINOCA

The diagnostic challenge to identify MINOCA and its aetiology represent a conundrum for the physicians. A systematic global approach should be pursued, including invasive and non-invasive techniques, in order to tailor the perfect management to the specific pathophysiological mechanism. ( Figure 4)

Clinical context

The initial evaluation of MINOCA patients consists in the assessment of the clinical context. Potential alternative diagnosis should be ruled out and all appropriate additional exams performed. A common cause of myocardial injury and consequent elevation of troponin markers without causing myocardial ischemia is pulmonary embolism. A suspicion of pulmonary embolism imposes D-dimer testing, B-type natriuretic peptide (BNP), and/or Computed tomography (CT) pulmonary angiography. Other causes of supply/demand mismatch as possible mechanism of myocardial injury such as hypertensive crisis, tachyarrhythmias, sepsis, severe anaemia, and cardiac contusion as well as other non-cardiac reasons for troponin elevation should be further investigated.

Both myocarditis and TTS are clinically subtle non-ischemic mechanisms of myocyte injury that can mimic an AMI and have been recently excluded from the MINOCA definition.

A history of atrial fibrillation, dilated cardiomyopathy, prothrombotic risk factors, recent deep vein thrombosis (DVT) or pulmonary embolism, prosthetic heart valves, infective endocarditis, atrial myxoma, and patent foramen oval may suggest for a coronary embolism cause of MINOCA.

Coronary angiography

The working diagnosis should exclude a “missed obstruction” and requires a careful evaluation of coronary angiography, as the occlusion of a small vessel due to plaque rupture or distal embolization may be overlooked. The threshold of 50% to define an obstructive coronary artery stenosis is arbitrary but consistent with American Heart Association/American College of Cardiology and European Society of Cardiology consensus on MINOCA [2, 116] However, a further classification according to the severity of the stenosis is needed as patient presenting with MINOCA and a larger atherosclerosis burden have a poorer prognosis. [118]

Plaque disruption occurs in vessels which may appear normal at coronary angiography, even though some degree of atherosclerosis is usually appreciated. Further investigations with cardiac magnetic resonance (CMR) and intravascular imaging are detrimental to delineate a final diagnosis.

Echocardiography

Echocardiography is used to assess ventricular function, the presence of ventricular thrombus, or cardiac tumours, assessment of atrial shunt and valvular heart disease. Regional left ventricle (LV) motion alterations corresponding to a finite vascular territory suggests an ischemic mechanism of MINOCA while typical wall motion abnormalities with apical ballooning indicate a TTS diagnosis.

Cardiac Magnetic Resonance

CMR is helpful to elucidate the underlying causes leading to a MINOCA presentation in as many as 87% of patients [118]. If performed early after admission may help to differentiate other causes of myocardial injury not related to myocardial ischemia as TTS or myocarditis. CMR is ideally suited to detect the typical wall motion abnormalities which tend to resolve very quickly, a typical oedema pattern and the absence of late gadolinium enhancement (LGE) associated with TTS. A non-ischemic pattern, with epicardial localization of LGE together with myocardial oedema may suggest a diagnosis of myocarditis.

CMR may diagnose an ischemic cause of MINOCA even when the area of necrosis is very limited and when the angiography appears completely normal. Current techniques allow CMR to detect as little as 1 g of infarcted myocardium [119]. Spontaneous thrombolysis of a coronary thrombosis results in CMR images of a small, well-defined area of LGE suggesting the embolization of atherothrombotic debris following plaque disruption as the most likely mechanism of myonecrosis. Despite being a game changer in the traffic light diagnostic algorithm, observational studies report only 3% use of CMR in all MINOCA patients. Even with an optimal work-up including CMR, 8% to 25% of these patients are discharged without a final diagnosis. [120]

Intravascular imaging

The angiographic signs of plaque disruption are often subjective and are limited to haziness or a small filling defect. The final diagnosis of plaque rupture or erosion relies on the use of intravascular modalities which go beyond angiography. Intravascular imaging may identify plaque disruption in approximately one-third of patients with MINOCA. [121, 122] Both Intravascular ultrasound (IVUS) and Optical Coherence Tomography (OCT) may be helpful for identifying unstable coronary substrates, or for ruling out other mechanisms such as coronary dissection or in situ thrombosis, which may not have been correctly appreciated during angiography. ( Figure 5) With its better resolution, OCT might be able to identify signs of plaque disruption, and particularly of plaque erosion, in a higher proportion of MINOCA patients compared to IVUS. [123] Time delay from the symptoms onset and intravascular imaging examination trend to influence its diagnostic value.

Coronary CT does not provide sufficient detail of the luminal interface.

Intravascular provocative test

There is currently a critical missing link between the use of the most appropriate diagnostic tests of complete (epicardial and microvascular) coronary artery function and final diagnosis of MINOCA. The diagnosis of vasospastic angina typically requires the documentation of coronary artery spasm. Spontaneous episodes may be fortuitously documented, but provocative spasm testing is often required to establish the final diagnosis. Over the years, the safety of spasm provocation tests has hampered the interventional cardiology community to include this exam in the diagnostic algorithms of ACS patients. Several spasm provocation testing methods have been developed, but the gold standard is currently the administration of high-dose intracoronary acetylcholine boluses. ( Figure 6)

Despite being largely performed in patients with CCS, spasm provocative testing is seldom performed in MINOCA patients during their index admission. A small recent study reported a high prevalence of positive provocative spasm (46.2%) and the safety associated to these procedures in this subset of patients. [124]

According to the latest European guidelines on the management of NSTEMI patients, intracoronary acetylcholine or ergonovine testing may be performed in the working diagnosis of MINOCA when coronary or microvascular spasm is suspected. [106]

FOCUS BOX 6
  • MINOCA should not be considered as a single entity but as a heterogeneous syndrome requiring a comprehensive multimodality diagnostic work-up to elucidate the correct aetiology
  • A broad evaluation and a multimodality assessment should include a detailed clinical assessment, LV function evaluation, careful review of coronary angiography, CMR and intracoronary imaging and provocative testing, when needed

Contemporary treatment of MINOCA

The management of MINOCA has scarce evidence-based literature, mostly derived from retrospective cohort/observational registries.

Given these therapeutic shortcomings and current limited knowledge, patients with MINOCA are less likely to receive appropriate medical treatment, even though they are likely to experience further coronary events [125]

The management strategy for patients with MINOCA should be defined based on the

following:

(1) in the initial setting, emergency supportive care should be provided to immediately address the underlying mechanism responsible for a patient unstable condition, particularly in case of life-threatening arrhythmias or cardiogenic shock;

(2) a working diagnosis approach aimed at excluding alternative diagnoses mimicking an AMI and identification of the underlying causes of MINOCA;

(3) targeted therapies based on specific aetiologies. The multiple causes encompassed in this variegated condition require a personalized approach. Table 4 summarizes the extensive array of tailored therapies;

(4) secondary prevention therapies should be considered irrespective of the cause of the MINOCA.

A stratified propensity analysis of 9138 patients with MINOCA enrolled in the SWEDEHEART registry (the Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapy) found a significantly lower event rate associated with the use of statins (hazard ratio, 0.77 [95% CI, 0.68–0.87]) and ACE inhibitors/ARBs (hazard ratio, 0.82 [95% CI, 0.73–0.93]) and a trend for a lower event rate with the use of β-blockers (hazard ratio, 0.86 [95% CI, 0.74–1.01]) at a mean follow-up of 4.1 years, suggesting a potential benefit of these medical therapies. Of note, the use of dual antiplatelet therapy (DAPT) was not associated with a lower event rate (hazard ratio, 0.90 [95% CI, 0.74–1.08]). However, this registry did not apply current MINOCA criteria, therefore the conclusions must be interpreted with caution. [126]

In general, pharmacological therapy with aspirin, statins, angiotensin-converting enzyme (ACE) inhibitors/ angiotensin receptor blocker (ARBs) as routine treatment may be suggested. The benefit of DAPT should be considered on an individual basis. The secondary prevention therapies largely target the atherothrombotic process. In MINOCA patients, however, the atherosclerotic burden is reduced or minimal.

Risk factor modification with non-pharmacological therapies, and cardiac rehabilitation should be strongly recommended.

Future perspectives

The current MINOCA BAT Randomized Evaluation of beta-Blocker and ACEI/ARB Treatment in MINOCA Patients (ClinicalTrials.gov Identifier: NCT03686696) will randomize 3500 patients with MINOCA to treatment with ACEIs/ARBs and beta-blockers or matching placebo. This trial will provide valuable data on the benefits or risks of routine cardioprotective therapies in patients with MINOCA.

FOCUS BOX 7
  • Reduction of angina burden and prevention of incident rehospitalizations in order to reduce healthcare-related costs and improve quality of life represent an urgent unmet clinical need in this patient population.
  • The ‘one-size-fits-all’ approach does not apply to all MINOCA patients. A tailored therapeutic approach should be adopted depending on the underlying pathophysiological mechanism responsible for the clinical presentation
  • Multi-centre clinical trials of diagnostic and therapeutic strategies are needed

Prognosis of MINOCA

Data on prognosis of MINOCA patients from current registries are heterogeneous and based on different aetiologies and different inclusion criteria.

Despite controversial data, most studies have shown that MINOCA patients have better outcomes than their counterparts with CAD. [15, 127, 128]

Nevertheless, there is a substantial risk of recurrent events during follow-up of MINOCA patients that is higher than what is observed in the general population without cardiovascular disease. [129]

Approximately 25% of patients with MINOCA will experience recurrence angina within the first 12 months. [130] A progression of coronary stenosis has been found in approximately half of the patients with higher mortality reported for patients who did not undergo a new coronary angiography. [131]

The SWEDEHEART study reported the following cardiovascular event rates: 13.4% of mortality, 7.1% of recurrent MI, 4.3% of ischemic stroke, 6.4% of hospitalization for heart failure, and 3.6% of hospitalization for bleeding.

An observational study on 9092 MINOCA patients from Nordenskjöld, found that 24% of the patients presented MACE and 14% died during follow-up. Most of MACE and death predictors among MINOCA patients are in common with those previously described for CAD patients, some of which are older age, diabetes, hypertension, current smoking, previous MI, previous stroke, and reduced LVEF. [131]

Interestingly, admission with ST-segment elevation on the ECG or with heart failure or shock were more strongly predictive of in-hospital death among patients with MINOCA than their counterparts with CAD.

There are limited data on outcomes of MINOCA patients based on the underlying cause, the multiple categories can have different prognoses which may be under- or overestimated when grouped them together in the same registries.

FOCUS BOX 8
  • MINOCA is associated with a non-negligible risk of mortality, rehospitalization, disability and angina burden at follow-up.
  • The next key step in MINOCA management is to demonstrate that tailored therapeutic approaches provide a significant improvement in angina status and quality of life, as well as better clinical outcomes with a drastic reduction in economic costs.

Conclusion

The clinical conundrum of INOCA and MINOCA represents a challenge for treating physicians and interventional cardiologists and calls attention to several important knowledge gaps. Multimodality diagnostic approach is of utmost importance to identify the underlying etiology. More evidence-based and tailored therapeutic strategies are needed to improve quality of life and prognosis of these patients.

Personal perspective – Alaide Chieffo

INOCA and MINOCA are two important clinical entities, frequently overlooked in clinical practice. Obtaining objective evidence on the underlying cause is key in formulating effective treatments.

Identifying the underlying mechanism ultimately leading to this spectrum of clinical conditions represents a heterogeneous clinical conundrum for treating clinician/interventional cardiologists. Diagnostic algorithm should rely on comprehensive investigational approach, including invasive assessment of coronary microvascular system and vasoreactivity testing. A multimodality diagnostic work-up will help to elucidate the correct aetiology and identifies different INOCA endotypes. The correct management of INOCA and MINOCA is still controversial due to the lack of large, randomized studies involving homogenous patient groups. In my perspective, a contemporary approach should be patient-focused, multidisciplinary and based on different lines of intervention addressing quality of life and prognosis.

I strongly believe that raising awareness among clinicians and providing them with adequate tools will counteract therapeutic nihilism and lead to a patient-centred diagnostic and therapeutic approach. Future prospective well-designed ongoing research is required to address several unmet needs in the diagnosis and management of these patients.