An EAPCI Expert Consensus Document on Ischaemia with Non-Obstructive Coronary Arteries, 2020, Kunadian et al

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An EAPCI Expert Consensus Document on Ischaemia with Non-Obstructive Coronary Arteries in Collaboration with European Society of Cardiology Working Group on Coronary Pathophysiology & Microcirculation Endorsed by Coronary Vasomotor Disorders International Study Group
Vijay Kunadian, Alaide Chieffo, Paolo G Camici, Colin Berry, Javier Escaned, Angela H E M Maas, Eva Prescott, Nicole Karam, Yolande Appelman, Chiara Fraccaro, Gill Louise Buchanan, Stephane Manzo-Silberman, Rasha Al-Lamee, Evelyn Regar, Alexandra Lansky, J Dawn Abbott, Lina Badimon, Dirk J Duncker, Roxana Mehran, Davide Capodanno, Andreas Baumbach

Abstract
This consensus document, a summary of the views of an expert panel organized by the European Association of Percutaneous Cardiovascular Interventions (EAPCI), appraises the importance of ischaemia with non-obstructive coronary arteries (INOCA).

Angina pectoris affects approximately 112 million people globally. Up to 70% of patients undergoing invasive angiography do not have obstructive coronary artery disease, more common in women than in men, and a large proportion have INOCA as a cause of their symptoms. INOCA patients present with a wide spectrum of symptoms and signs that are often misdiagnosed as non-cardiac leading to under-diagnosis/investigation and under-treatment. INOCA can result from heterogeneous mechanism including coronary vasospasm and microvascular dysfunction and is not a benign condition. Compared to asymptomatic individuals, INOCA is associated with increased incidence of cardiovascular events, repeated hospital admissions, as well as impaired quality of life and associated increased health care costs.

This consensus document provides a definition of INOCA and guidance to the community on the diagnostic approach and management of INOCA based on existing evidence from research and best available clinical practice; noting gaps in knowledge and potential areas for further investigation.

Link | PDF (Eur Heart J)

 

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Posting in relation to more generalised endothelial dysfunction as a proposed downstream mechanism in ME/CFS and LC. For LC, chest pain that is often diagnosed as non-cardiac is a recognised symptom, per the WHO clinical case definition.

CAD = coronary artery disease
CMD = coronary microvascular dysfunction
IHD = ischaemic heart disease
INOCA = ischaemia with non-obstructive coronary arteries
MVA = microvascular angina

 

[SNT Gatchaman]

A large proportion of patients (up to 70%) undergoing coronary angiography because of angina and evidence of myocardial ischaemia do not have obstructive coronary arteries but have demonstrable ischaemia. Studies carried out in the past two decades have highlighted that coronary microvascular dysfunction (CMD) and epicardial vascular dysfunction are additional pathophysiologic mechanisms of IHD. Coronary microvascular dysfunction and epicardial vasospasm, alone or in combination with coronary artery disease (CAD), are adjunctive mechanisms of myocardial ischaemia.

However, these conditions are rarely correctly diagnosed and, therefore, no tailored therapy is prescribed for these patients. As a consequence, these patients continue to experience recurrent angina with impaired quality of life, leading to repeated hospitalizations, unnecessary coronary angiography and adverse cardiovascular outcomes in the short- and long term.

A failure to diagnose epicardial CAD in a patient with documented angina/ischaemia should promote a subsequent search pathway to elucidate INOCA endotypes before a search for non-cardiac causes of chest discomfort is explored.

Patients with INOCA present with a wide spectrum of symptoms and signs that are often misdiagnosed as of non-cardiac origin, leading to under-investigation and under-treatment.

INOCA, like obstructive CAD, can also present with other symptoms such as breathlessness, pain between the shoulder blades, indigestion, nausea, extreme fatigue, weakness, vomiting, and/or sleep disturbances.

It is important to recognize that there is gender variation in the clinical manifestation of both obstructive and non-obstructive CAD. These differences in presentation are of particular relevance in young and middle-aged women and also men who do not present with classical anginal symptoms. With the same symptoms, women are much less likely to have obstructive CAD and much more likely to have CMD as a cause of their symptoms.

Importantly, INOCA is associated with a wide variation in clinical presentation and symptom burden may vary over time. These symptoms should not be automatically classified as non-cardiac in origin, particularly given the fact that women have a much higher prevalence of INOCA than men.

The prognosis of patients with INOCA is far from benign.

It must be noted, the condition is heterogeneous and not all patients with angina and no obstructive CAD have ischaemia as a cause of their symptoms. However, when ischaemia is documented through CMD or endothelial dysfunction the prognosis is further impaired. Meta-analyses have shown a two- to four-fold higher risk of adverse cardiovascular outcome for patients with CMD diagnosed by positron emission tomography (PET) or transthoracic Doppler echocardiography and a two-fold higher risk in patients with epicardial endothelial-dependent dysfunction. Vasospastic angina is associated with major adverse events including sudden cardiac death, acute MI, and syncope which may unfortunately occur before the diagnosis is established.

Should the possibility of non-obstructive causes of ischaemia not be considered by the treating physician, a coronary angiogram showing no obstructive disease may be followed by incorrect interpretation of the patient’s symptoms, avoidance of further diagnostic evaluation, and lack of adequate treatment. Indeed, coronary angiography in INOCA showing non-obstructive coronary arteries may result in inappropriate discontinuation of medical therapy, paradoxical reassurance by the treating physician and potentially, the physician may even refute the underlying symptoms. This approach is not patient-centred, as many will continue to have symptoms that will lead to rehospitalization, repeated diagnostic testing and inappropriate treatment.

 

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Cardiac ischaemia may also be caused by vascular dysfunction without obstructive CAD, a condition recently termed INOCA. In INOCA, the mismatch between blood supply and myocardial oxygen demands may be caused by CMD and/or epicardial coronary artery spasm.

Microvascular angina (MVA) is the clinical manifestation of myocardial ischaemia caused by CMD.

In all studies, there is a strong female preponderance for the condition. A large US multicentre study showed that nearly 39% of the patients selected for coronary angiography because of suspected angina and/or positive stress test have non-obstructive CAD.

Similarly, almost two-thirds (62%) of women referred for coronary angiography and enrolled in the National Heart, Lung, and Blood Institute-sponsored Women’s Ischaemia Syndrome Evaluation (WISE), did not have a significant obstructive stenosis.

Age, diabetes, hypertension, and dyslipidaemia were associated with impaired CMD both in the iPower study and WISE study.

Coronary microvascular dysfunction is associated with proinflammatory markers in women with INOCA.

... systematic lupus erythematosus and rheumatoid arthritis are associated with CMD and are frequently encountered in patients with angina and CMD. After menopause, inflammatory diseases occur more often in women compared to men, which may contribute to sex-differences in CMD.

In the absence of flow-limiting coronary artery disease, myocardial ischaemia can result from specific pathways of microcirculatory dysfunction. Two microcirculatory dysfunction endotypes account for most cases of MVA: structural microcirculatory remodelling and functional arteriolar dysregulation. In other words, microvascular dysfunction may be structural, functional or both.

The substrate of coronary spasm can be found in abnormal function of both vascular smooth muscle and endothelial cells.

Structural remodelling of the coronary microvasculature is associated with a decrease in microcirculatory conductance and impaired oxygen delivery capacity. This is typically caused by inward remodelling of coronary arterioles, with an increase in wall to lumen ratio, loss of myocardial capillary density (capillary rarefaction) or both.

Functional arteriolar dysregulation typically takes place in medium and large size arterioles, in which flow-mediated vasodilation is predominant. Under physiological conditions, an increase in myocardial oxygen consumption generates an upstream vasodilatory cascade in coronary resistance vessels. This is initiated by metabolically triggered vasodilation of distal arterioles, that are particularly sensitive to certain metabolites, and it is followed by flow-mediated (endothelium-dependent) vasodilation of larger arterioles located upstream, as well as epicardial vessels. In the presence of endothelial dysfunction, dysregulation of the described upstream vasodilatory cascade occurs. Thus, endothelial dysfunction is associated with impaired vasodilation and even paradoxical vasoconstriction of up-stream arteries and arterioles when myocardial oxygen demands increase.

 

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See also case report of 23 yo female Angina Simultaneously Diagnosed with the Recurrence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (2021, Diagnostics).

Herein, we present a case of a young female with newly diagnosed vasospastic or microvascular angina and concurrent exacerbation of ME/CFS severity. Her anginal symptoms, including exertional chest pain and transient chest discomfort, mimicked those of ME/CFS but were relieved after the administration of a calcium channel blocker. We emphasize the possibility of concurrent angina and exacerbation of ME/CFS and the importance of detecting cardiac ischemia to avoid unfavorable outcomes.

 

[SNT Gatchaman]

See also Coronary “Microvascular Dysfunction”: Evolving Understanding of Pathophysiology, Clinical Implications, and Potential Therapeutics (2023)

 

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Rethinking False Positive Exercise Electrocardiographic Stress Tests by Assessing Coronary Microvascular Function
Sinha; Dutta; Demir; De Silva; Ellis; Belford; Ogden; Li Kam Wa; Morgan; Shah; Chiribiri; Webb; Marber; Rahman; Perera

BACKGROUND
Exercise electrocardiographic stress testing (EST) has historically been validated against the demonstration of obstructive coronary artery disease. However, myocardial ischemia can occur because of coronary microvascular dysfunction (CMD) in the absence of obstructive coronary artery disease.

OBJECTIVES
The aim of this study was to assess the specificity of EST to detect an ischemic substrate against the reference standard of coronary endothelium-independent and endothelium-dependent microvascular function in patients with angina with nonobstructive coronary arteries (ANOCA).

METHODS
Patients with ANOCA underwent invasive coronary physiological assessment using adenosine and acetylcholine. CMD was defined as impaired endothelium-independent and/or endothelium-dependent function. EST was performed using a standard Bruce treadmill protocol, with ischemia defined as the appearance of ≥0.1-mV ST-segment depression 80 ms from the J-point on electrocardiography. The study was powered to detect specificity of ≥91%.

RESULTS
A total of 102 patients were enrolled (65% women, mean age 60 ± 8 years). Thirty-two patients developed ischemia (ischemic group) during EST, whereas 70 patients did not (nonischemic group); both groups were phenotypically similar. Ischemia during EST was 100% specific for CMD. Acetylcholine flow reserve was the strongest predictor of ischemia during exercise. Using endothelium-independent and endothelium-dependent microvascular dysfunction as the reference standard, the false positive rate of EST dropped to 0%.

CONCLUSIONS
In patients with ANOCA, ischemia on EST was highly specific of an underlying ischemic substrate. These findings challenge the traditional belief that EST has a high false positive rate.

Link | PDF (Journal of the American College of Cardiology)

Using comprehensive coronary physiology as the reference standard, ischemic ECG changes during exercise were highly specific for coronary microvascular dysfunction in our patient cohort. This is an important finding that highlights the limitations of using obstructive CAD as a reference standard to assess the accuracy of noninvasive imaging modalities.

 

[Sid]

See also case report of 23 yo female Angina Simultaneously Diagnosed with the Recurrence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (2021, Diagnostics).

I recently became aware of a case of a woman in her early 30s with preexisting POTS, anxiety and depression. Long story short, symptoms that were initially dismissed as anxiety etc. turned out to be a NSTEMI.

 

[NelliePledge]

I recently became aware of a case of a woman in her early 30s with preexisting POTS, anxiety and depression. Long story short, symptoms that were initially dismissed as anxiety etc. turned out to be a NSTEMI.

NSTEMI?

 

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Non-ST segment elevation myocardial infarction (ie heart attack / cardiac muscle damage, cell death; but without the typical ECG changes).