Coronary Microvascular Spasm as the Underlying Cause of the Angiographic Slow Flow Phenomenon

Abstract

Slow coronary flow is frequently seen during angiography in patients with angina and unobstructed coronary arteries. However, the pathophysiology of this finding remains largely unclear. We report a case of a 52-year-old woman with slow coronary flow caused by acetylcholine-induced microvascular spasm, as confirmed by intracoronary flow measurements. (Level of Difficulty: Beginner.)

Graphical abstract

Slow coronary flow is frequently seen during angiography in patients with angina and unobstructed coronary arteries. However, the pathophysiology of this…

History of Presentation

A 52-year-old white female presented to the clinic with exertional dyspnea (New York Heart Association [NYHA] functional classes II to III) and angina which had been occurring predominantly at rest for the previous 4 months.

Learning Objectives

• •The objectives of this case were to understand that microvascular spasm may lead to severe impairment of coronary blood flow resulting in angina and ischemic electrocardiography changes.
• •An additional objective included considering microvascular spasm as the underlying pathophysiological mechanism in patients with slow flow on coronary angiography.

Medical History

The patient’s cardiovascular risk factors consisted of a family history of coronary artery disease, smoking (12 pack-years, which stopped about 30 years ago), and well-controlled hypertension.

Differential Diagnosis

Coronary artery disease (CAD) and coronary vasomotor disorders were considered as differential diagnoses.

Investigations

The physical examination, laboratory results, and routine diagnostic test results, including resting electrocardiography (ECG) and echocardiography results were unremarkable. During an exercise ECG, the patient experienced dyspnea without ischemic ECG changes. Considering the patient’s pre-test probability and clinical likelihood for obstructive CAD based on the current guidelines of the European Society of Cardiology (1), noninvasive risk stratification was performed using coronary computed tomography angiography. Although only mild soft plaques (Agatson score of 0) were reported in the right coronary artery and the left circumflex artery, a moderate stenosis of unclear hemodynamic significance was suspected in the proximal left anterior descending (LAD) artery (Figure 1). For further evaluation of the suspected stenosis as well as assessment of the differential diagnosis of coronary vasomotor disorder, invasive coronary angiography (Figure 2) including combined measurement of fractional flow reserve (FFR), coronary flow reserve (CFR) and hyperemic microvascular resistance (HMR) (Figure 3), as well as acetylcholine (ACh) spasm provocation testing (Figure 4), were carried out with a Doppler flow/pressure wire (Volcano ComboWire 9515, Rancho Cordova, California) placed in the mid LAD/co-dominant diagonal branch.

Figure 1.

Coronary Computed Tomography Angiography

A moderate stenosis of the proximal left anterior descending artery (LAD) (arrow) was suspected on coronary computed tomography angiography, which was performed in search of coronary artery disease. LCX = left circumflex artery.

Figure 2.

Coronary Angiography

Invasive coronary angiography revealed plaques of (A) the right coronary artery (RCA) and (B) the left coronary artery without angiographically significant stenosis. LAD = left anterior descending artery; LCX = left circumflex artery.

Figure 3.

Combined Intracoronary Measurement of FFR and CFR

Combined intracoronary measurement of fractional flow reserve (FFR) and coronary flow reserve (CFF) in the left anterior descending artery (LAD). Hemodynamic significance of the LAD stenosis could be ruled out (FFR, 0.94 [upper white arrow]). The average peak flow velocity (APV) at baseline (white arrow left) was 14 cm/s and increased to 35 cm/s during adenosine-induced vasodilation resulting in a preserved CFR of 2.5 and an hyperemic microvascular resistance (HMR) of 2.4 (white arrow right).

Figure 4.

ACh Provocation Testing in the Left Coronary Artery with Simultaneous Intracoronary Pressure/Flow Assessment

Coronary flow was assessed in the proximal co-dominant diagonal branch. Average peak flow velocity (APV) at rest was 22 cm/s (A). Intracoronary injection of 100 μg of acetylcholine (ACh) led to symptom reproduction, severe coronary slow flow on angiography, ischemic electrocardiography (ECG) changes, and a significant reduction of the APV (5 cm/s [white arrow]) (B). Intracoronary nitroglycerin (200 μg) resulted in normalization of coronary blood flow (APV, 57 cm/s) and the ECG shifts (C). i.c. = intracoronary.

Hemodynamic significance of the LAD stenosis could be ruled out by intracoronary administration of 125 μg of adenosine (FFR: 0.94). Microvascular vasodilator capacity in response to adenosine was preserved (CFR: 2.5; HMR: 2.4 mm Hg·cm^-1·s) (Figure 3).

Stepwise intracoronary ACh provocation testing was performed according to a standardized protocol (2). After injecting 100 μg of ACh, the patient reported reproduction of her usual chest pain, and new ischemic ECG changes (ST-segment depression and negative T waves in leads II, III, aVF, and V₄ to V₆) accompanied by severe diffuse coronary slow flow (Thrombolysis in Myocardial Infarction flow grade 1) could be observed. Coronary slow flow was confirmed by Doppler flow assessment showing a significant reduction of average peak flow velocity in the absence of epicardial spasm. A subsequent intracoronary application of 200 μg of nitroglycerin led to a full restoration of coronary flow on the angiogram and normalization of coronary flow velocity as well as resolution of the patient’s symptoms and ischemic ECG changes (Figure 4, Videos 1, 2, and 3).

Online Video 1.

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Baseline coronary angiography.

Online Video 2.

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Slow coronary flow after intracoronary administration of 100 μg of acetylcholine.

Online Video 3.

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Normalization of blood flow after intracoronary administration of 200 μg of nitroglycerin.

Management

The diagnosis of coronary microvascular spasm was established, and treatment with a calcium channel blocker and nitrates was initiated.

Discussion

This case provides evidence for the hypothesis that coronary microvascular spasm can be the underlying pathophysiological mechanism of the slow coronary flow phenomenon. It is well known that coronary flow is highly dependent on coronary microvascular resistance, which is increased during microvascular spasm. Intracoronary Doppler flow measurements allow coronary blood flow velocity to be assessed directly under resting conditions or in response to vasoactive stimuli such as adenosine or ACh. Previous studies demonstrated that slow coronary flow in the absence of epicardial stenoses can be observed in up to 30% of patients undergoing coronary angiography (3). This phenomenon is thought to be caused by microvascular dysfunction (4), a condition that women are more likely to develop (5).

In the present case, the diagnosis of coronary microvascular spasm could be established according to standardized criteria (6) in a female patient with episodes of resting angina and was found to be associated with severe coronary slow flow on angiography. Women have been reported to have a higher prevalence of microvascular dysfunction (microvascular spasm and/or impaired microvascular vasodilator function) than men. Moreover, women are at higher risk of future adverse events and experience greater impairment of quality of life (5). This may not only be due to pathophysiological differences but can also be explained by differences in clinical presentation as well as less intensive and delayed diagnostic workup. The present case emphasizes that microvascular spasm should be considered as the underlying mechanism in patients with chest pain and coronary slow flow despite unobstructed coronaries (3,7). Establishing the diagnosis is of paramount importance to guide individualized pharmacological treatment approaches and to adequately counsel the patient. The current European Society of Cardiology guideline recommends the use of calcium channel blockers and nitrates for the treatment of vasospastic and microvascular angina (1), but despite the broad spectrum of antivasospastic and antianginal drugs currently available, morbidity remains high, particularly in female patients (5).

Follow-up

As often happens in patients with microvascular angina, symptom control proved to be challenging in this patient. The CorMicA (Coronary Microvascular Angina) trial recently showed that beta-blocker treatment is the first choice in patients with microvascular angina (8). However, in this patient, neither treatment with a beta-blocker nor treatment with a non-dihydropyridine (DHP) calcium channel blocker could improve the patient’s symptoms. In addition to an angiotensin-converting enzyme inhibitor and a statin, treatment with a DHP calcium channel blocker, nitrates, and ranolazine led to a partial improvement of the patient’s symptoms.

Conclusions

This case report provides new insights into the pathophysiology of coronary slow flow. Coronary microvascular spasm should be considered the underlying mechanism in patients presenting with this angiographic phenomenon. This is of special importance in female patients, because they have a higher prevalence and increased morbidity associated with microvascular dysfunction than men.