“Mama, Can You Die from a Broken Heart?” Exploring the Pathogenesis of Takotsubo Cardiomyopathy

October 9, 2024


By Justin Jewell

Peer Reviewed

We all have our guilty pleasures, and one of mine happens to be country music. On a cold night in February, as I struggled to stay afloat in my seemingly never-ending stack of Anki review flashcards, I fired up an old Spotify playlist to propel me over the finish line. I heard a catchy tune play through my headphones as the singer-songwriter duet Maddy & Tae proposed a critical question: “Mama, can you die from a broken heart?” Had the country stars been paying attention in their first-year cardiology courses, they may have remembered takotsubo cardiomyopathy. Often colloquially dubbed “broken heart syndrome,” this disease is typically preceded by acute emotional or physical stress. But how is the body’s response driving myocardial dysfunction, and why are post-menopausal women more commonly affected? Perhaps a better question would be, “Mama, how can you die from a broken heart?”

First, let’s begin with a review for any country musicians in the audience. Takotsubo cardiomyopathy was characterized in the 1990s by Hikaru Sato in Japan, who described cases of reversible left ventricular dysfunction in the absence of obstructive coronary artery disease.1 Ninety percent of patients with takotsubo cardiomyopathy are women over the age of 50, and it accounts for approximately 2% of patients who present to the hospital with suspected acute coronary syndrome.2 The condition is diagnosed with echocardiography showing hypokinesis of the left ventricular wall, most commonly in the apical region. Other causes of ventricular hypokinesis, such as obstructive coronary artery disease, myocardial infarction, or myocarditis must be excluded before a diagnosis of takotsubo cardiomyopathy can be made. This dysfunction causes characteristic “ballooning” of the apical region of the left ventricle, giving the heart the shape of a Japanese octopus trap, the namesake of the disease.

The pathogenesis of takotsubo cardiomyopathy remains a topic of ongoing debate and investigation, with several proposed theories as to its underlying mechanisms.

The most prominent theory implicates an inappropriate surge in catecholamines, particularly norepinephrine and epinephrine, released in response to an overwhelmingly stressful emotional or physical event.3 Norepinephrine primarily binds β1 receptors in cardiac myocytes, increasing heart rate and contractile force.3 Epinephrine also binds this receptor but has a higher affinity for the β2 receptor, another mediator of positive cardiac contractile force.3,4 However, epinephrine alters β2 receptor coupling at elevated concentrations, leading to an inhibitory signal and decreased contractile force.4,5 This decrease in cardiac inotropy explains the findings of hypokinetic ventricular wall segments on echocardiography. It has been postulated that the predilection for dysfunction in the apical region results from an increased concentration of β2 receptors.3 This distribution has been demonstrated in canine hearts but has yet to be studied in human models.3

In addition to catecholamine-induced toxicity, endothelial dysfunction is an emerging potential contributor to the pathogenesis of takotsubo cardiomyopathy. Endothelial dysfunction is characterized by impaired nitric oxide bioavailability and dysregulated vascular tone. Nitric oxide stimulates vasodilation and inhibits platelet aggregation and leukocyte adhesion.6 Thus, it is proposed that in takotsubo cardiomyopathy, endothelial cells’ impaired production of nitric oxide results in vasoconstriction and a prothrombotic state in the coronary microvasculature. This disruption is thought to impair coronary blood flow, contributing to the stunning of cardiac myocytes through microvascular ischemia.6,7 Studies showing an increased prevalence of diseases of endothelial dysfunction, such as Raynaud’s disease and migraines, in patients with takotsubo cardiomyopathy further support this relationship.8

Estrogen, a hormone with many proposed cardioprotective effects, has also been implicated as a mediator in takotsubo cardiomyopathy. The decline of estrogen in post-menopausal women is thought to be the reason that this population is disproportionately affected by the disease. Estrogen binds to endothelial cell receptors, enhancing nitric oxide production and promoting a vasodilatory state.9 Estrogen is also an inhibitor of many pro-inflammatory cytokines, reducing endothelial dysfunction and inflammatory responses in the vasculature.10 In cardiac myocytes, an estrogen deficiency is thought to impair calcium handling, putting these cells at further risk for catecholamine-induced toxicity and oxidative stress as intracellular calcium levels rise.11 Many interactions between estrogen and the sympathetic nervous system are currently being studied, including modifications of β-receptor activity. Mouse models have shown the protective effects of estrogen against catecholamine surge, with estrogen-deficient mice exposed to stress demonstrating higher heart rate and decreased left ventricular contractility.12

While there is still work to be done, it is clear that the pathogenesis of takotsubo cardiomyopathy revolves around the complex interplay of sympathetic stimulation, endothelial function, hormonal regulation, and other factors yet to be discovered. As our understanding of the mechanisms that drive takotsubo cardiomyopathy improves, so will our treatment targets and prevention strategies. Perhaps Maddie & Tae’s next album will include a song that answers the question, “Mama, how can we stop people from dying from a broken heart?”

By Justin Jewell is a Class of 2026 medical student at NYU Grossman School of Medicine

Reviewed by Matthew Vorsanger, MD Assistant Professor, Department of Medicine at NYU Grossman School of Medicine Director, Cardiac Rehabilitation, Bellevue Hospital Center

Image courtesy of Wikimedia Commons, source: Adhesive bandage drawing nevit.svg: Nevit Dilmen (talk)Love Heart symbol.svg: Nevit Dilmen (talk)derivative work: Nevit Dilmen, CC BY-SA 3.0 <https://creativecommons.org/licenses/by-sa/3.0>, via Wikimedia Commons

References

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