Pathways Case Record: Triggers and Mechanisms of Takotsubo Cardiomyopathy

A 72-year-old woman presented to the hospital after developing severe sudden onset substernal chest pain with shortness of breath while performing yard work after a social interaction. Her history included remote tobacco use, lymphangioleiomyomatosis with chronic dyspnea on exertion, hypertension, hyperlipidemia, gastroesophageal reflux disease, and mitral valve prolapse. On presentation, she appeared moderately ill, with sinus tachycardia and scattered wheezing. Her labs were unremarkable except for elevated blood sugar, lactate, cardiac troponin and white blood cell count. Chest X-ray revealed multifocal pneumonia and the chest CT revealed new ground-glass opacification, pleural effusions, and ballooning of the left ventricular apex. Furthermore, the transthoracic echocardiography demonstrated a newly depressed ejection fraction (EF) of 28% (compared to the 62% two years prior) with wall motion abnormalities at the apex, suggesting Takotsubo syndrome (TTS; also called Takotsubo cardiomyopathy or broken-heart syndrome).

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She was empirically treated for community-acquired pneumonia and underwent diuresis. Her course was further complicated by a left ventricular thrombus and subsequent right middle cerebral artery stroke. Her follow-up echocardiogram seven weeks after presentation showed recovered cardiac function with an EF of 73% without thrombus.

The Pathways Consult Service in the Department of Medicine at Massachusetts General Hospital was consulted and focused on three key questions:

1. How does psychological or physical stress lead to TTS?
2. What causes the focality of dyskinesis in TTS?
3. How can understanding the pathophysiology of TTS be used to better treat and/or prevent this condition in the future?

Background and Diagnosis

TTS is a reversible cardiomyopathy typically triggered by severe emotional and/or physical stress and presents with myocardial infarction symptoms but lacks occlusive pathology in the coronary arteries (J Med Life). Most TTS cases occur in post-menopausal women (~90%). These patients typically present with anginal equivalents (e.g., shortness of breath, sweating, extreme fatigue, and/or pain), echocardiogram (EKG) changes, and elevated troponins. This presentation prompts coronary angiography which does not yield a culprit lesion. The EKGs of these patients often reveal a classic pattern of cardiac dysfunction, specifically left ventricular apical hypokinesis and ballooning while otherwise hyperdynamic. This classic pattern occurs in approximately 85% of cases, with other patterns (e.g., mid-ventricular, bi-ventricular and basal) occurring with less frequency.

While the underlying pathophysiology of TTS remains poorly understood, several mechanisms have been proposed. The predominant mechanisms proposed include microvascular dysfunction and direct catecholamine toxicity. Although we have been unable to directly observe microvascular dysfunction, signs of dysfunction are apparent in TTS cases. For example, improvements in EF and wall motion abnormalities are seen following administration of adenosine, and markers of increased apoptosis are found in microvascular endothelial cells in endocardial biopsies (Eur Heart J, Clin Cardiol). The classic mechanism of action of direct catecholamine toxicity was thought to be overstimulation of cardiac adrenergic receptors leading to calcium overload and subsequent myocyte contractile dysfunction. Recent studies have demonstrated that very high concentrations of epinephrine outside the standard range, as seen in TTS, trigger a change in the beta-2 adrenergic receptor activity, resulting in reduced inotropy (N Engl J Med). This impact on cardiac contractility may explain the observed cardiac dysfunction seen in TTS patients. Additionally, since most TTS patients are post-menopausal women, the role of estrogen has been investigated. Indeed, reduced levels of estrogen is linked to elevated sympathetic drive as well as microvascular endothelial dysfunction.

Beta receptors are differentially expressed across the human myocardium, which could lead to regional differences in signaling upon catecholamine stimulation. One hypothesis is that this receptor variation could produce the anatomic distribution of TTS that is observed in many patients with this disease, including our patient. The use of a PET/CT with tracers specific to the sympathetic nervous system during active periods of TTS may provide a window into beta receptors signaling in this disease. The novel tracer C-CGP12177 specifically binds to postsynaptic neuron beta-2 receptors and was previously used in a study of chronotropic incompetence. While this may partially describe the phenotype observed in our patient, other factors may also play a critical role.

There is a yet-unexplained role for direct nervous system signaling contributing to changes in myocyte function. In addition to the known sympathetic and parasympathetic innervation, emerging data characterizes an extensive intrinsic cardiac nervous system, which may contribute to cardiac diseases such as TTS. To our knowledge, most of the existing work on innervation of the heart relates to pace-making and arrhythmia (J Cardiovasc Dev Dis). The role of innervation in contractility in the setting of psycho-physiologic stress is presently unknown. To fully understand this, anatomical and functional mapping in animal models could provide the better understanding needed to characterize intrinsic cardiac innervation. We hypothesized that both the distribution of beta receptors in the myocardium and dysfunction of the intrinsic cardiac nervous system could contribute to TTS susceptibility in our patient and in others like her.

Summary and Future Steps

The underlying mechanisms leading to TTS remain poorly understood. Current recommendations for the management of TTS are empiric and therapeutic strategies are based on acute cardiomyopathy stemming from other causes. However, given the current body of knowledge on the pathophysiology of TTS, it is likely that the phenotype may be impacted uniquely by drugs inhibiting or mimicking sympathetic nervous stimulation. Further investigations are warranted to better understand the pathway resulting in the severe, but reversible phenotype observed in TTS. Although these studies are unlikely to change the course of treatment for our patient, they could provide new strategies to ameliorate the dysfunction in TTS and improve patient care in the future.

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