Left anterior descending artery stenosis coexisting with Takotsubo cardiomyopathy: Innocent bystander or underlying culprit?

Abstract

Takotsubo Cardiomyopathy (TTC) is an acute heart disease, characterized by transient regional systolic dysfunction of the left ventricular typically affecting the apical segments. Initially thought to occur in the absence of significant coronary artery disease (CAD), this concept has evolved with increasing evidence of concurrent cases of TTC and significant CAD, presenting both diagnostic and therapeutic challenges. A 65-year-old woman developed acute coronary syndrome (ACS) after emotional stress, presenting with apical ballooning and severe left ventricular dysfunction that fully resolved within a month, with cardiac magnetic resonance imaging showing no late gadolinium enhancement. Coronary angiography revealed significant mid-left anterior descending (LAD) stenosis, leading to the hypothesis of apical Takotsubo cardiomyopathy coexisting with obstructive CAD in the LAD as an innocent bystander. While the coexistence of TTC and LAD stenosis has been reported, the simultaneous occurrence of these conditions presents a diagnostic dilemma. Accurate diagnosis requires a thorough assessment of the patient’s clinical presentation and findings from multimodal imaging.

Introduction

Takotsubo Cardiomyopathy (TTC), also known as Takotsubo syndrome (TTS) or broken heart syndrome or stress cardiomyopathy, is an acute heart failure disease, characterized by sudden, transient regional wall motion abnormalities (RWMAs) and left ventricular dysfunction which commonly affect the apical segments [1]. Initially described by Sato et al. in 1990 among the Japanese population [2], it predominantly affects postmenopausal women and is often precipitated by physical or emotional stress [3]. Although the exact pathophysiology of this disease remains unclear, it is generally believed that excessive sympathetic activity and stress related catecholamine may play a central role in its pathogenesis [4]. TTC typically manifests with clinical features that closely mimic acute coronary syndrome (ACS) creating a diagnostic challenge. Over two decades ago, it was defined as an acute cardiac condition that occurs in the absence of significant coronary artery disease (CAD) as outlined in the Mayo Clinic criteria [5]. However, recent studies have proposed that TTC and CAD can coexist, thereby challenging the previous criteria and the assumption that the presence of CAD precludes a diagnosis of TTS. The simultaneous occurrence of TTC and significant CAD creates a diagnostic dilemma. Discerning whether these two conditions represent a coincidental association or a mutually causal relationship is complex, particularly when apical Takotsubo cardiomyopathy occurs alongside LAD stenosis [3].

This article aims to underscore the diagnostic challenges encountered in an uncommon case report involving the coexistence of apical Takotsubo cardiomyopathy and significant left anterior descending artery stenosis.

Case presentation

A 65-year-old female, with a history of diabetes mellitus, was admitted to our hospital’s emergency department, with severe acute chest pain radiating to her right arm, along with dyspnea. These symptoms had started three days earlier, in the context of an emotional stress.

At admission, the patient was asymptomatic. Her blood pressure was approximately 135/64 mmHg, with a heart rate of 82 beats per minute and an oxygen saturation of 96% on room air. Cardiovascular examination revealed no abnormalities, with no murmurs, gallops, or rubs detected. Pulmonary auscultation showed clear lung fields bilaterally, with no wheezing, or crackles observed. The rest of examination was unremarkable.

The 12-lead electrocardiogram (ECG) (Fig. 1) showed necrotic Q waves with inversed T waves in the anterior leads (V1-V6). Chest radiography showed no abnormalities.

Fig. 1.

The 12-Lead Electrocardiogram revealing necrotic Q waves and inverted T waves in the anterior leads.

The laboratory results were within normal limits, except for an elevated high-sensitivity troponin T level of 5047 ng/ml (normal range <26 ng/ml).

The two-dimensional echocardiogram (Fig. 2) (Video 1. Supplementary Data) demonstrated severe left ventricular dysfunction, with a left ventricular ejection fraction (LVEF) of 36% by Simpson’s biplane method (SBP) (Fig. 2A), along with apical ballooning of the left ventricle (Fig. 2B).

Fig. 2.

(A) Transthoracic echocardiogram at admission (apical four- and two-chamber views) demonstrating severe left ventricular systolic dysfunction. (B) Apical four-chamber views in diastole and systole showing apical ballooning, characteristic of Takotsubo cardiomyopathy.

Considering the clinical context with an InterTak diagnostic score at 61 and echocardiographic findings, Takotsubo cardiomyopathy was suspected. However, distinguishing whether the presentation was attributable to an acute coronary syndrome or stress-induced cardiomyopathy remained challenging.

The patient was initially treated with Clopidogrel, aspirin, heparin, atorvastatin, and was taken immediately for cardiac catheterization.

Coronary angiography (Fig. 3) revealed significant stenosis of the mild left anterior descending artery with no visible thrombus. An initial diagnosis of an acute coronary syndrome was made, and given the delayed presentation (>48 hours), emergent angioplasty was deferred.

Fig. 3.

Coronary angiography showing significant stenosis of the mid left anterior descending artery.

Upon discharge, the patient was prescribed dual antiplatelet therapy, atorvastatin, a renin-angiotensin-aldosterone system (RAAS) inhibitor, a beta blocker, and an SGLT2 inhibitor.

At the four-week follow-up, the patient successfully returned to her regular activities without any signs of dyspnea or chest pain. The electrocardiogram had normalized. An echocardiography was performed, revealing the absence of the region wall abnormalities and the normalization of the ejection fraction to 59% (Fig. 4). Cardiac magnetic resonance imaging revealed complete recovery of normal left ventricular contractility, with a left ventricular ejection fraction of 64% and no evidence of myocardial late gadolinium enhancement (LGE), which typically rules out myocardial infarction as a differential diagnosis (Fig. 5). The patient’s recovery was uneventful and favorable.

Fig. 4.

(A) Follow-up transthoracic echocardiogram showing normalization of left ventricular ejection fraction (from 35% to 59%). (B) Apical four-chamber views in diastole and systole demonstrating complete resolution of apical ballooning, consistent with recovery from Takotsubo cardiomyopathy.

Fig. 5.

Cine cardiac MRI sequences performed one month later—including 4-chamber (A), 2-chamber gradient-echo (B), and short-axis ventricular function (C)—demonstrated complete recovery of left ventricular function without late gadolinium enhancement.

Based on follow-up findings, including a full recovery within one month and the absence of a myocardial late gadolinium enhancement on cardiac magnetic resonance imaging, a diagnosis of Apical Takotsubo cardiomyopathy coexisting with severe obstructive coronary artery disease in the left anterior descending artery as an innocent bystander was hypothesized.

Nevertheless, it remains challenging to determine whether an acute coronary syndrome associated with Takotsubo cardiomyopathy or an aborted anterior myocardial infarction can be excluded, as it presents a significant diagnostic dilemma.

Discussion

Takotsubo Cardiomyopathy is an acute cardiac disease, that is often induced by physical or emotional stress. It is characterized by sudden, transient regional wall motion abnormalities and left ventricular dysfunction which can affect the apical, midventricular, or basal segments [1]. This condition is associated with potentially life-threatening complications, including arrhythmias, left ventricular wall rupture, thrombosis and cardiogenic shock [5]. The incidence of TTS is increasing, accounting for approximately 2% to 3% of all patients presenting with ACS, with a higher prevalence in postmenopausal women [6]. The pathophysiology of TTC remains unclear and seems to be multifactorial. The main pathogenetic theories include stress-related catecholamine, coronary spasm and microvascular dysfunction. Additional factors such as genetic predisposition, estrogen deficiency, acute coronary atherothrombosis, inflammatory mechanisms, metabolic and energetic disturbances, impaired cognitive and emotional brain function, have also been proposed [7]. The clinical manifestations of TTC are characterized by clinical features that closely mimic ACS [8]. Therefore, distinguishing between the two conditions remains a major diagnostic challenge. Coronary angiography has been considered the gold standard in the diagnostic assessment of TTC as several diagnostic criteria, including the Mayo Clinic criteria (Fig. 5), define the broken heart syndrome as a cardiac condition occurring in the absence of significant CAD [5] (Fig. 6).

Fig. 6.

The Mayo Clinic criteria for the diagnosis of takotsubo cardiomyopathy [12].

However, recent studies have demonstrated that stress cardiomyopathy can coexist with CAD with a percentage that ranges broadly from 10% to 60%. This challenges the traditional assumption that the presence of CAD rules out the possibility of a TTS diagnosis. ³ To address this, the Heart Association of European Society of Cardiology recently introduced the International Takotsubo diagnostic criteria (InterTAK diagnostic criteria) (Table 1) improving the diagnostic approach for this disease by accounting for this coexistence [5]. A comparative overview of the InterTak and Mayo Clinic Criteria is provided in Table 2.

Table 1.

The Inter TAK criteria for the diagnosis of Takotsubo cardiomyopathy.

1	Patients show transienta left ventricular dysfunction (hypokinesia, akinesia, or dyskinesia) presenting as apical ballooning or midventricular, basal, or focal wall motion abnormalities. Right ventricular involvement can be present. Besides these regional wall motion patterns, transitions between all types can exist. The regional wall motion abnormality usually extends beyond a single epicardial vascular distribution; however, rare cases can exist where the regional wall motion abnormality is present in the subtended myocardial territory of a single coronary artery (focal TTS).b
2	An emotional, physical, or combined trigger can precede the Takotsubo syndrome event, but this is not obligatory.
3	Neurologic disorders (eg, subarachnoid haemorrhage, stroke/transient ischaemic attack, or seizures) as well as pheochromocytoma may serve as triggers for takotsubo syndrome.
4	New ECG abnormalities are present (ST-segment elevation, ST-segment depression, T-wave inversion, and QTc prolongation); however, rare cases exist without any ECG changes.
5	Levels of cardiac biomarkers (troponin and creatine kinase) are moderately elevated in most cases; significant elevation of brain natriuretic peptide is common.
6	Significant coronary artery disease is not a contradiction in takotsubo syndrome.
7	Patients have no evidence of infectious myocarditis.b
8	Postmenopausal women are predominantly affected.

^aWall motion abnormalities may remain for a prolonged period of time or documentation of recovery may not be possible. For example, death before evidence of recovery is captured.

^bCardiac magnetic resonance imaging is recommended to exclude infectious myocarditis and diagnosis confirmation of takotsubo syndrome.

Table 2.

Comparative analysis of Inter TAK and Mayo Clinic diagnostic criteria for Takotsubo syndrome.

	Inter TAK diagnostic criteria	Mayo Clinic criteria
Triggering factors	Emotional, physical, or combined triggers. It recognizes secondary TTS.	Less emphasis on antecedent or secondary triggers.
Clinical presentation	Acute chest pain or dyspnea. Transient LV dysfunction with regional wall motion abnormalities beyond single coronary distribution.	Acute chest pain or dyspnea. Transient LV dysfunction typically apical ballooning.
ECG findings	ST-segment elevation, T-wave inversion, QT prolongation (not required but supportive).	ST-segment elevation, T-wave inversion (not specific).
Coronary angiography/CAD exclusion	Absence of obstructive CAD is supportive but not mandatory (Its presence does not exclude TTS)	Absence of obstructive CAD is required.
Left ventricular dysfunction pattern	Regional wall motion abnormality extending beyond a single coronary territory(apical, midventricular, basal, or focal variants).	Apical ballooning is classic (other patterns recognized but less emphasized).
Biomarkers	Mild elevation of troponin relative to extent of LV dysfunction. BNP often elevated.	Troponin elevation mild. BNP not mandatory.
Exclusion of other conditions	Must exclude myocarditis, pheochromocytoma, and other causes.	Must exclude myocarditis and pheochromocytoma.

Nevertheless, the simultaneous occurrence of TTC and significant CAD creates a diagnostic dilemma. It remains unclear whether this is a coincidental association or a bidirectional causative interaction [3]. In most cases, CAD represents an incidental finding without a causal role in TTC, acting either as an innocent bystander or a potential contributing factor. In TTC patients, CAD often includes both modest coronary lesions and severe coronary stenosis [3]. All coronary arteries can be affected, including the LAD [9]. Common cardiovascular risk factors can partially explain this coexistence. In another scenario, TTC may occur in the context of ACS, or ACS may develop within the setting of TTS [10]. When ACS acts as a triggering factor for TTS, the mechanisms underlying ACS—such as increased myocardial oxygen demand, coronary artery spasm, heightened platelet activity, and plaque rupture— and severe pain associated with ACS may contribute to the development of TTS [11]. A significant proportion of ACS patients with a culprit lesion in the LAD artery may show a Tako Tsubo pattern. Indeed, stress cardiomyopathy associated with ACS has been shown to predominantly involve the LAD artery. Conversely, ACS may rarely result from TTS [3].

In this article, we highlight the diagnostic challenges encountered in a case report involving the coexistence of apical Takotsubo cardiomyopathy and significant coronary disease in the LAD artery. The diagnostic dilemma revolves around three potential scenarios: (1) Takotsubo cardiomyopathy coexisting with significant stenosis of the LAD artery as an innocent bystander; (2) An anterior ACS complicated by Takotsubo cardiomyopathy; (3) A transient ischemia mimicking apical ballooning. We considered TTC with LAD stenosis as a bystander the most likely scenario.

This diagnosis was supported by the following clinical and imaging findings: a recent history of emotional stress in a postmenopausal woman, an interTAK score of 61, moderately elevated troponin levels, echocardiographic evidence of apical ballooning with severe ventricular dysfunction, complete recovery of RWMAs and left ventricular function over time prior to angiographic intervention, absence of myocardial late gadolinium enhancement on cardiac MRI (a characteristic finding that typically distinguishes TTC from ACS), and the lack of visible thrombus on coronary angiography. Nonetheless, diagnosing TTS in the setting of CAD remains highly challenging.

Distinguishing between the two disorders requires a comprehensive approach, incorporating clinical, biological, and imaging findings. Main electrocardiographic, laboratory, and imaging parameters differentiating TTS from ACS are summarized in Table 3 [3]. Clinical manifestations of TTS occur typically in the context of physical or emotional stress and are mostly similar to those with ACS. Electrocardiographic parameters in TTS overlap with ACS, but certain clues exist. For instance, QTc tends to increase in TTC, but decrease in ACS. ST-segment elevation in anterior leads without reciprocal ST-segment depression and Q waves, can be useful for the differential diagnosis with ACS [13]. Based on clinical and electrocardiographic findings, the International Takotsubo Registry developed the InterTAK Diagnostic Score (Table 4) to help differentiate between TTS and non-ST-elevation ACS. A score ≥50 identifies nearly 95% of TTS cases 0 [14].

Table 3.

Main electrocardiographic, biochemical and imaging features distinguishing TTS from ACS.

	ACS	TTC
Laboratory	Marked elevation of troponin Reduced NT-pro BNP-to-c Tn I ratio	Moderate elevation of troponin Marked increase in NT-pro BNP levels Elevated NT-pro BNP-to-c Tn I ratio
Electrocardiogram	Regional ST segment and reciprocal abnormalities T wave inversion Arryhthmias	ST-segment elevation and T-wave inversion in precordial leads without reciprocal changes ST-segment depression in aVR Dynamic prolongation of the QTc interval
Echocardiography	Normal or persistent left ventricular function Regional wall motion abnormalities typically limited in extent	Transient but severe left ventricular dysfunction Apical ballooning pattern Wall motion abnormalities extending beyond a single coronary territory Wall Motion Score Index ≥ 1.75
CMR	Transmural or subendocardial late gadolinium enhancement (LGE) Regional wall motion abnormalities	Generally absent late gadolinium enhancement (LGE), or only modest focal/ patchy LGE Characteristic patterns of wall motion abnormalities Reduced left atrial function
Coronary angiography Ventriculography	Obstructive coronary artery disease	Normal, nonobstructive, or obstructive coronary artery disease Apical “nipple” sign Perfusion–contraction mismatch
SPECT/PET SPECT with MIBG	Significant reduction of perfusion	Normal or mildly reduced myocardial perfusion Persistent sympathetic denervation in dysfunctional segments

Table 4.

The inter TAK score for the diagnosis of Takotsubo cardiomyopathy.

Female sex	25 points
Emotional stress	24 points
Physical stress	13 points
No ST-segment depressiona	12 points
Psychiatric disorders	11 points
Neurologic disorders	9 points
QTc prolongation	6 points

≤ 70 points Low/ intermediate probability of TTS.

> 70 points High probability of TTS.

^aExcept in lead avR.

In TTS, the limited extent of tissue necrosis results in lower cardiac troponin and CK-MB peak levels compared to those observed in myocardial infarction. Moreover, the troponin/CK-MB ratio has proven to be an effective diagnostic parameter for differential diagnosis. N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels are also elevated in TTS, making their measurement a valuable tool for assessing cardiac damage and monitoring recovery. Emerging biomarkers, such as Fetuin-A, IGFBP-2, and TNF-α, demonstrate potential for differentiating TTS from ACS [3,14]. Transthoracic echocardiography (TTE) is the first-line imaging modality for patients with suspected TTS. The hallmark feature of TTS is the apical ballooning pattern of the left ventricle. Unlike ACS, RWMAs in TTS are not limited to a specific coronary artery territory. This characteristic is a key diagnostic indicator for TTS. Some studies suggest that the RWMAs in TTS can extend beyond the distribution of the LAD artery. In the acute phase of TTS, the left ventricular systolic dysfunction is pronounced. However, contrasting to AMI, this dysfunction is transient, and substantially reduced with complete recovery of left ventricular function. A recent study demonstrated that patients with TTS exhibit a higher wall motion score index (WMSI), which may assist in distinguishing TTS from ACS. Specifically, the study found that the presence of four or more regions exhibiting RWMA and a WMSI of 1.75 or higher are predictive of TTS. Assessment of global longitudinal strain, untwist rate, and time to peak untwisting, can provide additional diagnostic value [3,15]. Coronary angiography is commonly performed in the acute phase of presentation to differentiate between TTS and ACS. However, the presence of significant coronary artery stenosis, even in the LAD artery, does not rule out the diagnosis of TTS. Intravascular imaging technique offer superior diagnostic value by providing detailed insights into the coronary artery’s structural and morphological characteristics [3]. The combination of coronary angiography with left ventriculography can help identify a perfusion-contraction mismatch, favoring TTS [16]. One-third of TTS patients with apical ballooning show preserved contractility at the apex, known as the “apical nipple sign,” a useful marker for distinguishing TTS from anterior MI [17]. Cardiac magnetic resonance imaging (CMR) is increasingly recognized as an essential diagnostic tool particularly in the subacute phase. Diagnostic criteria for TTS at the acute phase includes a combination of typical RWMAs, myocardial oedema, and the absence of irreversible tissue injury, as evidenced by the lack of late gadolinium enhancement (LGE) [18]. The absence of LGE in dysfunctional LV regions is a key distinguishing feature that differentiates TTS from other conditions, such as ACS where subendocardial or transmural LGE typically corresponds to a vascular territory, and acute myocarditis, which often presents with epicardial or patchy LGE [18,19]. Nonetheless, the discrimination between ischemia without any irreversible myocardial damage and TTC still remains challenging. In fact, the absence of LGE, which may also be absent in a small subset of ACS patients, does not definitively diagnose TTS in all cases [20]. A study demonstrated that the few patients with true aborted myocardial infarction who exhibited no myocardial scarring consistently maintained a preserved left ventricular ejection fraction and displayed no evidence of wall motion abnormalities, in contrast to TTS [21]. Recent studies suggest that left atrial function is markedly reduced during the acute phase of TTS compared to anterior myocardial infarction, providing further insight into its pathophysiology [22]. Nuclear imaging modalities, though uncommonly used in practice, can be also. Perfusion scintigraphy, often shows normal or mildly reduced perfusion in dysfunctional segments in TTS [16,23]. SPECT (Single photon emission computed tomography) imaging with 123I-metaiodobenzylguanidine (123I-MIBG) provides insights into the sympathetic innervation of the heart. 123I-MIBG uptake is diminished for months despite nearly normal perfusion in dysfunctional segments. Combining SPECT perfusion imaging with 123I-MIBG SPECT during the subacute phase enables the exclusion of ACS, which is typically marked by both reduced innervation and perfusion [24].

TTS is a complex acute cardiac condition that mimics ACS and involves various interconnected pathophysiological mechanisms. Given that the two conditions can coexist, distinguishing between them can be challenging, particularly when apical TTS occurs alongside LAD stenosis.

Conclusion

The simultaneous occurrence of TTS and CAD represents a critical diagnostic challenge. Accurate differential diagnosis requires a multimodal approach combining clinical assessment, imaging, and functional evaluation. Emerging techniques such as intravascular imaging, advanced molecular methods, and invasive assessment of coronary microcirculation may further enhance diagnostic precision and reduce the risk of misdiagnosis.

Patient consent

Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Appendix. Supplementary materials

Video 1: Echocardiogram at admission with a 4 apical view showing severe left ventricular dysfunction with apical ballooning suggestive of Takotsubo cardiomyopathy