Sigmoid Septum: A Bystander or Contributor to a Left Ventricular Outflow Tract Obstruction in Takotsubo Syndrome - A Case Report with a Literature Review

Abstract

Approximately 20% of patients with Takotsubo syndrome (TTS) develop complications such as left ventricular outflow tract obstruction (LVOTO). The published data suggest that a significant proportion of these patients have predisposing septal hypertrophy or sigmoid septum. However, the pathophysiology regarding this connection has not yet been fully elucidated. We herein present the case of a 75-year-old female patient with TTS complicated by LVOTO, which was successfully managed. During the follow-up, mild basal septal hypertrophy was observed. Subsequent exercise and dobutamine stress echocardiography were performed to reveal the mechanism of LVOTO in TTS.

Introduction

Takotsubo syndrome (TTS), formerly known as “Takotsubo cardiomyopathy”, “stress cardiomyopathy” or “broken heart syndrome”, is an abrupt and reversible cardiac disorder often triggered by stressful events (1). Although initially thought to be benign, TTS has been shown to result in serious clinical complications including death (2). In 20% of patients, TTS can be complicated by a left ventricular outflow tract (LVOT) obstruction (LVOTO) and subsequent mitral regurgitation (MR) (3). It has been hypothesized that this complication arises from two distinct mechanisms. One mechanism involves catecholamine toxicity causing basal hyperkinesis and consequent LVOTO, which secondarily induces the Venturi effect, thus resulting in systolic anterior motion (SAM) and MR (4,5). On the other hand, this sequence could also be preceded by re-oriented intraventricular drag forces caused by alterations in left ventricular geometry during the acute phase of TTS, thus resulting in a “pushing” impact on the mitral leaflets towards the septum and initiating SAM before LVOTO (4). This complication may stem from predisposing factors such as features of hypertrophic cardiomyopathy (HCM), prolonged mitral valve leaflets, anterior mitral valve leaflet displacement, and/or anomalous papillary muscle, which, combined with the flow force on the mitral valve, initially induces SAM, consequently leading to LVOTO (4,5). In either case, this clinical scenario presents a significant challenge for the diagnosis and management of TTS. Additionally, the convergence of these two mechanisms could cause ambiguity and potentially lead to an incorrect diagnosis and treatment. Moreover, the long-term management and prognosis of this subset of patients have yet to be thoroughly studied (5). Stress echocardiography may be performed to assess the underlying mechanisms, patient prognosis, and treatment efficacy (5,6). We herein present a demanding case of LVOTO in a patient with TTS and mild septal hypertrophy, who was successfully diagnosed and treated and then was further examined using stress echocardiography.

Case Report

A 75-year-old female patient was brought to the hospital by Emergency Medical Services due to acute-onset chest pain and electrocardiographic (ECG) signs indicative of an inferoposterolateral ST-elevation myocardial infarction (STEMI) (Fig. 1A, B). The patient complained of dull, constant chest pain that began 90 min prior to admission, without radiation, and was not associated with any physical precipitating factors. However, the patient reported experiencing an emotionally stressful period in the weeks leading up to pain onset. Upon admission, she was conscious, oriented, afebrile, and eupneic, with a blood pressure of 140/90 mmHg and a heart rate of 70 beats per minute, without any signs of heart failure, Killip class I. Cardiac auscultation revealed a systolic murmur at Erb's point.

Figure 1.

Electrocardiogram upon admission. (A) ST segment elevation in leads I, V5-V6, II, III, and aVF, accompanied by reciprocal ST segment depression in leads V1-V3. (B) ST segment elevation>0.5 mm in the posterior leads - V7, V8, and V9 - mirroring the ST segment depression in leads V1-V3.

The patient had a documented history of regular cardiology follow-up. Six years previously, the patient was admitted for third-degree atrioventricular block, thus necessitating the placement of a permanent dual-chamber rate-modulated pacemaker (DDDR). Her medical history included hypothyroidism, left inguinal hernia surgery, and ankle surgery. Notably, she presented several risk factors for cardiovascular diseases, including hypertension, tobacco smoking, and a positive family history.

The differential diagnosis of acute-onset chest pain with concurrent ischemic changes on ECG encompasses a spectrum of conditions, with acute coronary syndrome (ACS) being among the most critical considerations. Therefore, based on the clinical and ECG findings, STEMI was highly suspected. However, other conditions that may mimic STEMI, including TTS, acute myocarditis, prolonged coronary vasospasm, and spontaneous coronary artery dissection, could not be ruled out (7).

A comprehensive diagnostic workup was initiated to differentiate between the aforementioned acute conditions. As a matter of priority, urgent coronary angiography was performed and showed non-obstructive coronary artery disease (Fig. 2A-C). At the same time, left ventriculography was performed, thus revealing apical and anterolateral akinesis with hypercontractile basis (Fig. 3A, B; Supplementary material 1) - typical wall motion abnormalities of TTS. Moderate-to-severe MR was also observed.

Figure 2.

Coronary angiogram upon admission. (A) Left coronary artery in anterior-posterior cranial projection. (B) Left coronary artery in anterior-posterior caudal projection. (C) Right coronary artery.

Figure 3.

Left ventriculography upon admission. (A) Diastole. (B) Systole.

The cardiac biomarker panel revealed a significantly elevated level of high-sensitivity troponin I, measuring 1,502.2 ng/L.

Subsequently, the first transthoracic echocardiography (TTE) was conducted, demonstrating akinesis of the apex and all apical segments (apical ballooning) (Supplementary material 2) with a reduced left ventricular (LV) ejection fraction (LVEF) of approximately 40% and signs of diastolic dysfunction (E/e'=10.6). Furthermore, moderate-to-severe MR was observed (Fig. 4 and Supplementary material 3), which was initially suspected to be due to prolapse of the posterior leaflet (PPL) and rupture of the chordae tendineae. Because of the high suspicion of rupture of the chordae tendineae and consequent PPL, the patient was already considered a candidate for urgent cardiac surgery. However, under control TTE by seasoned experts, a dynamic LVOTO was observed, with the pulse wave Doppler through LVOT revealing maximal velocity of 4.26 m/s and an LVOT pressure gradient of 72.55 mmHg, presenting a “dagger-shaped” Doppler signal, indicative of significant LVOTO (Fig. 5A). Moreover, a SAM of the anterior mitral leaflet was captured (Fig. 5B; Supplementary material 2), with PPL and chordae tendineae rupture seemingly unlikely.

Figure 4.

Transthoracic echocardiogram with color Doppler upon admission showing moderate-to-severe mitral regurgitation (the green signal extending across the lateral wall of the left atrium to the roof of the left atrium, marked with red arrows).

Figure 5.

(A) The pulse wave Doppler through LVOT upon admission revealing a LVOT maximal velocity of 4.26 m/s and an LVOT pressure gradient of 72.55 mmHg, presenting a “dagger-shaped” Doppler signal, indicative of significant LVOT obstruction. (B) Transthoracic echocardiography upon admission showing systolic anterior motion of the anterior mitral valve leaflet (arrow). LVOT: left ventricular outflow tract

By further excluding myocarditis, our patient met all the criteria outlined in the 2018 International Expert Consensus Document for the diagnosis of TTS (2). Therefore, TTS with LVOTO and consequent SAM-induced MR was diagnosed.

Due to the highly suspected inferolateral STEMI, a prehospital loading dose of dual antiplatelet therapy was initiated. Upon cardiac catheterization, unfractionated heparin (70 IU/kg) was administered. Immediately after the diagnosis of TTS was established, because the patient was hemodynamically stable, low-dose beta-blocker therapy was initiated with oral bisoprolol at an initial dose of 2.5 mg once a day, which was then increased to 7.5 mg once a day. After initiating beta-blockers and achieving adequate clinical stabilization with gradually resolving LVOTO, and as the patient was hypertensive with a low LVEF, the angiotensin-converting enzyme inhibitor (ACEI) ramipril was cautiously started at 1.25 mg once daily and slowly titrated up to 2.5 mg once daily. Considering the pathophysiological mechanism of TTS with reduced LVEF, LVOTO, and MR secondary to SAM, adequate intravenous fluid therapy combined with diuretic therapy was administered and adjusted based on the clinical, laboratory, and echocardiographic findings. This management approach resulted in the recovery of myocardial wall motion and LVEF (Supplementary material 4), a decrease in LVOT pressure gradient and maximal outflow velocity (Fig. 6), and MR (Supplementary material 5), observed by TTE one week after the treatment. During hospitalization, low-molecular-weight heparin was administered daily as thromboprophylaxis and was discontinued after echocardiographic recovery. At the time of discharge, maintenance therapy, including acetylsalicylic acid, beta-blockers, ACEI, and statins, was prescribed.

Figure 6.

Post-management pulse wave Doppler through LVOT revealing an LVOT maximal velocity of 1.20 m/s and an LVOT maximal pressure gradient of 5.77 mmHg one week after the treatment. LVOT: left ventricular outflow tract

One month later, the patient did not have any symptoms, and follow-up TTE was performed, which showed complete recovery of LVEF and diastolic function (E/e'=7.0), resolution of LVOTO (Supplementary material 6), and preserved mitral valve function. It also revealed a sigmoid interventricular septum and mild basal septal hypertrophy, with an LV basal septal wall thickness of 16 mm and an LV posterior wall thickness at end-diastole of 11 mm. Therefore, based on echocardiographic data, patient age, long-standing hypertension, and no family history of HCM, a diagnosis of non-HCM basal septal hypertrophy was established.

Furthermore, exercise stress echocardiography (ESE) was conducted to evaluate whether a significant gradient in the LVOT could be induced by physical activity, as this may consequently affect the patient's prognosis and create vagueness between TTS with LVOTO on one side and septal hypertrophy with dynamic, latent LVOTO, which secondarily causes LV apical ballooning on the other side. The cardiopulmonary exercise test (bicycle spiroergometry) with echocardiography was performed using the ramp 10 protocol (Table 1). There was a non-significant increase in the LVOT pressure gradient up to 15.08 mmHg at maximum effort and a non-significant escalation in MR, advancing to mild MR at maximum effort. These changes were observed at a peak heart rate of 95 bpm (78% of the target submaximal heart rate), at a maximum load of 55 watts (54% of predicted maximum load), and at a peak oxygen consumption (VO₂) of 16.62 mL/min/kg (97% of predicted peak VO₂). The respiratory exchange ratio (RER) reached 0.89. No LVOTO was observed under these conditions.

Table 1.

Stress Echocardiography Data at Rest and Maximum Stress across Follow-up Intervals.

SE type and time-points*		ESE Max stress workload (Watts)	VO2 (mL/min/kg)	RER	Heart rate (bpm)	BP (mmHg)	LVOT velocity (m/s)	LVOT pressu regradient (mmHg)	SAM	MR grade
1-month follow-up ESE with BB	Rest	/	/	/	70	120/70	1.58	10.00	-	I
	Maximum stress	55	16.62 (97% of predicted peak VO2)	0.89	95 (78% of the target submaximal heart rate)	150/80	1.94	15.08	-	II
6-month follow-up ESE without BB	Rest	/	/	/	70	110/75	1.58	10.00	-	I
	Maximum stress	84	15.94 (93% of the predicted peak VO2)	0.91	115 (94% of the target submaximal heart rate)	150/80	1.74	12.13	-	II
6-month follow-up DSE without BB	Rest	/	/	/	60	120/65	1.47	8.65	-	I
	Maximum stress*	/	/	/	82	110/60	4.58	83.9	+	I

+: present; -: absent; *at a peak dose of 20 µg/kg/min of dobutamine.

SE: stress echocardiography, BP: blood pressure, BB: beta-blocker, DSE: dobutamine stress echocardiography, ESE: exercise stress echocardiography, LVOT: left ventricular outflow tract, RER: respiratory exchange ratio, MR: mitral regurgitation, SAM: systolic anterior motion, VO₂: peak oxygen consumption

As the patient did not achieve the predicted maximum workload and submaximal heart rate, and since the ESE was performed without the discontinuation of beta-blockers, we conducted a control ESE after beta-blocker discontinuation at the six-month follow-up (Table 1), excluding all factors that could hinder the potential to reach submaximal heart rate and predicted maximum load, in order to confirm LVOT non-inducibility. The control ESE revealed a non-significant increase in the LVOT pressure gradient, from 10.00 mmHg at rest to 12.13 mmHg at maximum effort, and a non-significant escalation in MR, progressing from grade I to grade II at maximum effort. Both changes were detected at a peak heart rate of 115 bpm (94% of the target submaximal heart rate), with a maximum load of 84 watts (83% of the predicted maximum load) and a peak VO₂ of 15.94 mL/min/kg (93% of the predicted peak VO₂). The RER was 0.91. Neither LVOTO nor SAM were detected under these circumstances.

Furthermore, we performed dobutamine stress echocardiography (DSE) (Table 1). We followed a DSE protocol that started with an infusion of 5 μg/kg/min of dobutamine, increasing by 5 μg/kg/min every 3 min, up to a maximum of 20 μg/kg/min. This led to a significant increase in the LVOT pressure gradient, from 8.65 mmHg at rest (Fig. 7A) to 83.9 mmHg at peak dose (Fig. 7B), accompanied by SAM and hypotension (110/60 mmHg), but without increase in MR. Global longitudinal strain (GLS) has increased from -18.8% to -21.1%. Under basal conditions, reduced values of regional strain were recorded in the apical segments and the basal septal region (Fig. 8A). At a dobutamine dose of 20 μg/kg/min, regional strain improved in the apical segments, but the strain worsened in the basal segments corresponding to the sigmoid septum, which is typical in the presence of a sigmoid septum (Fig. 8B). DSE did not provoke any new disturbances in segmental kinetics, but it did provoke dynamic LVOT obstruction and revealed the presence of latent LVOT obstruction.

Figure 7.

(A) Pulse wave Doppler through the LVOT at 6-month follow-up, showing an LVOT maximal velocity of 1.47 m/s and an LVOT maximal pressure gradient of 8.65 mmHg, observed at rest. (B) Dobutamine stress echocardiography with pulse wave Doppler through the LVOT at 6-month follow-up, showing an LVOT maximal velocity of 4.58 m/s and an LVOT maximal pressure gradient of 83.94 mmHg, observed at a peak dose of 20 μg/kg/min of dobutamine. LVOT: left ventricular outflow tract

Figure 8.

Global longitudinal strain (GLS) at 6-month follow-up at rest (A) and at a peak dobutamine dose (B). (A) Reduced values of regional strain in the apical segments and basal septal region. (B) Improvement of regional strain in the apical segments, and an impairment in the basal segments.

Discussion

TTS is an acute and transient heart condition often associated with stress and it is more commonly observed in postmenopausal women (1). It is characterized by new ECG changes and pronounced LV apical akinesis, mirroring the clinical presentation of ACS, particularly anterolateral STEMI (8). However, a diffuse ST-elevation ECG pattern is frequently observed in TTS (9). In conjunction with ECG manifestations suggestive of TTS and echocardiographic identification of regional wall motion abnormalities extending beyond a single epicardial vascular distribution, coronary angiography with LV is imperative to confirm the diagnosis of TTS. This procedure revealed LV apical ballooning and basal hyperkinesis in the absence of obstructive coronary artery disease. In addition to this typical apical ballooning, TTS can manifest as midventricular ballooning and rarely as basal ballooning (10).

LVOTO as a complication of TTS

Distinguishing ACS presents only one challenging differential diagnostic scenario. LVOTO is observed in approximately 20% of patients, the occurrence of LVOTO is observed. Although there is a substantial amount of data regarding TTS accompanied by LVOTO, and subsequent SAM and MR, the core pathophysiological mechanisms remain unclear.

The most widely accepted hypothesis is that apical hypokinesis/akinesis, with subsequent basal hyperkinesis caused by catecholamine toxicity, leads to hypercontractile and narrowed LVOT (5). This causes LVOTO with a high flow velocity and a consequent Venturi suction effect on the anterior mitral leaflet, thus leading to SAM and secondary MR (4,5). These mechanisms leading to LVOTO and SAM are also commonly, although not invariably, influenced by a predisposing interventricular septal bulge (sigmoid septum) or a reduced LV cavity (4,11-13).

Although broadly recognized, the earlier suggested mechanism lacks substantiating evidence (5). Another newly proposed mechanism for combined LVOTO and SAM is that SAM may occur first because of the flow force on the mitral valve resulting from LV shape alterations during the acute phase of apical TTS, usually accompanied by specific morphological features of HCM, such as septal hypertrophy, sigmoid septum, elongated mitral leaflets, displaced anterior mitral leaflet, and/or abnormal papillary muscles (4,5). This sequence may lead to mitral-septal contact and secondary LVOTO (5).

In our patient, with only mild non-HCM basal septal hypertrophy and no other mitral valve or papillary muscle abnormalities, SAM was more likely to have been induced by Venturi forces generated within the obstructed LVOT due to basal hyperkinesis than by the “pushing” impact of re-oriented interventricular drag forces on the mitral leaflets, although both could contribute. Since DSE induced LVOTO and subsequently SAM, but without an increase in MR, it is less likely that SAM occurred first, inducing LVOTO in our patient. In any event, the sigmoid septum was probably a contributing predisposing factor rather than a bystander. In addition to understanding the mechanisms of LVOTO, SAM, and MR, it is important to exclude other causes of MR, such as mitral valve prolapse, ruptured chordae tendineae, papillary muscle rupture, mitral annular calcification, and infective endocarditis.

Acute LV ballooning in TTS

Notably, there are divergent etiologies that contribute to LV ballooning in TTS. The most popular theory suggests that LV ballooning is directly caused by a catecholamine surge and direct toxicity to cardiomyocytes and/or coronary epicardial and/or microvascular vasospasm or underlying coronary microvascular dysfunction, termed neurohumoral TTS (5). Conversely, an additional posited mechanism suggests that LV ballooning in individuals with TTS may arise from pre-existing LVOTO secondary to mild HCM (5,13,14). Sherrid et al. demonstrated that among a cohort of 44 patients diagnosed with TTS and LVOTO, specific morphological characteristics reminiscent of HCM were identified in the majority of patients prior to the development of TTS (15). Moreover, Singh et al. suggested the presence of important overlying mechanisms in neurohumoral TTS and obstructive HCM with LV apical ballooning (16). These studies imply that TTS with accompanying LVOTO might not be a unique clinical entity, but rather a variant of HCM induced by a stressful event and characterized by dynamic LVOTO and acute LV apical ballooning (4,13,15). Nevertheless, this theory is still founded only on speculation and contrasts with the more widely accepted initial neurohumoral hypothesis (4) and the novel hypothesis (13). Madias recently introduced a new hypothesis regarding the pathophysiology of TTS in patients with acute LV ballooning, LVOTO, and HCM (13). The authors suggested that the condition might be rooted in an autonomic sympathetic nervous system/catecholamine-induced temporary LVOTO, which could lead to an elevated afterload, resulting in a supply demand mismatch and subsequently causing a brief episode of myocardial ischemic injury (13). A similar theory was proposed by Merli et al. (17). Regardless of the proposed mechanisms of apical ballooning, current data support a significant relationship between coronary microvascular dysfunction (CMD) and TTS, with CMD potentially contributing to the development and severity of TTS (18). A study by Ekenbäck et al. (19) reported that 78% of TTS patients exhibited CMD as measured by the index of microcirculatory resistance (IMR). While some authors propose CMD as a possible cause of TTS, others regard it merely as an epiphenomenon (13). Since no confirmed hypothesis exists, it is recommended to further investigate the aforementioned novel pathophysiological hypothesis while sustaining our focus on all other established theories regarding the pathophysiology of TTS.

In our patient, the finding of mild basal septal hypertrophy could support the second, “HCM-based” potential mechanisms of SAM, latent LVOTO, and LV ballooning (5), while also posing a challenge in differentiating between TTS with LVOTO and septal hypertrophy with dynamic LVOTO in the acute setting (15). Therefore, this additional clue in the differential diagnosis remains to be thoroughly evaluated and understood, with the stress echocardiographic assessment of LVOTO inducibility currently being one of the most reliable diagnostic and prognostic approaches.

A comprehensive understanding of the pathophysiology underlying LVOTO, SAM, and MR, coupled with meticulous echocardiographic assessment by seasoned experts, is imperative to prevent a misdiagnosis and the performance of unnecessary invasive intervention, and to pursue the right management strategy.

Management of TTS with LVOTO

In the acute management of hemodynamically stable patients with TTS without LVOTO, the standard treatment is to relieve congestion with diuretics or vasodilators and treat systolic heart failure with ACEIs or angiotensin receptor blockers (20).

Alternatively, in hemodynamically stable patients with LVOTO, considering the proposed catecholamine toxicity mechanism, the administration of a low-dose beta-blocker therapy is pivotal (5,20,21). This approach aims to prolong diastolic time, thereby increasing preload and reducing basal contractility, which mitigates LVOTO and serves as a fundamental aspect of LVOTO management in TTS (5,20,21).

Although ACEIs are not recommended for TTS with cardiogenic shock and LVOTO (20), our patient was clinically stable and hypertensive. Consequently, after initiating beta-blocker therapy and decreasing the LVOT gradient, we included ACEIs as part of the systolic heart failure treatment (20).

In the management of patients with HCM and dynamic LVOTO, first-line pharmacotherapy includes beta-blockers (22,23), whereas septal reduction therapy is indicated when severe symptoms and persistent outflow tract obstruction are present and refractory to medical therapy (24).

Regarding the long-term management of TTS, ACEIs or angiotensin receptor blockers along with low-dose beta-blockers and loop diuretics (as needed) should be continued for at least three months or until the recovery of the LV function can be obtained (21). However, the long-term management of TTS with LVOTO and predisposing structural abnormalities suggestive of HCM have yet to be elucidated (5).

Stress echocardiography in the follow-up of TTS with LVOTO

Following proper management, further assessment of myocardial wall motion and LVOT gradient during the recovery phase is imperative to understand the mechanism of LVOTO and LV apical ballooning, adjust current therapy, and anticipate the patient's prognosis.

Exercise stress echocardiography has recently been used to evaluate LV contractility, LVOT gradient, and the efficacy of beta-blocker management in patients with TTS (5,6). It has been favored over dobutamine stress echocardiography, which is a known trigger for TTS (25,26) and it poses a significant risk of TTS recurrence (26). However, it is noteworthy that there are case reports of ESE-induced TTS (27-29). In the literature, several studies evaluated the role of ESE in the prognosis of LVOTO in patients with TTS and/or HCM (5,6,30-32). However, the long-term outcomes of patients with LV ballooning and LVOTO using stress echocardiography have not been fully researched.

Notably, Yakupoglu et al. reported ESE in symptomatic patients with previous TTS-induced reversible dysfunction of LV contractility (6). Furthermore, Citro et al. reported a significant increase in the LVOT gradient caused by SAM and mitral-septal contact after ESE in a symptomatic patient with HCM one month before the onset of acute LV ballooning (5). The suggested mechanism behind these occurrences involves increased activity of the autonomic nervous system during exercise, along with elevated norepinephrine levels, potentially resulting in endothelial impairment, microcirculation dysfunction, heightened cardiac stress, coronary artery spasm, and direct toxicity to the myocardium (26).

Given the presence of mild septal hypertrophy and sigmoid septum in our patient, it became imperative to evaluate the LV contractile function, LVOT, and mitral valve function, thereby potentially elucidating the mechanism behind the prior LVOTO and LV apical ballooning. Since beta-blockers were not discontinued and our patient did not achieve the submaximal heart rate or predicted maximum load during ESE, we decided to conduct a follow-up ESE with beta-blocker discontinuation, in which both workload and heart rate were higher. However, the ESE examination did not reveal inducible LVOTO. Therefore, we decided to conduct dobutamine stress echocardiography, which showed significant LVOTO with SAM and hypotension, but without an increase in MR and LV apical ballooning. Hence, the absence of an inducible increase in the LVOT gradient during ESE in our patient's case may indicate that higher and continuous catecholamine stress is needed to induce LV apical ballooning and LVOTO. This may substitute the first theory of neurohumoral TTS and subsequent LVOTO with SAM. In contrast, DSE at a peak dose of 20 μg/kg/min induced an increase in the LVOT pressure gradient. This finding supports the theory of latent LVOTO due to septal hypertrophy, which has been shown to manifest in acute TTS in some cases (32). Although LV apical ballooning was not observed, we can hypothesize that if the dobutamine dose was higher and prolonged, there might be LVOTO-induced LV apical ballooning as well, thus DSE-induced TTS. Furthermore, more intense/prolonged dobutamine stimulation might also result in severe MR due to higher Venturi forces and longer and more pronounced contact of the anterior mitral leaflet with the sigmoid septum, thus significantly disrupting mitral coaptation. Considering the above, we propose two main hypotheses for TTS with LVOTO in this patient with a sigmoid septum. First, latent LVOTO, predisposed by the sigmoid septum, manifests in the acute setting of isolated neurohumoral TTS due to the hypercontractile basal segments of the LV caused by psychological stress and consequent catecholamine surge. The second, and recently more recognized hypothesis, could be that the catecholamine effect, along with the contribution of the sigmoid septum, first caused LVOTO, which in turn led to an afterload-based supply/demand mismatch and subsequent acute LV apical ballooning/TTS. If the latter was the case, then TTS may have never occurred if there was no contribution from the sigmoid septum. However, in both scenarios, acute and intense catecholamine stimulation was required and regarded as the primary culprit, while the sigmoid septum was a contributor, that is, a structural predisposition, to develop LVOTO and possibly TTS. Therefore, in this case, the sigmoid septum was probably not a bystander. An additional theory that could supplement the contributory effect of septal hypertrophy is the potential role of myocardial wall edema, which may be present during the acute phase of TTS (33). Myocardial wall edema involves the mid-anterior wall and apical segments, corresponding to areas of hypokinesis, but it can also lead to the transient thickening of the septum, which, in conjunction with basal hypercontractility, may result in LVOTO (34). However, in our patient, LVOTO was more likely predisposed by true, non-transient septal hypertrophy and further triggered/caused by catecholamine overspill-induced basal hypercontractility, rather than by the so-called “pseudohypertrophy” resulting from myocardial edema during the acute phase of TTS, which has predominantly been shown to occur in the apical region (13,33).

As there was neither LVOTO nor apical ballooning with ESE, whether under beta-blockers or not, this could indicate an effective management strategy with no risk of LVOTO under physiological physical stress conditions. However, it is important to note that the target submaximal heart rate was not achieved during the ESE test.

The main possible reasons why our patient did not reach a submaximal heart rate and maximum load at the first ESE were the patient's age, previous ankle surgery, hypothyroidism, or chronotropic incompetence (possibly due to failure of beta-blocker discontinuation before the test). Chronotropic incompetence due to permanent DDDR was unlikely, as the patient underwent regular device function check-ups. Therefore, at the follow-up ESE, the beta-blocker was discontinued, and although the heart rate and workload were higher, the submaximal heart rate remained unachieved. Consequently, due to the patient's age, previous ankle surgery, an unachieved submaximal heart rate, and non-inducible LVOTO at follow-up ESE, dobutamine stress echocardiography was performed. Although there was a risk of TTS recurrence, it was considered to be low, as ESE did not induce LVOTO, SAM, or apical ballooning, and only a low dose of dobutamine was administered.

Literature review

A review of the literature included 27 studies that presented 34 case reports of patients with TTS in combination with LVOTO and HCM/non-HCM septal hypertrophy or sigmoid septum. The review was conducted by searching the PubMed and Web of Science databases on June 12, 2024, using the keywords presented in Table 2. A re-evaluation and re-search was then performed to search for new studies on July 31, 2024. The PRISMA flow diagram of the search method is shown in Fig. 9 (35). The exclusion criteria were all types of publications that did not fall into case reports and case series with or without literature review, while the inclusion criteria were a diagnosis of TTS, LVOTO, and septal hypertrophy (HCM or non-HCM)/sigmoid septum. All cases included in the literature review are shown in Table 3, which presents the patients' clinical characteristics, left ventriculography findings, echocardiographic findings, follow-up data, and outcomes.

Table 2.

Keywords Used in Database Searches.

PubMed	(takotsubo OR tako-tsubo OR stress cardiomyopathy OR broken heart syndrome) AND (left ventricular outflow tract obstruction) AND (hypertrophy OR hypertrophic cardiomyopathy OR basal septal hypertrophy OR septal bulge OR sigmoid septum)
Web of Science	[ALL=(takotsubo) OR ALL=(tako-tsubo) OR ALL=(stress cardiomyopathy) OR ALL=(broken heart syndrome)] AND ALL=(left ventricular outflow tract obstruction) AND [ALL=(hypertrophy) OR ALL=(hypertrophic cardiomyopathy) OR ALL=(basal septal hypertrophy) OR ALL=(sigmoid septum)]

Figure 9.

A PRISMA flow diagram illustrating the literature review search method.

Table 3.

Literature Review of 34 Patients with TTS Combined with LVOTO and HCM/sigmoid Septum.

Reference	Age	Gender	Trigger of TTS	Known HCM	Killip class	Left ventriculography	ECHO findings on admission					ECHO findings on FU					IVS characteristics on ECHO (LVSWT)	Stress ECHO	SRT	Outcome
							LVEF	LVOT gradient	SAM	MR		Time to FU	Wall-motion abnormalities	LVOT gradient	SAM	MR
(36)	66	F	N/A	+	N/A	N/A	N/A	109 mmHg	+	Severe		1 month	Resolved	Decreased, but still significant	N/A	N/A	N/A	N/A	+	Absence of SAM, decreased MR, and disappearance of basal obstruction after SRT
(47)	62	F	Emotional stress	-	IV	Apical ballooning; LVOT gradient of 50 mmHg		N/A	+	Severe		~2 weeks	Resolved	None	N/A	N/A	Modest septal bulge (12 mm)	DSE on 13th day showed dynamic LVOT gradient of 250 mmHg with a late peaking, accompanied by severe MR due to SAM; apical akinesis	-	HCM diagnosed via endomyocardial biopsy; discharged on BB therapy; uneventful course
(37)	67	F	Emotional stress	+	I	Apical ballooning	35%	35 mmHg	+	N/A		2 weeks	N/A	No change	+	N/A	Asymmetric septal hypertrophy (14 mm)	N/A	-	Discharged on 3rd day on BB therapy
(48)	48	M	None	-	I	Apical ballooning	43%	96 mmHg; 105 mmHg after Valsalva maneuver	+	N/A		1 year	N/A	27 mmHg; 95 mmHg after Valsalva maneuver	N/A	N/A	Asymmetric septal hypertrophy (up to 20 mm)	N/A	+	Discharged on 3rd day on BB therapy; 1 year later presented with progressive exertional dyspnea, chest pain, and presyncope, and underwent SRT
(30)	60	M	Unspecified stress	+	IV	Apical ballooning; LVEF of 10-20%; no LVOT gradient	N/A	N/A	N/A	N/A		After stabilization (intrahospital)	N/A	20-55 mmHg	N/A	N/A	N/A (N/A)	ESE prior to admission: LVOT gradients of 50 mmHg at rest and 118 mmHg at peak exercise	+	Discharged after 3 weeks; ESE 2 years after SRT: non-significant LVOT gradient of 10 mmHg at rest, and 23 mmHg at peak exercise
(49)	70	F	None	-	I	Apical ballooning; LVEF of 35%; no LVOT gradient	Normal†	20 mmHg†; 70 mmHg after Valsalva maneuver†	+†	N/A		3 months	N/A	50 mmHg	N/A	N/A	Septal hypertrophy (24 mm)	N/A	-	Discharged on BB therapy; uneventful course 3 months later
(38)	51	M	None	+	I	Apical ballooning; LVOT gradient >100 mmHg; severe MR	43%	40 mmHg (reduced in contrast to baseline LVOT gradient of 85 mmHg)	N/A	N/A		~2 weeks	N/A	7 mmHg	-	Improved	HOCM with IVS hypertrophy (19 mm)	Prior ESE showed LVOT gradient of 105 mmHg after exercise	-	Discharged on 23rd day on BB therapy; uneventrful course
(31)	67	M	Physical stress	+	I	LVOT gradient of 55 mmHg	Normal	105 mmHg after Valsalva maneuver	N/A	N/A		1 month	Resolved	N/A	N/A	N/A	HCM (N/A)	ESE 1 month later showed an exercise-induced LVOT gradient of 80 mmHg	-	Discharged on BB therapy; uneventful course
(50)	82	F	Physical stress	-	I	Apical ballooning; LVOT gradient of 70 mmHg	N/A	40 mmHgδ	+	N/A		3 days	Apical hypokinesis	None	N/A	N/A	Sigmoid septum with basal septal hypertrophy (N/A)	N/A	-	Discharged on BB therapy; uneventful course
(39)	63	M	None	+; LWSVT of 19 mm	I progressing to IV	LVOT gradient of 38 mmHg	28%	114 mmHg during IABP counterpulsation	+	N/A		2 weeks	Apical akinesis	30 mmHg	N/A	N/A	Asymmetric septal hypertrophy (19 mm)	N/A	+	Discharged after 2 weeks; readmitted 3 months later for chest pain and underwent successful SRT
(51)	68	F	N/A	δ	I	Apical ballooning; LVOT gradient of 46 mmHg	30%	25-35 mmHg	+	N/A		3 days after VA-ECMO	N/A	Significant LVOTO	+	N/A	Asymmetrical septal hypertrophy (19 mm)δ	N/A	+	Discharged; no dynamic LVOTO 3 months after SRT
(52)	65	F	N/A	-	IV	N/A	N/A	>60 mmHg	+	Moderate		2 days	Unchanged anterior thinning and akinesis	Improvement of subaortic obstruction	N/A	-	Sigmoid septum (N/A)	N/A	-	Discharged; uneventful course 3 months later
												3 months	Resolved	N/A	-	-
(17)	74	F	Physical stress	-	I	N/A	N/A	80 mmHg	N/A	N/A		2 weeks	Mild apical hypokinesis	10 mmHg	N/A	N/A	Localized mid-ventricular septal thickening (12 mm)	Low-dose DSE 20 days later provoked LVOT gradient of 80 mmHg and DSE stunning response	-	At 1 year FU, strain/strain rate imaging data showed normal LV systolic deformation with no evidence of abnormal residual post-systolic deformation in the apical segments
(17)	72	F	Physical stress	N/A	I	Apical ballooning	N/A	63 mmHg	N/A	N/A		2 weeks	Resolved	12 mmHg	N/A	N/A	Localized mid-ventricular septal thickening (14 mm)	Low-dose DSE 20 days later provoked LVOT gradient of 62 mmHg (which resolved during the recovery) and DSE stunning response	-	At 6 months FU, strain/strain rate imaging data showed normal LV systolic deformation with no evidence of significant post-systolic shortening
(17)	71	F	Unspecified stress	N/A	I	Apical ballooning	N/A	64 mmHg	N/A	N/A		2 weeks	Resolved	8 mmHg	N/A	N/A	Localized mid-ventricular septal thickening (13 mm)	Low-dose DSE 20 days later provoked LVOT gradient of 60 mmHg (which resolved during the recovery) and DSE stunning response	-	At 6 months FU, strain/strain rate imaging data showed normal LV systolic deformation in all LV segments
(17)	75	F	Unspecified stress	N/A	I	N/A	N/A	70 mmHg	N/A	N/A		2 weeks	Resolved	10 mmHg	N/A	N/A	Localized mid-ventricular septal thickening (13 mm)	Low-dose DSE 20 days later provoked LVOT gradient of 60 mmHg (which resolved during the recovery) and DSE stunning response	-	At 6 months FU, strain/strain rate imaging data showed normal LV systolic deformation in all LV segments
(40)	81	F	Physical stress	+	III progressing to IV	N/A	20-25%	>90 mmHg	+	Severe		5 days	Mild apical and apical septal hypokinesis	22 mmHg	N/A	N/A	Basal asymmetric hypertrophy (N/A)	N/A	-	Discharged on the 5th day in stable condition; course after the discharge not reported
(41)	84	F	Emotional stress	+	N/A	Apical ballooning; LVOT gradient of 100 mmHg	N/A	N/A	N/A	N/A		10 days	Resolved	Improved	N/A	N/A	Asymmetric septal hypertrophy (N/A)	N/A	-	Improved during hospitalization; further course not reported
(53)	70	F	Physical and emotional stress; alcohol abuse	-	I	Apical ballooning; LVOT gradient of 90 mmHg; moderate MR	40-45%	64 mmHgꝬ	+	N/A		6 days	Mild apical hypokinesis	None	N/A	N/A	Asymmetric interventricular septal hypertrophy (15 mm)	N/A	-	Discharged on the 6th day on BB therapy; uneventful course 2 months after the discharge
												1 month	Resolved
(54)	75	F	N/A	-	IV	Apical ballooning; LVEF of 70%	N/A	157 mmHg	+	Moderate		5 days	Resolved	None	N/A	N/A	Sigmoid-shaped septum without LV hypertrophy (N/A)	N/A	-	Discharged on BB therapy; 2 weeks later diagnosed with latent LVOTO and continued to take BB therapy
(54)	76	M	N/A	-	IV	Apical ballooning; LVEF of 47 %; moderate MR	N/A	100 mmHg	N/A	N/A		1 week	Resolved	None	N/A	N/A	Sigmoid-shaped septum without LV hypertrophy (N/A)	DSE after 6 months provoked increase in LVOT gradient from 7 mmHg to 125 mmHg	-	Discharged on BB therapy; 6 months later diagnosed with latent LVOTO and continued to take BB therapy
(54)	85	F	N/A	-	I	Apical ballooning; LVEF of 51%	N/A	90 mmHg	+	Moderate		1 week	Resolved	None	N/A	N/A	Sigmoid-shaped septum without LV hypertrophy (N/A)	DSE after 6 months provoked increase in LVOT gradient from 14 mmHg to 100 mmHg	-	Discharged on BB therapy; TTS recurrance 6 months later; diagnosed with latent LVOTO and continued to take BB therapy
(54)	79	F	N/A	-	I	Apical ballooning; LVEF of 41%; mild MR	N/A	111 mmHg	N/A	N/A		1 week	Resolved	None	N/A	N/A	Concentric LV hypertrophy (14 mm)	N/A; cardiac catheterization with dobutamine infusion was performed 10 days after ECHO recovery and induced LVOT gradient of 100 mmHg	-	Discharged on BB therapy for latent LVOTO; 5 years later, LVOTO worsened, requiring permanent pacemaker implantation
(55)	81	F	N/A	-	IV	N/A	Depressed	98 mmHg	+	Moderate		3 weeks	Resolved	20 mmHg; 70 mmHg after Valsalva maneuver	-	N/A	LV hypertrophy (19 mm)	N/A	-	Clinical condition markedly improved after treatment; normal LV function after 3 weeks; further course not reported
(42)	49	M	Alcohol abuse	+	N/A	Apical ballooning; low LVEF	30%	81 mmHg	+	N/A		2 days	Resolved	25 mmHg; reappearance of the midventricular obstruction at the level of papillary muscle	-	N/A	Asymmetric basal septal wall hypertrophy (18 mm)	N/A	-	Cardiac MRI performed at the 5th day showed no oedema or early/late gadolinium enhancement in the previously affected segments; further course not reported
(56)	63	F	Emotional stress	-	II	N/A	30-35%	51 mmHg	+	Moderate		4 days	Mild apical hypokinesis	Resolution of the LVOTO	-	N/A	Transient sigmoid-shaped septum (N/A)	N/A	-	Discharged; uneventful course 6 weeks after the discharge
(32)	70	F	Physical stress	Sigmoid-shaped septum	I	Apical ballooning; LVEF of 42%; LVOT gradient of 66 mmHg; mild MR	N/A	60 mmHg	N/A	None		~2 weeks¶	Resolved¶	None¶; dobutamine infusion provoked LVOT gradient of 100 mmHg¶	N/A	N/A	Sigmoid-shaped septum without LV hypertrophy (N/A)	Treadmill exercise test was performed on the 15th day, after initiating BB therapy, and it did not provoke LVOTO	-	Discharged on BB therapy; uneventful course
(43)	81	F	Physical stress	+	III	N/A	50%	107 mmHg	+	Present		22 days	Resolved	13 mmHg	-	Significantly improved	Septal hypertrophy (N/A)	N/A	-	Discharged on 23rd day; uneventful course throughout the FU period
(44)	70	M	N/A	+	II progressing to IV	Apical ballooning; LVEF of 30%; LVOT gradient of 70 mmHg	25%	90 mmHg	N/A	Mild		1 day after surgery	Hyperdynamic LV	None	N/A	N/A	Increased IVS thickness (17 mm)	2 years previously ESE showed LVOT gradient of 100 mmHg	+	Discharged after surgery; uneventful course 2.5 years later
(44)	58	M	N/A	+	IV	N/A	N/A	135 mmHg	N/A	N/A		4 days after surgery	Resolved	None	N/A	N/A	Increased basal anterior septum thickness (16 mm)	N/A	+ (mitral valve replacement surgery)	Discharged on the 8th postoperative day; further course not reported
(45)	79	F	None	+	III	Apical ballooning; LVEF of 25%	N/A	20 mmHg; dynamic LVOTO	N/A	Severe		2 months	Resolved	Dynamic LVOTO was relatively less severe	N/A	N/A	Basal hypertrophied septum and known HOCM (N/A)	N/A	-	Discharged on 4th day; uneventful course 2 months later
(46)	78	F	Emotional stress	+⸀	IV	Apical ballooning	Severely depressed	Up to 120 mmHg	+	Severe		13 days (after second TASH)	Moderate apical ballooning	21 mmHg	-	Mild to moderate	Septal hypertrophy (N/A)	N/A	+	Discharged after second TASH; uneventful cours 8 weeks later
(57)	63	F	N/A	-	III	Apical ballooning; LVOT gradient of 45 mmHg	N/A	Confirmed LVOTO	+	Moderate		N/A	N/A	N/A	N/A	N/A	Hypertrophic LV (N/A)	After 3 months DSE showed LV hypertrophy and dynamic LVOTO	-	Discharged on 6th day with persistent LV dysfunction on BB therapy; uneventful course 3 months later
(58)	63	F	Physical stress	-	IV	Apical ballooning; LVOT gradient of 120 mmHg	N/A	N/A	+	N/A		3 weeks	Resolved	None	-	N/A	IVS hypertrophy (20 mm)	Isoproterenol stress ECHO after 21 days induced SAM and provoked the LVOT gradient of 75 mmHg	-	No course reported after 3 weeks
+: present; -: absent; †three days later; §obtained after i.v. administration of metoprolol; δconfirmed by ECHO obtained 13 months before admission; Ꝭcalculated using the modified Bernoulli equation (p=4V²) based on the maximum atrioventricular velocity obtained; ⸀ECHO-guided TASH performed 6 months before presentation, but 6 weeks before presentation there was a recurrence of symptomatic LVOT gradient increase; ¶obtained via cardiac catheterization. BB: beta-blocker, CS: cardiogenic shock, DSE: dobutamine stress echocardiography, ECHO: echocardiography, ESE: exercise stress echocardiography, F: female, FU: follow up, HCM: hypertrophic cardiomyopathy, HOCM: hypertrophic obstructive cardiomyopathy, IABP: intra-aortic balloon pump, IVS: interventricular septum, LV: left ventricle, LVEF: left ventricular ejection fraction, LVOT: left ventricular outflow tract, LVOTO: left ventricular outflow tract obstruction, LVSWT: left ventricular septal thickness, M: male, MR: mitral regurgitation, MRI: magnetic resonance imaging, N/A: not applicable, SAM: systolic anterior motion, SRT: septal reduction treatment, TASH: transcoronary ablation of septal hypertrophy, TTS: Takotsubo syndrome, VA-ECMO: veno-arterial extracorporeal membrane oxygenation

The reviewed cases included patients ranging in age from 48 to 85 years, most of whom were female. In most cases, physical or emotional stress precipitated the onset of TTS.

Of the 34 cases, 14 had a history of diagnosed HCM prior to presentation with TTS and LVOTO (30,31,36-46), and in one case, there was a previously known sigmoid septum (32). In the remaining cases, newly diagnosed septal hypertrophy/septal bulges were registered on admission or during follow-up echocardiographic examinations (13,17,47-58). In one specific case, a transient sigmoid septum was noted in the setting of acute LV ballooning with LVOTO, which was hypothesized to be due to an inflammatory surge coupled with catecholamine overload (56).

Clinically, 12 patients presented with or progressed to cardiogenic shock, most of whom had SAM and/or a significant MR on TTE. Additionally, most of the other patients, regardless of clinical status, had SAM and some degree of MR, with a pressure gradient across the LVOT ranging from 20 to 157 mmHg.

Regarding management, the largest proportion of patients in the reviewed cases was treated with intravenous or oral beta-blockers, with or without hemodynamic support, which resulted in clinical improvement and a significant decline in the LVOT gradient upon TTE (17,31,32,37,38,40,42,43,45,47,50,52-55,57,58). In one case, symptom improvement was observed, but there was no mitigation of the LVOT pressure gradient (49). In all other cases, septal reduction therapy was required because of the persistently significant pressure gradient across the LVOT (30,36,39,44,46,48,51).

To examine LVOT gradient inducibility and diagnose any potential latent LVOT obstruction during follow-up, some of the reviewed case reports in the literature used dobutamine stress echocardiography (17,47,54,57), exercise stress echocardiography (30-32), and isoprenaline stress echocardiography (58). In most cases, latent LVOTO was thus diagnosed. Regarding ESE, in a patient with a known diagnosis of HCM, ESE conducted one month after the TTS episode with LVOT obstruction showed an exercise-induced LVOT gradient of 80 mmHg (31). In one patient with HCM, ESE was performed two years after septal reduction therapy and it showed a non-significant LVOT gradient during peak exercise (30). Finally, similar to our patient, a female patient with a predisposed non-HCM sigmoid septum did not experience an increase in the LVOT gradient during an exercise stress test 15 days after a TTS episode with LVOT obstruction (32). However, in that instance, a treadmill exercise test was used, in contrast to the semi-supine bicycle exercise test used in our patient. In addition, the exercise test in that patient was conducted after the initiation of beta-blocker therapy, whereas earlier that day, before therapy initiation, cardiac catheterization revealed a dobutamine-provoked LVOT gradient of 100 mmHg. In light of the DSE findings, Merli et al. conducted DSE with dobutamine infusion up to a peak dose of 20 μg/kg/min in four patients (17). They observed a significant increase in the intracavity dynamic gradients at the peak dose in all four cases, along with a DSE response of apical myocardial segments typical of stunned myocardium. However, this occurred on the 20th day of follow-up, whereas in our case, there was LVOTO with less pronounced apical stunning at the 6-month follow-up. The findings of Merli et al., on the other hand, could support the theory of LVOTO-induced LV apical ballooning (17).

Limitations

This case study, along with a literature review, was associated with two limitations. The first limitation is the initial exclusive reliance on ESE to evaluate LVOTO inducibility. Although ESE is commonly used and is generally safe, it may be insufficient in certain cases to evaluate LVOTO inducibility. In such instances, DSE should be supplemented to better predict the patient prognosis and to develop an appropriate treatment plan. Second, this literature review was not systematic, as the search strategy was based solely on two databases and a citation search, thereby limiting the comprehensiveness and depth of the analysis.

Conclusion

This case of TTS with LVOTO and MR combined with sigmoid septum sheds light on an inadequately researched and profoundly intricate domain within the field of cardiology. Furthermore, this case highlights that the subset of patients with this presentation necessitates expeditious recognition and meticulous evaluation to discern it from alternative etiologies of MR as well as from obstructive HCM with apical ballooning. Making a prompt and precise diagnosis of these patients is imperative to determine the optimal therapeutic approach.

Additionally, regular patient surveillance is of paramount importance in assessing the therapeutic efficacy, prognostication, and understanding the disease pathogenesis. Particular emphasis has been placed on stress echocardiography, which has emerged as a prospective diagnostic cornerstone for this purpose.

The authors state that they have no Conflict of Interest (COI).

Supplementary Material

Video S1. Left ventriculography upon admission.

Left ventriculography upon admission revealing apical and anterolateral akinesia with a hypercontractile basis - typical wall motion abnormalities of Takotsubo syndrome.

Video S2. Transthoracic echocardiography (three-chamber view) upon admission.

Transthoracic echocardiography (three-chamber view) upon admission showing akinesis of the apex and all apicalsegments with apical ballooning. Systolic anterior motion is alsoevident.

Video S3. Transthoracic echocardiography (four-chamber view) on admission.

Transthoracic echocardiography (four-chamber view) on admission showing moderate-to-severe mitral regurgitation.

Video S4. Post-management transthoracic echocardiography (five-chamber view).

Post-management transthoracic echocardiography (five-chamber view) showing recovery of myocardial wall motion without apical ballooning and without systolic anterior motion one week after treatment.

Video S5. Post-management transthoracic echocardiography (four-chamber view).

Post-management transthoracic echocardiography (four-chamber view) showing no mitral regurgitation one week after treatment.

Video S6. Follow-up transthoracic echocardiogram (three-chamber view) with color Doppler one month after.

Follow-up transthoracic echocardiogram (three-chamber view) with color Doppler one month after indicating resolution of the left ventricular outflow tract obstruction and mitral regurgitation.