Paradoxical coronary vasospasm and transient apical ballooning in a post-menopausal woman: An imaging case report of an unusual INOCA presentation

Abstract

Ischemia with non-obstructive coronary artery disease (INOCA), a common cause of angina, can occur due to coronary vasospasm, microvascular dysfunction, endothelial dysfunction, atherosclerosis or a combination of these mechanisms. We describe a case of adenosine-associated paradoxical coronary vasospasm and Takotsubo-like apical ballooning in a postmenopausal woman with underlying mild coronary atherosclerosis and microvascular dysfunction.

Highlights

• •Adenosine withdrawal can induce paradoxical coronary vasospasm.
• •Coronary vasospasm can result in apical ballooning and left ventricular dysfunction
• •Estrogen deficiency and abnormal coronary vasoreactivity may contribute to coronary vasospasm.
• •Quantitative stress perfusion cardiac MRI has an emerging role in INOCA patients.

1. Introduction

Adenosine, a coronary vasodilator, is generally used to treat supraventricular tachycardia, and also used as a pharmacological agent in stress myocardial perfusion imaging studies. Adenosine is occasionally associated with paradoxical coronary vasospasm [1], [2], [3], [4], [5]. We describe a case of transient left ventricular apical ballooning mimicking Takotsubo-like syndrome in a postmenopausal woman after adenosine withdrawal during stress perfusion cardiac magnetic resonance imaging (CMR).

2. Case description

A 64-year-old obese, Caucasian woman with hypertension and paroxysmal atrial fibrillation presented with recurrent episodes of severe debilitating chest pain for six months. The episodes were cramping in nature without clear triggers and were relieved with rest and deep breathing. She had significant fatigue, dizziness and near syncope during the episodes. Her medications included apixaban, olmesartan and atenolol. The patient had recently discontinued hormone replacement therapy. She also reported ongoing emotional stress.

Echocardiography and nuclear stress testing were unremarkable. A coronary computed tomography (CT) angiogram revealed non-obstructive disease in the right coronary artery and a wrap-around left anterior descending artery (LAD) with mild diffuse narrowing in the mid to distal LAD (Fig. 1). Adenosine stress perfusion CMR was performed as part of a research protocol. Six minutes post adenosine infusion, the patient developed severe chest pain similar to her presenting symptoms. Cine imaging during this episode revealed marked left ventricular dysfunction with extensive thinning and dyskinesis of the mid to distal anterior wall and apex (Fig. 2, Video 2). ST segment elevation was noted on telemetry. Quantitative myocardial perfusion assessment on the stress CMR images demonstrated severely reduced stress myocardial blood flow (1.2 ml/g/min; normal >2.3 ml/g/min).

Fig. 1.

Minimal non obstructive coronary artery disease on Coronary CT Angiography, Multiplanar reformatted views of the right coronary artery (RCA), left anterior descending (LAD) and left circumflex (LCX). The coronary angiogram reveals minimal non-obstructive disease in the RCA and a wrap-around LAD with mild diffuse narrowing in the mid to distal LAD.

Fig. 2.

Apical ballooning 6 min post Adenosine stress CMR. Top panel: Long axis SSFP images of the left ventricle at rest demonstrate normal thickness of the left ventricle with normal systolic contraction at rest (mid systolic frame). Bottom panel: Long axis SSFP images obtained during an episode of chest pain 6 min post Adenosine stress demonstrate marked thinning and dyskinesis of the mid to apical anterior and antero-septal segments with apical ballooning. The marked apical ballooning was reversed after sublingual nitroglycerine as seen in the accompanying video (Video 2).

Apical ballooning 6 min post Adenosine stress CMR. Top panel: Long axis SSFP images of the left ventricle at rest demonstrate normal thickness of the left ventricle with normal systolic contraction at rest (mid systolic frame). Bottom panel: Long axis SSFP images obtained during an episode of chest pain 6 min post Adenosine stress demonstrate marked thinning and dyskinesis of the mid to apical anterior and antero-septal segments with apical ballooning. The marked apical ballooning was reversed after sublingual nitroglycerine as seen in the accompanying video (Video 2).

The symptoms and wall motion abnormalities were reversed with sublingual nitroglycerin. Based on her clinical picture, she was diagnosed with vasospastic (Prinzmetal's) angina. The patient had complete relief of her chest pain symptoms with high dose diltiazem during two years of outpatient follow up.

3. Discussion

Ischemia with non-obstructive coronary artery disease (INOCA) is an under recognized cause of chest pain in women [6] and can result in significant morbidity and mortality [7], [8]. INOCA predominantly affects women more than men. Women often develop ischemia in response to mental, emotional, and psychological triggers relative to men who generally have physical triggers [9]. Women, when compared to men, have a different activation of their limbic system and hypothalamic-adrenocortical axis that can explain their increased cardiovascular susceptibility to emotional stress [9]. Stress activates the sympathetic nervous system and induces a catecholamine surge that can result in coronary spasm and direct myocardial injury [10]. Our patient did not report anxiety or claustrophobia during the stress test.

Our patient had minimal coronary artery disease, however she developed extensive wall motion abnormalities and apical ballooning during stress testing. Apical ballooning with coronary macrovascular spasm has been reported on occasion [11]. The perfect match between the segmental dysfunction in the anterior wall and apex and the wrap-around LAD along with the transient ST elevation suggests that macrovascular spasm in the LAD was the likely culprit. According to the INTERTAK consensus document, classic apical ballooning phenotype is rare but possible if the wall motion abnormality is in the territory of a single epicardial coronary artery such as the wrap-around LAD in our case [12]. Our patient's symptoms were consistent with coronary spasm and were immediately relieved with sublingual nitroglycerin. Although our patient did not undergo invasive angiography and provocative testing to confirm epicardial coronary artery spasm, the quick recovery with nitroglycerin is consistent with vasospastic angina.

The exact mechanism of adenosine associated vasospasm is not fully understood. Coronary spasm from adenosine is rare but has been reported previously during stress testing and during treatment of supraventricular tachycardia [1], [2], [3], [4], [5]. Adenosine binds to A2A receptors on vascular smooth muscle that results in coronary vasodilation with a negative chronotropic effect [2]. One possible mechanism of paradoxical coronary vasospasm is the abrupt withdrawal of the short acting vasodilator effect of adenosine [13]. Patients with Prinzmetal's angina may have increased susceptibility to vasospasm with the withdrawal of adenosine [3]. Additionally, adenosine stimulates baroreceptors by the vasodilator and hypotensive effect, which leads to sympathetic activation and increased plasma catecholamine concentration and this can further contribute to coronary spasm [4].

Patients with vasospastic angina have abnormal vasoreactivity and potentially have increased susceptibility to vasospasm with adenosine withdrawal [3]. Concomitant atherosclerosis, as seen in this patient, is not uncommon in vasospasm. Other contributing factors are her postmenopausal status and recent cessation of hormone replacement therapy. The decreased estrogen level in postmenopausal women has been known to contribute to endothelial dysfunction and abnormal coronary vasoreactivity [14].

Coronary vasospasm (micro or macro) is an important mechanism causing INOCA. Positron emission tomography is the most validated modality to evaluate microvascular dysfunction with robust prognostic data. Quantitative myocardial perfusion by CMR has an emerging role in the diagnosis of microvascular disease. In the absence of regional perfusion abnormalities, a globally reduced stress myocardial blood flow can be due to obstructive three vessel coronary artery disease or microvascular disease or both [15]. In our patient, coronary CT angiography did not demonstrate obstructive three vessel disease. The global stress myocardial blood flow however was significantly reduced (1.2 ml/g/min), suggesting underlying microvascular dysfunction. The extensive wall motion abnormalities after adenosine withdrawal are consistent with epicardial vasospasm superimposed on microvascular dysfunction.

Coronary vasospasm and Takotsubo-like apical ballooning from adenosine withdrawal has not been previously reported. It is possible that adenosine withdrawal potentially unmasked the coronary vasospasm in our patient. Further studies are needed to understand the interplay between emotional stress, hormonal status, coronary plaque burden, epicardial and microvascular coronary flow and physiology in the evaluation of INOCA.

In conclusion, we report an unusual case of INOCA, where coronary vasospasm during adenosine stress CMR resulted in severe left ventricular dysfunction and Takotsubo-like apical ballooning in a postmenopausal woman after recent cessation of hormone replacement therapy. Additionally, the patient also had mild coronary atherosclerosis and microvascular dysfunction. Microvascular dysfunction was diagnosed based on quantitation of stress myocardial blood flow on CMR. This case illustrates the multifactorial etiology of INOCA that included non-obstructive atherosclerosis, coronary vasospasm and microvascular dysfunction. Quantitative stress perfusion CMR has an emerging role in elucidating the mechanisms of INOCA.

The following is the supplementary data related to this article.

Video 1

Thin slice axial images of the coronary CT angiogram demonstrates minimal coronary atherosclerosis. There was no significant obstructive coronary disease.

Video 2

The left panel shows normal left ventricular contractility at rest on the cine CMR steady state free precession (SSFP) images. The second panel demonstrates normal myocardial perfusion with no regional perfusion defects on first pass gadolinium imaging with Adenosine stress. The third panel demonstrates apical ballooning and severe left ventricular dysfunction that was captured fortuitously, when patient developed severe cramping chest pain similar to her presenting symptoms, while still in the scanner. This occured 6 minutes post Adenosine stress. The last panel demonstrates normalized left ventricular function on transthoracic echocardiography, after patient recieved sublingual Nitroglycerine.

Funding

This case is part of a research study conducted by Dr. Kadiyala and Dr. Reichek at Saint Francis Hospital and Heart Center, Roslyn, NY funded by AHA grant award 0885055N: Plaque Morphology on coronary CT angiography: Relationship to perfusion reserve by quantitative stress CMR.

Dr. Michos is partially funded by the Amato Fund for Women's Cardiovascular Health research at Johns Hopkins University, Baltimore, MD.

Disclosures

Drs. Kadiyala, Patibandla, and Michos have no relevant relationships with industry to disclose. Unrelated to this topic area, Dr. Michos reports advisory boards for Astra Zeneca, Amarin, Bayer, Boehringer Ingelheim, Esperion, Novarits, and Novo Nordisk.

CRediT authorship contribution statement

Madhavi Kadiyala: Conceptualization, Supervision, Roles/Writing - original draft, Writing - review & editing.

Saikrishna Patibandla: Roles/Writing - original draft, Writing - review & editing.

Nathaniel Reichek (posthumous): Writing - review & editing.

Erin Michos: Writing - review & editing.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Madhavi Kadiyala reports financial support was provided by American Heart Association. Madhavi Kadiyala reports a relationship with National Institutes of Health that includes: funding grants. This case is part of a research study conducted by Dr. Kadiyala and Dr. Reichek at Saint Francis Hospital, Roslyn, NY funded by AHA grant award 0885055N: Plaque Morphology on coronary CT angiography: Relationship to perfusion reserve by quantitative stress CMR. Dr. Kadiyala has funding from NIH/NIGMS award number 2U54GM104942-02: Quantitative myocardial blood flow assessment by Adenosine stress CMR in perimenopausal women with Hormone replacement therapy.

Dr. Michos is partially funded by the Amato Fund for Women's Cardiovascular Health research at Johns Hopkins University, Baltimore, MD.