Hypertrophic cardiomyopathy (HCM) is a common genetic heart disease characterized by frequent left ventricular (LV) outflow tract obstruction [1, 2, 3]. In recent years the clinical spectrum of HCM has grown to include patients with outflow obstruction but with normal to mild LV thickness [4, 5, 6]. A subset of HCM patients, often with mild septal thickening, present acutely with apical ballooning and severe LV outflow tract (LVOT) obstruction that can progress to refractory heart failure or cardiogenic shock [7, 8]. In addition to apical ballooning, these patients share multiple clinical features with classical neurohumoral apical Takotsubo syndrome (TTS), including chest pain, electrocardiogram (ECG) changes, elevated cardiac biomarkers, and lack of angiographic coronary stenosis [9]. For this review, our guiding principle is that there are at least two proposed causes of acute apical ballooning. The first and most commonly cited hypothesis is that ballooning is caused by direct catecholamine toxicity to the cardiomyocytes, or through microvascular ischemia [10, 11]. More recently, a second hypothesis has emerged. This postulates that in some patients with underlying HCM, LV ballooning is caused by the sudden onset of latent and severe LVOT obstruction, resulting in severe afterload mismatch and supply-demand ischemia [9]. In this review, we describe how the clinical presentation of LV ballooning can obscure the difference between the two potential etiologies. The pathophysiology of each etiology will be reviewed, as well as how echocardiography and catheterization can help to define the cause of LV ballooning and thus guide the most appropriate treatment. We searched PubMed and reviewed references in published manuscripts for patients with HCM complicated by acute LV ballooning syndrome, as well as patients with TTS and suspected underlying HCM.

Our literature search yielded case series [7, 8, 9, 12, 13, 14], case reports [15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38], one prospective cohort study [39], and one systematic review [40] that described cases of obstructive HCM with LV ballooning overlapping with neurohumoral Takotsubo syndrome (TTS). We propose key features to differentiate these diagnoses, as shown in Fig. 1. Case reports describe the presence of LV outflow tract (LVOT) obstruction in TTS cases [18, 19, 21, 22, 41]. Case series suggest that up to 18% of patients with acute LV ballooning have an intraventricular pressure gradient [42, 43], with up to 25% of patients demonstrating LVOT obstruction [44]. In such cases, systolic anterior motion (SAM) of the mitral valve has been attributed to a geometric change in the shape of the LV, with a narrowed hyperkinetic outflow track and Venturi effect. However, most evidence suggests that SAM is caused by flow drag, which is the pushing force of flow that begins at low LV velocities and drives mitral leaflets into the septum, as shown in Fig. 2 [9]. Pertinent to this, a severely akinetic or severely hypokinetic LV apex generates low instantaneous ejection velocities [13]. Velocities apical to the mitral valve are not high, thus precluding a Venturi effect. Multiple case reports of LV apical ballooning in patients with HCM describe how prompt treatment of septal hypertrophy, predominantly medically but notably also after emergency myectomy or alcohol septal ablation, can lead to resolution of LVOT obstruction and rapid clinical improvement [19, 22, 23, 24]. While many of these patients were diagnosed with overlapping TTS and HCM, the almost immediate clinical improvement of shock and ballooning after surgical relief of septal hypertrophy and LVOT obstruction provides striking evidence that acute apical ballooning is in many cases a direct complication of severe obstructive HCM [8, 15, 20, 45].

Fig. 1.

Central figure highlighting the pathophysiological, diagnostic, and management differences between patients presenting with acute apical ballooning due to Takotsubo syndrome (TTS) versus obstructive hypertrophic cardiomyopathy (HCM). LVOT, left ventricular outflow tract; LV, left ventricle; LHC, left heart catheterization; IV, intravenous; RAAS, renal-angiotensin-aldosterone system.

Fig. 2.

The cardiac loop and SAM of the mitral valve. Flow within the LV follows a U-turn redirection between the LV inflow and outflow tracts, and goes around the mitral valve. The close proximity of the LV inflow and outflow tracts makes this anatomy susceptible to small perturbations, resulting in SAM in vulnerable individuals. In obstructive HCM, the mitral valve is swept into the septum by the pushing force of flow, also known as flow drag. Flow originates from a posterior and lateral direction, redirected by the septal bulge. As it does so, flow catches the mitral valve from its ventricular aspect and sweeps it into the septum. Reproduced by permission of the authors [52]. SAM, systolic anterior motion; LV, left ventricle; HCM, hypertrophic cardiomyopathy.

A major challenge in differentiating classical neurohumoral apical TTS from HCM with acute LV ballooning is the overlapping epidemiology of these syndromes. Up to 90% of TTS cases present in postmenopausal women [16]. A retrospective case series of patients who developed apical ballooning from obstructive HCM also revealed that 10 of the 13 patients (77%) with this syndrome were female, with a mean age of 64 $\pm$ 7 years [7]. A systematic review of 18 cases of overlapping TTS and HCM found that 77.8% of patients were female, with a median age of 66.2 years [40]. The overlapping demographics of patients presenting with TTS and HCM with acute LV ballooning can lead to etiologic and diagnostic misclassification. A retrospective cohort study using diagnostic codes from electronic medical records suggested that up to 30% of cases initially diagnosed as TTS were re-assessed as HCM with LV ballooning after detailed echocardiographic analysis [9]. Even with more routine presentation, obstructive HCM remains underdiagnosed in population studies, with up to one-third of cases being misclassified [46]. Consequently, a more detailed understanding of the clinical presentation, pathophysiological changes, and clinical course of HCM with apical ballooning may improve our ability to accurately diagnose obstructive HCM in this scenario.

The clinical presentation of patients with obstructive HCM with LV ballooning share several overlapping features with TTS. Patients with these syndromes typically have chest pain, dyspnea, syncope, ST-segment changes on ECG, and elevated cardiac biomarkers, consistent with acute coronary syndrome (Fig. 3 (Ref. [9]) and Fig. 4) [7, 42]. The initial diagnostic workup for both conditions includes transthoracic echocardiogram (TTE), which typically shows apical hypokinesis with basal hyperkinesis. Coronary angiography excludes obstructive disease in both conditions [40].

Fig. 3.

HCM with mild asymmetric septal hypertrophy, LVOT obstruction, and acute apical ballooning syndrome. A 63-year-old woman was admitted with near-syncope, hypotension, and NSTEMI (troponin I of 0.64 ng/mL). Coronary arteries were angiographically normal. LV cineangiography revealed acute apical ballooning. Left heart catheterization revealed an aortic pressure of 89/51 with a gradient of 100 mmHg. Following intravenous metoprolol, the patient’s outflow tract gradient improved to 40 mmHg, and her BP improved to 105/80 mmHg. A stress TTE performed 22 months after presentation demonstrated normal LV wall motion and no resting gradient. Following stress, TTE revealed mitral-septal contact and a peak LVOT gradient of 81 mmHg. This patient had very mild septal thickening HCM with acute apical ballooning due to LVOT obstruction presenting clinically as TTS. After recovery of LV systolic function, she continued to have severe LVOT gradients provocable after exercise. (A) Echocardiogram performed on admission (systolic frame) revealed apical and mid-LV ballooning with severe hypokinesis (arrowheads) and mitral-septal contact (white arrow). (B) Color Doppler (systolic frame) demonstrated severe mitral regurgitation (MR) (red arrow) and turbulence in the LV outflow tract (yellow arrow). (C) Pulsed-wave (PW; top) and continuous wave (CW; bottom) Doppler tracings obtained on admission TTE. PW Doppler at the level of the LVOT revealed a mid-systolic drop in PW Doppler velocities (“lobster claw abnormality”). The nadir in the drop of the PW Doppler corresponds to the peak of the CW gradient in the outflow tract (139 mmHg, bottom), as shown by the red dotted line. The PW velocity in mid-systole is low at 20 cm/sec, due to LV systolic dysfunction. Reproduced with permission Am J Cardiol [9]. HCM, hypertrophic cardiomyopathy; LVOT, left ventricular outflow tract; NSTEMI, Non-ST segment elevation myocardial infarction; LV, left ventricle; TTE, transthoracic echocardiogram; TTS takotsubo syndrome.

Fig. 4.

Left heart catheterization and peak-to-peak pressure tracings of the patient described in Fig. 3, obtained using a retrograde pullback approach. (A) Pullback method for LV and aortic pressure tracings demonstrate a 60 mmHg gradient across the LVOT. (B) Aortic pressure tracings in the catheterization laboratory demonstrate a hypotensive patient with a systemic blood pressure of 87/51 mmHg. (C) Given the concern for acute apical ballooning due to severe LVOT obstruction in HCM, the patient was administered IV metoprolol 15 mg. Fifteen minutes later, aortic pressure tracings demonstrate improved systemic blood pressures to 110/60 mmHg, as well as an improved LVOT gradient to 40 mmHg. LV, left ventricle; LVOT, left ventricular outflow tract; HCM, hypertrophic cardiomyopathy; IV, intravenous.

Differentiating HCM with LV ballooning from TTS involves primarily the careful measurement of echocardiographic wall thickness (particularly at the basal septum), dedicated evaluation of outflow tract obstruction, echocardiographic elucidation of mitral valve pathology including SAM of mitral valve leaflets, and the evolution over time of the illness (Figs. 3,4, Supplementary Figs. 1,2). A potential source of diagnostic confusion is the relatively mild septal hypertrophy observed in obstructive HCM patients with apical ballooning [1, 3]. With obstructive HCM, it is important to note that septal hypertrophy, elongated mitral leaflets, papillary muscle abnormalities, and anterior displacement of the mitral leaflets persist on imaging well after the acute episode of apical ballooning. Indeed, a retrospective study noted that all 13 cases of acute apical ballooning had imaging features of obstructive HCM long after their acute presentation [7, 8, 9, 43].

Typical HCM-related mitral valve abnormalities occur in approximately 30% of patients with acute LV ballooning, and specifically in patients with outflow obstruction and septal hypertrophy. This provides striking evidence that obstructive HCM is their primary underlying condition. Patients with HCM commonly have primary abnormalities of the mitral valve and apparatus [3, 20], including leaflet elongation, anomalous papillary muscle insertion, and anteriorly displaced papillary muscles [3, 20] (Supplementary Fig. 3). On the other hand, patients with neurohumoral TTS experience catecholamine toxicity of their cardiomyocytes and thus have no cause for mitral leaflet elongation or other primary mitral valve pathology.

LVOT obstruction is seen in up to 75% of patients with HCM and is associated with worse clinical outcomes [3, 47]. LVOT gradients $\ge$30 mmHg are indicative of obstruction and may be present at rest or with provocative maneuvers (latent obstruction) [3]. LVOT obstruction in HCM is caused by septal hypertrophy and anatomic alterations to the mitral valve apparatus, leading to an overlap of the inflow and outflow portions of the left ventricle (Fig. 2) [3, 48, 49, 50, 51, 52]. The overlap allows LV systolic flow to strike the ventricular surface of the mitral apparatus on its way to the LVOT, causing SAM and mitral-septal contact [52]. This pathophysiologic hallmark of HCM is typically diagnosed using TTE, but may also be revealed by cardiac magnetic resonance imaging (MRI), left ventriculography, and invasive hemodynamics (Figs. 3,4, Supplementary Figs. 1,2).

The LVOT gradient in HCM demonstrates dynamic variation, particularly in response to changes in cardiac preload, afterload, contractility, and hence catecholamines [53, 54]. In rare circumstances, patients with HCM and latent obstruction may experience severe and unrelenting increases in the LVOT gradient, progressing to LV apical ballooning and even heart failure with cardiogenic shock [7, 8, 32]. A retrospective study of two HCM treatment programs found that 0.9% of HCM patients experienced acute LV ballooning associated with dynamic LVOT obstruction and mean gradients of 92 $\pm$ 37 mmHg [7]. It is hypothesized that severe LVOT obstruction (usually $>$50 mmHg) independently leads to acute apical ballooning through afterload mismatch and supply-demand ischemia [15, 17]. A graphic demonstration of the corrosive effect of LV outflow obstruction by afterload mismatch is the Doppler finding of a mid-systolic drop in LV ejection velocities, the so-called “lobster claw abnormality” (Fig. 3) [55]. Myocardial ischemia is well documented in obstructive HCM and results from: (1) supply-demand ischemia from high LV pressures and decreased arterial and coronary perfusion pressures; (2) elevated LV diastolic filling pressures contributing to lower transcapillary perfusion pressures; and (3) narrowing of intramyocardial small coronary arterioles due to medial and intimal hyperplasia [56, 57, 58].

Neurohumoral TTS is believed to be mediated by high circulating catecholamine levels [10]. Patients with LV ballooning have higher levels of circulating catecholamines than those with acute myocardial infarction from occlusive coronary disease [59]. Several etiologies have been proposed to explain how excess catecholamines can mediate LV ballooning in TTS, including microvascular dysfunction, direct cardiomyocyte toxicity, paracrine influence, and myocardial inflammation [10, 59]. The current leading hypotheses are summarized in Supplementary Table 1. Although excess catecholamine has been implicated in the proposed mechanism for neurohumoral TTS, it is also worth noting that elevated levels can also increase the severity of LVOT obstruction, thereby leading to prolonged high gradients in patients with latent obstruction. This overlap adds to the challenge of correct diagnosis within this population.

Although the above findings may be useful for differentiating TTS from HCM with latent obstruction and apical ballooning, the clinical evolution of the disease process over time is often the most useful for differentiating the two entities. Several case reports found that patients who presented acutely with LV apical ballooning and were diagnosed with TTS continued to show septal hypertrophy, LVOT obstruction, and mitral pathology for several weeks to months after initial presentation, and were ultimately diagnosed as HCM with obstruction [12, 25, 26, 37]. Therefore, the continued evidence of such abnormalities on imaging after acute improvement of wall motion abnormalities would indicate the presence of underlying HCM. At our center, several of these patients required late surgical myectomy and mitral repair once their symptoms proved refractory to medication.

In such cases, additional diagnostic and therapeutic modalities may improve the diagnostic accuracy. Cardiac MRI and rarely also endomyocardial biopsy have been used to diagnose underlying HCM [25, 27, 30]. Typical findings on cardiac MRI include LV hypertrophy ranging from diffuse global hypertrophy to focal segmental hypertrophy, as well as further anatomical characterization of the LVOT, papillary muscles, and subvalvular apparatus [60]. Patients with HCM may have variable papillary muscle anatomy, including anomalous anterior papillary muscle displacement and accessory papillary muscles [50, 60]. The presence of late gadolinium enhancement (LGE) by cardiac MRI in HCM can range from no LGE in patients with mild hypertrophy, to extensive LGE, thus conferring diagnostic as well as prognostic value [60]. Cardiac MRI has been used to define LV hypertrophy following acute episodes of apical ballooning. In HCM, cardiac MRI characteristically shows myocardial fibrosis and increased extracellular volumes without evidence of myocardial edema [27, 30]. Conversely, one case report described how LV apical edema mimicked apical HCM. At follow-up, cardiac MRI showed resolution of myocardial edema and wall hypertrophy, thus confirming the diagnosis of TTS [28]. This modality offers promise for distinguishing between TTS and HCM in ambiguous cases.

The current literature search found no dedicated reviews that focused on the role of diagnostic left heart catheterization in this population. A central tenet of this review is that left heart catheterization and the measurement of trans-outflow tract gradients are essential in LV ballooning and can provide etiologic diagnosis.

The ability to differentiate LV apical ballooning in obstructive HCM versus neurohumoral TTS is particularly important for guiding appropriate treatment.

As highlighted in this review, there may be significant overlap in the clinical presentation of neurohumoral TTS and obstructive HCM with apical ballooning. Key features that may help to differentiate these entities include the presence of LVOT obstruction, mitral valve pathology, and the persistence of echocardiographic HCM following acute presentation. Since up to 30% of affected patients may be misdiagnosed, it is important for invasive cardiologists and echocardiographers to explore the key distinguishing features of obstructive HCM from neurohumoral TTS to better determine the diagnosis and tailor therapy. Patients with HCM and LVOT obstruction are treated with intravenous beta blockade and phenylephrine for hypotension. In contrast, patients with neurohumoral TTS are given supportive treatment in the acute setting. Observational data supports the role of RAAS inhibitors in this population, presumably after excluding patients with LVOT obstruction. In patients with HCM and apical ballooning complicated by shock, mechanical support that decreases afterload or preload should be avoided, and VA-ECMO may be preferred if available. Refractory shock may improve after septal reduction therapy, which is often performed with ancillary mitral shortening. Treatment of such patients and their unique pathology requires familiarity with the obstructive HCM ballooning syndrome, as well as a trained and equipped team that is ready to intervene.

AS, LR, DM, and MS designed the review, performed the research, and analyzed the data. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

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This research received no external funding.

The authors declare no conflict of interest.