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Age-Related Variations in Takotsubo Syndrome
Victoria L. Cammann, Konrad A. Szawan, Barbara E. Stähli, Ken Kato, Monika Budnik, Manfred Wischnewsky, Sara Dreiding, Rena A. Levinson, Davide Di Vece, Sebastiano Gili, Rodolfo Citro, Eduardo Bossone, Michael Neuhaus, Jennifer Franke, Benjamin Meder, Miłosz Jaguszewski, Michel Noutsias, Maike Knorr, Susanne Heiner, Fabrizio D’Ascenzo, Wolfgang Dichtl, Christof Burgdorf, Behrouz Kherad, Carsten Tschöpe, Annahita Sarcon, Jerold Shinbane, Lawrence Rajan, Guido Michels, Roman Pfister, Alessandro Cuneo, Claudius Jacobshagen, Mahir Karakas, Wolfgang Koenig, Alexander Pott, Philippe Meyer, Marco Roffi, Adrian Banning, Mathias Wolfrum, Florim Cuculi, Richard Kobza, Thomas A. Fischer, Tuija Vasankari, K.E. Juhani Airaksinen, L. Christian Napp, Rafal Dworakowski, Philip MacCarthy, Christoph Kaiser, Stefan Osswald, Leonarda Galiuto, Christina Chan, Paul Bridgman, Daniel Beug, Clément Delmas, Olivier Lairez, Ekaterina Gilyarova, Alexandra Shilova, Mikhail Gilyarov, Ibrahim El-Battrawy, Ibrahim Akin, Karolina Poledniková, Petr Toušek, David E. Winchester, Jan Galuszka, Christian Ukena, Gregor Poglajen, Pedro Carrilho-Ferreira, Christian Hauck, Carla Paolini, Claudio Bilato, Yoshio Kobayashi, Toshihiro Shoji, Iwao Ishibashi, Masayuki Takahara, Toshiharu Himi, Jehangir Din, Ali Al-Shammari, Abhiram Prasad, Charanjit S. Rihal, Kan Liu, P. Christian Schulze, Matteo Bianco, Lucas Jörg, Hans Rickli, Gonçalo Pestana, Thanh H. Nguyen, Michael Böhm, Lars S. Maier, Fausto J. Pinto, Petr Widimský, Stephan B. Felix, Ruediger C. Braun-Dullaeus, Wolfgang Rottbauer, Gerd Hasenfuß, Burkert M. Pieske, Heribert Schunkert, Martin Borggrefe, Holger Thiele, Johann Bauersachs, Hugo A. Katus, John D. Horowitz, Carlo Di Mario, Thomas Münzel, Filippo Crea, Jeroen J. Bax, Thomas F. Lüscher, Frank Ruschitzka, Jelena R. Ghadri, Grzegorz Opolski and Christian Templin
Summary By: Adriana C. Mares - Founder & President, The Institute of Cardiology at El Paso
Overall Study Question:
Are there any age-related differences in clinical outcomes for patients with Takotsubo Syndrome (TTS) enrolled in the International Takotsubo Registry (ITR)?
Study Summary:
From 2011 to 2017, investigators enrolled over 2, 000 patients diagnosed with TTS in the ITR within 36 sites and 11 countries. Investigators analyzed and stratified the study population into three groups based on their age (younger: ≤50 years, middle-age: 51-74 years, elderly: ≥75 years). As well, baseline characteristics, hospital course, along with short- and long-term mortality were compared among groups. Kaplan-Meier estimates were used to analyze all-cause mortality, and the log-rank test was executed for group comparisons. Furthermore, a landmark analysis with a landmark set at 60 days was conducted to investigate long-term mortality beyond the acute phase (Mukherjee, 2020).
Of 2,098 TTS patients, 242 (11.5%) patients were ≤50 years of age, 1,194 (56.9%) were 51-74 years of age, and 662 (31.6%) were ≥75 years of age. Although the population was predominantly female, younger patients were more often men (12.4% vs. 10.9% vs. 6.3%; p = 0.002) and had an increased prevalence of acute neurological disorders (16.3% vs. 8.4% vs. 8.8%; p = 0.001) or psychiatric disorders (14.1% vs. 10.3% vs. 5.6%; p < 0.001) compared with middle-aged and elderly TTS patients. Furthermore, younger patients more often had cardiogenic shock that required inotropes and ventilator support (15.3% vs. 9.1% vs. 8.1%; p = 0.004) and had a numerically higher in-hospital mortality (6.6% vs. 3.6% vs. 5.1%; p = 0.07); which was not significant at multivariate analysis. According to the authors, younger patients with TTS have a significant high risk of developing severe complications such as acute neurological disorders, psychiatric disorders, and cardiogenic shock that require intensive care compared with middle-aged and elderly TTS patients ( Cammann, 2020; Mukherjee, 2020).
My Insights:
TTS was once mistaken as acute myocardial infarction and is, now, predominantly known to manifest in 90% of cases in women with a mean age of 65 to 75 years old (Wang, 2020). This study recognized that TTS is just as existent in male as in female patients. As noted in the editorial comment of this paper, the exact pathophysiological mechanism remains uncertain however four stages could represent the pathophysiological and mechanistic roles of sympathetic nervous system (SNS) activation, catecholamine overload, and the brain-heart connection in patients with TTS ( Wang, 2020; Fuster, 2020).
As investigators concluded that younger patients enrolled in ITR had a higher prevalence for acute neurological disorders compared with middle-aged and elderly TTS patients, it brings awareness to how there is a difference in clinical outcomes based on age and sex. Thus, clinicians must be appropriately informed to promptly monitor the status of TTS in this young patient population as they could present with high degree of complications via a sympathetic storm, microvascular dysfunction, and/or acute myocardial stunning.
Age-Related Variations in Takotsubo Syndrome
Victoria L. Cammann, Konrad A. Szawan, Barbara E. Stähli, Ken Kato, Monika Budnik, Manfred Wischnewsky, Sara Dreiding, Rena A. Levinson, Davide Di Vece, Sebastiano Gili, Rodolfo Citro, Eduardo Bossone, Michael Neuhaus, Jennifer Franke, Benjamin Meder, Miłosz Jaguszewski, Michel Noutsias, Maike Knorr, Susanne Heiner, Fabrizio D’Ascenzo, Wolfgang Dichtl, Christof Burgdorf, Behrouz Kherad, Carsten Tschöpe, Annahita Sarcon, Jerold Shinbane, Lawrence Rajan, Guido Michels, Roman Pfister, Alessandro Cuneo, Claudius Jacobshagen, Mahir Karakas, Wolfgang Koenig, Alexander Pott, Philippe Meyer, Marco Roffi, Adrian Banning, Mathias Wolfrum, Florim Cuculi, Richard Kobza, Thomas A. Fischer, Tuija Vasankari, K.E. Juhani Airaksinen, L. Christian Napp, Rafal Dworakowski, Philip MacCarthy, Christoph Kaiser, Stefan Osswald, Leonarda Galiuto, Christina Chan, Paul Bridgman, Daniel Beug, Clément Delmas, Olivier Lairez, Ekaterina Gilyarova, Alexandra Shilova, Mikhail Gilyarov, Ibrahim El-Battrawy, Ibrahim Akin, Karolina Poledniková, Petr Toušek, David E. Winchester, Jan Galuszka, Christian Ukena, Gregor Poglajen, Pedro Carrilho-Ferreira, Christian Hauck, Carla Paolini, Claudio Bilato, Yoshio Kobayashi, Toshihiro Shoji, Iwao Ishibashi, Masayuki Takahara, Toshiharu Himi, Jehangir Din, Ali Al-Shammari, Abhiram Prasad, Charanjit S. Rihal, Kan Liu, P. Christian Schulze, Matteo Bianco, Lucas Jörg, Hans Rickli, Gonçalo Pestana, Thanh H. Nguyen, Michael Böhm, Lars S. Maier, Fausto J. Pinto, Petr Widimský, Stephan B. Felix, Ruediger C. Braun-Dullaeus, Wolfgang Rottbauer, Gerd Hasenfuß, Burkert M. Pieske, Heribert Schunkert, Martin Borggrefe, Holger Thiele, Johann Bauersachs, Hugo A. Katus, John D. Horowitz, Carlo Di Mario, Thomas Münzel, Filippo Crea, Jeroen J. Bax, Thomas F. Lüscher, Frank Ruschitzka, Jelena R. Ghadri, Grzegorz Opolski and Christian Templin
Summary By: Adriana C. Mares - Founder & President, The Institute of Cardiology at El Paso
Overall Study Question:
Are there any age-related differences in clinical outcomes for patients with Takotsubo Syndrome (TTS) enrolled in the International Takotsubo Registry (ITR)?
Study Summary:
From 2011 to 2017, investigators enrolled over 2, 000 patients diagnosed with TTS in the ITR within 36 sites and 11 countries. Investigators analyzed and stratified the study population into three groups based on their age (younger: ≤50 years, middle-age: 51-74 years, elderly: ≥75 years). As well, baseline characteristics, hospital course, along with short- and long-term mortality were compared among groups. Kaplan-Meier estimates were used to analyze all-cause mortality, and the log-rank test was executed for group comparisons. Furthermore, a landmark analysis with a landmark set at 60 days was conducted to investigate long-term mortality beyond the acute phase (Mukherjee, 2020).
Of 2,098 TTS patients, 242 (11.5%) patients were ≤50 years of age, 1,194 (56.9%) were 51-74 years of age, and 662 (31.6%) were ≥75 years of age. Although the population was predominantly female, younger patients were more often men (12.4% vs. 10.9% vs. 6.3%; p = 0.002) and had an increased prevalence of acute neurological disorders (16.3% vs. 8.4% vs. 8.8%; p = 0.001) or psychiatric disorders (14.1% vs. 10.3% vs. 5.6%; p < 0.001) compared with middle-aged and elderly TTS patients. Furthermore, younger patients more often had cardiogenic shock that required inotropes and ventilator support (15.3% vs. 9.1% vs. 8.1%; p = 0.004) and had a numerically higher in-hospital mortality (6.6% vs. 3.6% vs. 5.1%; p = 0.07); which was not significant at multivariate analysis. According to the authors, younger patients with TTS have a significant high risk of developing severe complications such as acute neurological disorders, psychiatric disorders, and cardiogenic shock that require intensive care compared with middle-aged and elderly TTS patients ( Cammann, 2020; Mukherjee, 2020).
My Insights:
TTS was once mistaken as acute myocardial infarction and is, now, predominantly known to manifest in 90% of cases in women with a mean age of 65 to 75 years old (Wang, 2020). This study recognized that TTS is just as existent in male as in female patients. As noted in the editorial comment of this paper, the exact pathophysiological mechanism remains uncertain however four stages could represent the pathophysiological and mechanistic roles of sympathetic nervous system (SNS) activation, catecholamine overload, and the brain-heart connection in patients with TTS ( Wang, 2020; Fuster, 2020).
- Stage I- There is significant evidence that acute myocardial stunning observed in this syndrome following physical or emotional stress is the result of the sympathetic remediated microvascular dysfunction.
- Stage II- The predominance of TTS in women could be explained by how resting sympathetic nervous activity increases with age. Older individuals demonstrate augmented cardiac sympathetic stimulation due to the increase of noradrenaline and impaired noradrenaline neuronal reuptake. As well, there are significant decreases in cardiac vagal tone and baroreceptor sensitivity with a concomitant decrease in sympathetic activation. Perhaps more important is that estrogens can attenuate the sympathetic response to mental stress and regulate endothelial function and vasomotor tone up regulating endothelial nitric oxide synthase activity. All of these factors may be dysregulated because of estrogen level decrease in women as they age.
- Stage III - Sympathetic tone may be correlated with microvascular function related to the microvascular tone. There are four possible sections to categorize risk of TTS:
- High risk group – Postmenopausal women who have both increase in sympathetic tone and microvascular dysfunction.
- Low risk group- Young and healthy population who have low sympathetic tone and an appropriate microvascular function.
- Medium risk- Middle age population including perimenopausal women who may have risk factors for cardiovascular disease and microvascular dysfunction, but have appropriate sympathetic tone.
- Medium risk- Young middle age population with high sympathetic tone and some degree of depression taking medications such as serotonin, norepinephrine reuptake inhibitors that help increase the activity of these two molecules in the brain and periphery.
- Stage IV- Although group two is classified to having the lowest risk to developing TTS, when they actually develop it there is a severe clinical presentation with an increase of sympathetic stimulation (storm) that ultimately results in a more severe clinical presentation. It is a storm that not only manifest the disease but manifests with worse complications of the disease requiring intensive care.
As investigators concluded that younger patients enrolled in ITR had a higher prevalence for acute neurological disorders compared with middle-aged and elderly TTS patients, it brings awareness to how there is a difference in clinical outcomes based on age and sex. Thus, clinicians must be appropriately informed to promptly monitor the status of TTS in this young patient population as they could present with high degree of complications via a sympathetic storm, microvascular dysfunction, and/or acute myocardial stunning.
References
Cammann VL, Szawan KA, Stähli BE, Kato K, Budnik M, Wischnewsky M, et al. Age-Related Variations in Takotsubo Syndrome. J Am Coll Cardiol. 2020;75(16):1869-77. Doi: 10.1016/j.jacc.2020.02.057
Mukherjee DP. Age-Related Variations in Takotsubo Syndrome. https://www.acc.org/latest-in-cardiology/journal-scans/2020/04/22/15/17/age-related-variations-in-takotsubo. Published April 22, 2020. Accessed April 25, 2020
Fuster V. Apple Podcasts Preview. Apple Podcasts Preview. April 2020. https://podcasts.apple.com/us/podcast/age-related-variations-in-takotsubo-syndrome/id932118437?i=1000472091405
Wang X, Pei J, Hu X. The Brain-Heart Connection in Takotsubo Syndrome: The Central Nervous System, Sympathetic Nervous System, and Catecholamine Overload. Cardiol Res Pract. 2020;2020:4150291. Published 2020 Mar 9. doi:10.1155/2020/4150291
Back to other Article Summaries
Cammann VL, Szawan KA, Stähli BE, Kato K, Budnik M, Wischnewsky M, et al. Age-Related Variations in Takotsubo Syndrome. J Am Coll Cardiol. 2020;75(16):1869-77. Doi: 10.1016/j.jacc.2020.02.057
Mukherjee DP. Age-Related Variations in Takotsubo Syndrome. https://www.acc.org/latest-in-cardiology/journal-scans/2020/04/22/15/17/age-related-variations-in-takotsubo. Published April 22, 2020. Accessed April 25, 2020
Fuster V. Apple Podcasts Preview. Apple Podcasts Preview. April 2020. https://podcasts.apple.com/us/podcast/age-related-variations-in-takotsubo-syndrome/id932118437?i=1000472091405
Wang X, Pei J, Hu X. The Brain-Heart Connection in Takotsubo Syndrome: The Central Nervous System, Sympathetic Nervous System, and Catecholamine Overload. Cardiol Res Pract. 2020;2020:4150291. Published 2020 Mar 9. doi:10.1155/2020/4150291
Back to other Article Summaries