Pathophysiology

Pathophysiology refers to the study of abnormal changes in body functions that cause, result from, or accompany disease processes. The pathophysiology of takotsubo syndrome (TTS) is still not entirely understood, but there has been significant progress in understanding this syndrome since it was first described over 30 years ago. Several pathophysiological mechanisms for TTS have been proposed over the years, but there does not seem to be a single explanation that fits all cases of TTS. The more we learn about TTS, the greater the number of questions that arise.  Current thinking is that TTS may result from more than one pathophysiological phenomenon.Solving the enigma of TTS is like putting together a complex jigsaw puzzle as depicted below by Templin and colleagues,2 with researchers working to find out where the pieces fit as new information becomes available.

Figure 1: The Unsolved Puzzle of Takotsubo Syndrome (Click HERE to enlarge)

Image reproduced from Templin et al. (2016). Takotsubo Syndrome Underdiagnosed Underestimated but Understood, JACC, 67(16):1937-194. Accessed from  https://doi.org/10.1016/j.jacc.2016.03.006 . Used under Elsevier User Licence.

 

Previously proposed mechanisms of TTS

Microvascular dysfunction (MVD) is a common finding in TTS, and it is uncertain whether it is a cause or effect of TTS. When present in the acute phase of TTS,
MVD is usually transient and its recovery correlates with improved myocardial function, suggesting that it is an effect of the myocardial  oedema and inflammation
that occurs in TTS, rather than a cause.  Macrovascular dysfunction, including aborted myocardial infarction, coronary vasospasm and spontaneous coronary artery dissection have been reported in association with TTS, and while these may potentially serve as triggers for TTS in some individuals, they are not consistently found in people with TTS.

What is currently known about the pathophysiology of TTS?

It is generally accepted that catecholamines have a central role in the pathophysiology of  TTS. Catecholamines are proteins that serve as neurotransmitters. They are sometimes described as chemical messengers that move signals between the brain and the body. Catecholamines that naturally occur in the body are dopamine, epinephrine (adrenaline), and norepinephrine (noradrenaline). Catecholamines control a variety of functions in the body and they are essential in the 'fight or flight' response that is triggered by physical or emotional stress. Dopamine, epinephrine and norepinephrine can also be manufactured synthetically and be administered as a therapeutic drug in certain clinical situations. There are several other synthetic drugs that may mimic or enhance the actions of epinephrine and norepinephrine in the body. Evidence  supports a central role for catecholamines in the pathophysiology of TTS .

  • TTS is preceded by an acute emotionally stressful event (primary TTS) or physical illness or trauma (secondary TTS) in most cases.
  • Plasma catecholamines are substantially elevated in patients with TTS.
  • Epinephrine, norepinephrine, isoprenaline (isoproteranol), dopamine, and phenylephrine have all been shown to induce TTS-like changes in humans and animal models.4
  • Several clinical conditions associated with acute severe sympathetic neural activation or adrenal catecholamine release such as acute subarachnoid haemorrhage, pheochromocytoma, and acute thyrotoxicosis can trigger TTS.5,6
  • The multiple morphological changes seen in the myocardium in TTS (contraction band necrosis and interstitial mononuclear inflammatory
    response ) match those seen after catecholamine-induced cardiotoxicity3,6 
  • Elevated norepinephrine levels have been found in the coronary sinus of patients with TTS, suggesting an increase in the local release of myocardial catecholamines 6a      

Recently added pieces to the puzzle

Direct effects of catecholamines on the ventricular myocardium (heart muscle)

High levels of circulating catecholamines seriously impair the ability of the heart to pump effectively. This is known as 'neurogenic stunning' or 'catecholamine stunning'.

Epinephrine‑induced switch in signal trafficking

It has been proposed that high levels of circulating epinephrine may trigger a switch in the intracellular signal trafficking from Gs (stimulatory) to Gi (inhibitory) protein signaling through the B2 adrenoreceptor (B2AR) that is negatively inotropic with greatest effect at the apical myocardium, explaining apical ballooning seen in TTS. It is proposed that this mechanism is cardioprotective. and may have evolved  to limit catecholamine-induced myocardial toxicity during acute stress.13 However, it is not certain how this applies to forms of TTS other than apical ballooning.6

Nitrosative stress

Immunohistologic studies of myocardium from people with TTS have shown evidence of nitrosative stress,14 with increased 3-nitrotyrosine (a marker of nitrosative stress) and potentially poly(ADP-ribose), a downstream product of poly (ADP-ribose) polymerase (PARP)-1 activation, which can impair cardiac energetics,15 a factor that may explain why people with TTS experience fatigue and symptoms long after the initial event. Also of interest, nitric oxide synthase can couple to the β2AR.16

Inflammation

Following initial contractile dysfunction, the longer term sequelae of TTS involves cardiac inflammation.16 Endomyocardial biopsy shows mononuclear infiltrates and contraction band necrosis, a unique form of myocyte injury characterised by hypercontracted sarcomeres, dense eosinophilic transverse bands, and an interstitial mononuclear inflammatory response. Contraction-band necrosis has been described in clinical states of endogenous and exogenous catecholamine excess.5 Slowly resolving global myocardial oedema is present on magnetic resonance imaging17 and as this subsides, a process of global microscopic fibrosis develops in its place, which can be detected as early as 4 months.18

For some who have experienced TTS, extreme fatigue and lethargy  continues for months. Many also report ongoing symptoms of chest pain, dyspnoea, palpitations and lightheadedness. It is it is important to understand the processes linking the acute changes in contractility with the downstream inflammatory changes that worsen long-term prognosis for people with TTS.

The brain-heart axis

The pathophysiology of TTS integrates neuroendocrine physiology, potentially involving the cognitive centres of the brain, including the hypothalamic–pituitary–adrenal (HPA) axis. Templin and colleagues have recently demonstrated that structural anatomical brain differences exist between patients with TTS and healthy controls. These differences involve the limbic network ,including the insula, amygdala, cingulate cortex, and hippocampus, all of which are thought to contribute to emotional processing and the autonomic nervous system. These findings strengthen the current concept of the involvement of the brain–heart interaction in TTS. It is not clear whether these differences existed before TTS, and so they could be a cause or an effect of TTS. 19

1Akashi, Y. J., Nef, H. M., & Lyon, A. R. (2015). Epidemiology and pathophysiology of Takotsubo syndrome. Nature Reviews Cardiology, 12(7), 387. https://doi.org/10.1038/nrcardio.2015.39
2Templin, C., Napp, L.C. and Ghadri, J.R., 2016. Takotsubo syndrome: underdiagnosed, underestimated, but understood? Journal of the American College of Cardiology, 67(16) https://doi.org/10.1016/j.jacc.2016.03.006
3Kido, K. and Guglin, M., 2017. Drug-induced takotsubo cardiomyopathy. Journal of Cardiovascular Pharmacology and Therapeutics22(6), pp.552-563. https://doi.org/10.1177/1074248417708618
4Redfors, B., Ali, A., Shao, Y., Lundgren, J., Gan, L.M. and Omerovic, E., 2014. Different catecholamines induce different patterns of takotsubo-like cardiac dysfunction in an apparently afterload dependent manner. International Journal of Cardiology174(2), pp.330-336.
5Wittstein, I.S., Thiemann, D.R., Lima, J.A., Baughman, K.L., Schulman, S.P., Gerstenblith, G., Wu, K.C., Rade, J.J., Bivalacqua, T.J. and Champion, H.C., 2005. Neurohumoral features of myocardial stunning due to sudden emotional stress. New England Journal of Medicine352(6), pp.539-548.
6Shams, Y. and Tornvall, P., 2018. Epidemiology, pathogenesis, and management of takotsubo syndrome. Clinical Autonomic Research, 28(1), pp.53-65.
6aKume T, Kawamoto T, Okura H, et al. Localrelease of catecholamines from the hearts of patients with tako-tsubo-like left ventriculardysfunction. Circ J 2008;72:106–8.
7Vitale, C., Rosano, G.M. and Kaski, J.C., 2016. Role of coronary microvascular dysfunction in Takotsubo cardiomyopathy. Circulation Journal, pp.CJ-15. https://doi.org/10.1253/circj.CJ-15-1364.
8Al-Hijji, M.A. and Prasad, A., 2018. Coronary vasomotor dysfunction in apical ballooning (Takotsubo) syndrome: An innocent bystander or a prime suspect?International Journal of Cardiology, 250, pp.56-57.
9Ibanez, B., Navarro, F., Cordoba, M.P.M.A., M-Alberca, P. and Farre, J., 2005. Tako-tsubo transient left ventricular apical ballooning: is intravascular ultrasound the key to resolve the enigma?. Heart, 91(1), pp.102-104. https://doi.or/10.1136/hrt.2004.035709
10Hoyt, J., Lerman, A., Lennon, R.J., Rihal, C.S. and Prasad, A., 2010. Left anterior descending artery length and coronary atherosclerosis in apical ballooning syndrome (Takotsubo/stress induced cardiomyopathy). International journal of cardiology, 145(1), pp.112-115. https://doi.org/10.1016/j.ijcard.2009.06.018
11Shams, Y. and Henareh, L., 2013. Spontaneous coronary artery dissection triggered post-ischemic myocardial stunning and takotsubo syndrome: two different names for the same condition. Cardiovascular Revascularization Medicine, 14(2), pp.109-112. https://doi.org/10.1016/j.carrev.2012.11.00510.1016/j.carrev.2012.11.005
12El Mahmoud, R., Mansencal, N., Pilliére, R., Leyer, F., Abbou, N., Michaud, P., Nallet, O., Digne, F., Lacombe, P., Cattan, S. and Dubourg, O., 2008. Prevalence and characteristics of left ventricular outflow tract obstruction in Tako-Tsubo syndrome. American Heart Journal, 156(3), pp.543-548. https://doi-org.access.library.unisa.edu.au/10.1016/j.ahj.2008.05.002
13Lyon, A.R., Rees, P.S., Prasad, S., Poole-Wilson, P.A. and Harding, S.E., 2008. Stress (Takotsubo) cardiomyopathy—a novel pathophysiological hypothesis to explain catecholamine-induced acute myocardial stunning. Nature Reviews Cardiology, 5(1), p.22.
14Nguyen, T.H., Neil, C.J., Sverdlov, A.L., Ngo, D.T., Chan, W.P., Heresztyn, T., Chirkov, Y.Y., Tsikas, D., Frenneaux, M.P. and Horowitz, J.D., 2013. Enhanced NO signaling in patients with Takotsubo cardiomyopathy: short-term pain, long-term gain?. Cardiovascular drugs and therapy27(6), pp.541-547.
15Surikow, S.Y., Nguyen, T.H., Stafford, I., Chapman, M., Chacko, S., Singh, K., Licari, G., Raman, B., Kelly, D.J., Zhang, Y. and Waddingham, M.T., 2018. Nitrosative stress as a modulator of inflammatory change in a model of Takotsubo syndrome. JACC: Basic to Translational Science3(2), pp.213-226.
16Couch, L.S. and Harding, S.E., 2018. Takotsubo Syndrome: Stress or NO Stress? JACC Basic Transl Sci. Apr; 3(2): 227–229. 10.1016/j.jacbts.2018.03.002
17Neil, C., Nguyen, T.H., Kucia, A., Crouch, B., Sverdlov, A., Chirkov, Y., Mahadavan, G., Selvanayagam, J., Dawson, D., Beltrame, J. and Zeitz, C., 2012. Slowly resolving global myocardial inflammation/oedema in Tako-Tsubo cardiomyopathy: evidence from T2-weighted cardiac MRI. Heart98(17), pp.1278-1284.
18Schwarz, K., Ahearn, T., Srinivasan, J., Neil, C.J., Scally, C., Rudd, A., Jagpal, B., Frenneaux, M.P., Pislaru, C., Horowitz, J.D. and Dawson, D.K., 2017. Alterations in cardiac deformation, timing of contraction and relaxation, and early myocardial fibrosis accompany the apparent recovery of acute stress-induced (takotsubo) cardiomyopathy: an end to the concept of transience. Journal of the American Society of Echocardiography30(8), pp.745-755.
19Templin, C., Hänggi, J., Klein, C., Topka, M.S., Hiestand, T., Levinson, R.A., Jurisic, S., Lüscher, T.F., Ghadri, J.R. and Jäncke, L., 2019. Altered limbic and autonomic processing supports brain-heart axis in Takotsubo syndrome. European Heart Journal, Vol.40(15), p.1183-1187 10.1093/eurheartj/ehz068