Takotsubo syndrome associated with coronary microvascular dysfunction: A case study

Abstract

The patient, a 68-year-old man, presented to our emergency room with chest pain, prompting an emergency cardiac catheterization due to elevated cardiac troponin-I levels. While no obvious coronary artery stenosis was found, there was evidence of apical ballooning wall motion in the left ventricle, leading to a diagnosis of takotsubo syndrome. Three months later, he occasionally experienced chest pain at rest, prompting us to conduct another cardiac catheterization. Left ventriculography showed normal contraction. Suddenly, he experienced chest pain accompanied by ST elevation, which occurred spontaneously. Subsequently, slow-flow phenomenon was observed in the intermediate part of left anterior descending artery (LAD). We promptly administered nitroglycerin to alleviate the symptoms. Following the diagnosis of coronary microvascular dysfunction (CMD), he started calcium-channel blocker therapy and remained asymptomatic. One year later, we re-performed cardiac catheterization to further explore his condition. Acetylcholine provocation test was performed, which showed no epicardial coronary spasm. However, lactic acid elevation was observed in the coronary sinus blood sample. Additionally, a coronary physiological measurement in the LAD revealed a high index of microcirculatory resistance and low coronary flow reserve. Based on this series of clinical events, we inferred a significant contribution of CMD to the patient's condition.

Learning objective

Coronary microvascular dysfunction (CMD) is increasingly recognized as an important cardiovascular disease, leading to myocardial ischemia, which is occasionally associated with takotsubo syndrome (TTS). In this report, we present a case of spontaneous CMD associated with TTS. This case emphasizes the significance of accurate diagnosis and appropriate treatment, highlighting the importance of recognizing CMD in patients with TTS.

Introduction

Takotsubo syndrome (TTS) was first described in 1990, and since then, a wide variety of TTS cases have been reported [1]. Some triggering stimuli for TTS have been identified, including fluctuations in hemodynamics and emotional stress, but nearly one-third of patients have no evident trigger. The mechanisms of TTS are thought to involve catecholaminergic myocardial stunning, microvascular dysfunction, increased inflammation, and changes in cardiomyocyte metabolism. However, it is unclear whether these factors are the cause or the result of TTS.

Recently, patients with symptoms suggestive of ischemic heart disease but no obstructive coronary arteries (INOCA) have been widely recognized. In INOCA patients, coronary functional abnormalities could be involved, including vasospastic angina (VSA) and/or coronary microvascular dysfunction (CMD). CMD includes coronary microvascular spasm and diastolic dysfunction of the coronary microvasculature, leading to myocardial ischemia [2].

In this report, we present a case of TTS with strongly associated CMD as the etiology.

Case report

A 68-year-old male patient presented at our hospital's emergency room due to sudden chest pain. He suddenly experienced chest pain accompanied by cold sweats at rest in the morning. Afterward, he briefly improved, but he continued to have intermittent chest pain of varying intensity for about an hour. He had no smoking habit and no family history of cardiovascular disease. He was prescribed oral medication for diabetes and hypertension, consisting of linagliptin 5 mg per day, empagliflozin 10 mg per day, and olmesartan 20 mg per day. His electrocardiogram (ECG) showed no ST changes (Online Fig. 1), but his serum chemistry indicated an abnormal elevation of cardiac troponin-I levels (Online Fig. 2). Consequently, we performed an emergency cardiac catheterization for diagnosis, which revealed 25–50 % atherosclerotic stenosis in both the right coronary artery (RCA) and the left coronary artery (LCA) (Fig. 1a, b). However, it did show apical ballooning wall motion of the left ventricle (LV) (Fig. 1c, d). The following day, his ECG displayed negative-T waves in leads II, III, aVF, and V2-V6 (Online Fig. 3), leading to a diagnosis of TTS. He was discharged without any additional medication. Three months later, he visited our hospital for a follow-up, and his ECG showed not negative-T waves but nonspecific ST changes (Online Fig. 4). However, after the TTS diagnosis, he occasionally felt chest pain at rest. Subsequently, we performed another cardiac catheterization. Left ventriculography showed normal contraction of the LV (Online Fig. 5). Coronary angiography (CAG) without nitroglycerin (NTG) revealed a spastic coronary artery in both RCA and LCA. In particular, CAG revealed that the left anterior descending artery (LAD) had 75–90 % stenosis in the intermediate part (segment #7) (Fig. 2a, b). However, he had no symptoms, and his ECG showed no ST-T changes.

Fig. 1.

1st cardiac catheterization (a) CAG of RCA (LAO) (b) CAG of LCA(LAO-CRA) (c) LVG (LAO, end-diastolic phase) (d) LVG (LAO, end-systolic phase).

Fig. 2.

2nd cardiac catheterization (a) CAG with no NTG of RCA (LAO) (b) CAG with no NTG of LCA(LAO-CRA) (c) ECG of LCA at sudden chest pain (d) CAG of LCA at sudden chest pain (LAO-CRA).

Fig. 3.

3rd cardiac catheterization (a, b) CAG with no NTG of LCA(a; RAO-CAU, b; LAO-CRA) (c) The measurement of Lactate during Ach provocation test (d) The coronary physiological measurements in the LAD.

Subsequently, we planned to conduct an acetylcholine provocation test for further diagnosis. Unexpectedly, he experienced chest pain accompanied by ST elevation, which occurred spontaneously (Fig. 2c). We immediately performed CAG, and a slow-flow phenomenon was observed in the intermediate part of the LAD, particularly at the distal site of the coronary stenosis (Fig. 2d). We promptly administered NTG to alleviate the symptoms, and his condition improved.

After the injection of NTG, CAG revealed that the stenosis of LAD (segment #7 of American Heart Association classification) was reduced to under 50 % stenosis. We then performed pressure wire measurement on LAD and confirmed resting full-cycle ratio (RFR) of 0.95 and fractional flow reserve (FFR) of 0.86. Consequently, we diagnosed coronary microvascular dysfunction (CMD). Following the diagnosis of CMD, he started calcium-channel blocker therapy (CCB, benidipine 8 mg per day) and remained asymptomatic for one year.

One year later, we re-performed cardiac catheterization to further explore his condition. Prior to the cardiac catheterization, we discontinued CCB for 1 week. CAG without NTG showed LAD had 50 % stenosis in segment #7 (Fig. 3a, b). The acetylcholine provocation test was performed, which showed no epicardial coronary spasm. However, lactic acid elevation was observed in the coronary sinus blood sample (Fig. 3c). Additionally, we performed coronary physiological measurements for index of microcirculatory resistance (IMR) and coronary flow reserve (CFR) in the LAD. The measurements revealed an IMR of 89 and a CFR of 1.0 in the LAD (Fig. 3d). Based on these findings, we determined that continuing CCB and angiotensin receptor blocker was appropriate for his treatment. This series of clinical events led us to infer a significant contribution of CMD to the patient's condition.

Discussion

TTS is characterized by regional wall motion abnormalities that reflect impairment of myocardial contractility in the absence of culprit epicardial coronary artery disease [1]. Some triggering mechanisms for TTS have been reported, including fluctuations in hemodynamics and emotional stress. However, the precise pathophysiological mechanisms responsible for TTS remain unclear. It is reported that nearly one-third of patients have no evident trigger [1]. In this case, the patient did not experience any significant stress that could have acted as a trigger. CMD is an important cardiac disorder involving abnormal microvascular resistance, impaired coronary vasorelaxation, and microvascular spasm, which leads to myocardial ischemia. The role of coronary microcirculation in TTS was previously described in several studies, which showed CMD in patients with TTS [3]. The coronary microvascular function of the TTS patients was investigated through coronary physiological measurements for IMR and CFR, the acetylcholine or ergonovine provocation test, the increase in thrombolysis in myocardial infarction frame count during CAG, and several myocardial perfusion imaging tests [[4], [5], [6]]. In this case, we also examined the coronary microvascular function using both coronary physiological measurements and the acetylcholine provocation test. Additionally, we observed a slow-flow phenomenon during the spontaneous attack of CMD in the 2nd cardiac catheterization. Spontaneous events of CMD are rare to report, making our case report particularly important. In fact, our case showed ST-elevation and coronary slow-flow in the LAD during spontaneous chest pain. Furthermore, CAG with NTG showed no significant stenosis. Our case leads to a diagnostic criteria of VSA according to “the guidelines of the JCS/CVIT/JCC 2023 Guideline on Diagnosis and Treatment of Vasospastic Angina (Coronary Spastic Angina) and Coronary Microvascular Dysfunction” [7]. However, the diagnostic criteria for VSA were not met during the 3rd cardiac catheterization. The slow-flow phenomenon occurred not at the site of stenosis, but rather at the distal site of the stenosis, so we could not rule out the contribution of CMD. From this case, we think that spontaneous events of CMD must be distinguished from the diagnostic criteria of VSA.

Certainly, we should consider the possibility of false negatives in acetylcholine provocation testing and the potential improvement in some coronary functions due to oral medication therapy. Moreover, we think that this case may have been caused by vasospasm in both epicardial coronary vessel and the microvasculature. A previous report mentioned that CMD may contribute during the initial stages of TTS [8]. However, in this case, the timing of the onset of CMD is unclear. Since the 3rd catheterization was performed during the chronic phase, it may appear to be manifest, but it is not clear exactly when it began. In this case, there may have been underlying CMD based on conditions such as diabetes. While the causal relationship between CMD and TTS is not clear in this case, it is inferred that there was significant involvement. It is reported that TTS is triggered by an excessive release of catecholamines. On the other hand, the surge in catecholamines can also lead to vascular dysfunction, including CMD and/or VSA [1,4]. Therefore, we conducted the 3rd cardiac catheterization to investigate further. The results revealed that this case exhibited severe CMD, which included coronary microvascular spasm and diastolic dysfunction of the coronary microvasculature. A recent report described that, among 519 TTS cases followed for an average of 5.2 years, 7.5 % of patients experienced recurrence, and 16.2 % died [9]. The report suggests that CMD might be a contributing factor to both recurrence and fatal outcomes of TTS, emphasizing the significance of appropriate treatment to prevent such events [10]. Thus, this case report highlights the importance of precise diagnosis and appropriate treatment for patients with TTS.

Funding sources

The authors declare that there are no funding sources.

Patient permission/consent statement

Informed consent was obtained from the patient.

Declaration of competing interest

The authors declare that there is no conflict of interest.

Appendix A. Supplementary data

Supplementary figures