European Heart Journal

Kotecha, Tushar; Knight, Daniel S; Razvi, Yousuf; Kumar, Kartik; Vimalesvaran, Kavitha; Thornton, George; Patel, Rishi; Chacko, Liza; Brown, James T; Coyle, Clare; Leith, Donald; Shetye, Abhishek; Ariff, Ben; Bell, Robert; Captur, Gabriella; Coleman, Meg; Goldring, James; Gopalan, Deepa; Heightman, Melissa; Hillman, Toby; Howard, Luke; Jacobs, Michael; Jeetley, Paramjit S; Kanagaratnam, Prapa; Kon, Onn Min; Lamb, Lucy E; Manisty, Charlotte H; Mathurdas, Palmira; Mayet, Jamil; Negus, Rupert; Patel, Niket; Pierce, Iain; Russell, Georgina; Wolff, Anthony; Xue, Hui; Kellman, Peter; Moon, James C; Treibel, Thomas A; Cole, Graham D; Fontana, Marianna

doi: 10.1093/eurheartj/ehab075pmid: 33596594

BackgroundTroponin elevation is common in hospitalized COVID-19 patients, but underlying aetiologies are ill-defined. We used multi-parametric cardiovascular magnetic resonance (CMR) to assess myocardial injury in recovered COVID-19 patients.Methods and resultsOne hundred and forty-eight patients (64 ± 12 years, 70% male) with severe COVID-19 infection [all requiring hospital admission, 48 (32%) requiring ventilatory support] and troponin elevation discharged from six hospitals underwent convalescent CMR (including adenosine stress perfusion if indicated) at median 68 days. Left ventricular (LV) function was normal in 89% (ejection fraction 67% ± 11%). Late gadolinium enhancement and/or ischaemia was found in 54% (80/148). This comprised myocarditis-like scar in 26% (39/148), infarction and/or ischaemia in 22% (32/148) and dual pathology in 6% (9/148). Myocarditis-like injury was limited to three or less myocardial segments in 88% (35/40) of cases with no associated LV dysfunction; of these, 30% had active myocarditis. Myocardial infarction was found in 19% (28/148) and inducible ischaemia in 26% (20/76) of those undergoing stress perfusion (including 7 with both infarction and ischaemia). Of patients with ischaemic injury pattern, 66% (27/41) had no past history of coronary disease. There was no evidence of diffuse fibrosis or oedema in the remote myocardium (T1: COVID-19 patients 1033 ± 41 ms vs. matched controls 1028 ± 35 ms; T2: COVID-19 46 ± 3 ms vs. matched controls 47 ± 3 ms).ConclusionsDuring convalescence after severe COVID-19 infection with troponin elevation, myocarditis-like injury can be encountered, with limited extent and minimal functional consequence. In a proportion of patients, there is evidence of possible ongoing localized inflammation. A quarter of patients had ischaemic heart disease, of which two-thirds had no previous history. Whether these observed findings represent pre-existing clinically silent disease or de novo COVID-19-related changes remain undetermined. Diffuse oedema or fibrosis was not detected.

Dweck, Marc R

doi: 10.1093/eurheartj/ehaa1106pmid: 33462579

Graphical abstract Open in new tabDownload slide In a single scan, multisystem 18F-FDG-PET imaging allows simultaneous interrogation of vascular inflammation, psychological stress, and bone marrow activation following myocardial infarction. Moderate associations are observed between 18F-FDG activity in these disparate organ systems; however, further work is now required to assess the causality and directionality or these associations. Several potential pathways that might exist in isolation or in combination to explain these associations are outlined Graphical abstract Open in new tabDownload slide In a single scan, multisystem 18F-FDG-PET imaging allows simultaneous interrogation of vascular inflammation, psychological stress, and bone marrow activation following myocardial infarction. Moderate associations are observed between 18F-FDG activity in these disparate organ systems; however, further work is now required to assess the causality and directionality or these associations. Several potential pathways that might exist in isolation or in combination to explain these associations are outlined This editorial refers to ‘Stress-associated neurobiological activity is linked with acute plaque instability via enhanced macrophage activity: a prospective serial 18F-FDG-PET/CT imaging assessment’, by J.W. Kim et al., doi:10.1093/eurheartj/ehaa1095. Molecular cardiovascular positron emission tomography (PET) imaging is a rapidly developing and exciting field. Modern scanners and image processing techniques now allow the non-invasive assessment of disease activity in the cardiovascular system, providing complementary information to the anatomic and functional information provided by computed tomography (CT), cardiovascular magnetic resonance (CMR), and echocardiography. In principle, the activity of any biological process can be targeted. Indeed, a wide range of tracers have recently become available in humans, allowing assessment of inflammation, calcification, fibrosis, and platelet activity.1,2 This has major potential to improve our pathological understanding of disease but also to impact clinical care: molecular PET imaging now plays a central role in the clinical assessment of patients with cardiac sarcoidosis, prosthetic valve endocarditis, and cardiac device infection. For many years [18F]fluorodeoxyglucose (18F-FDG) was the predominant, indeed the only, molecular tracer in this field. A glucose analogue, 18F-FDG accumulates in cells and tissues according to their glycolytic requirements. Uptake in cancer cells is high, underlying its widespread use in oncology imaging. In the cardiovascular system 18F-FDG has been used as a marker of inflammation, on the basis that inflammatory cells use more glucose than surrounding cells. However, glucose is also the preferred energy source for the myocardium, which frequently obscures pathological 18F-FDG uptake in the heart, leading many investigators to seek more specific inflammatory tracers. In the manuscript by Kim et al. published in this issue of the European Heart Journal, the authors have elegantly harnessed 18F-FDG’s low specificity to their advantage, turning this apparent weakness into a strength.3 Indeed, on a single scan and with a single tracer, the authors were able to simultaneously assess carotid artery inflammation, amygdala activity in the brain (as a marker of emotional stress), and haemopoietic activity in the bone marrow, providing key insights into the concordant activity of these disparate organ systems following acute myocardial infarction (MI). This builds on the pioneering work by Ahmed Tawakol’s lab that first used this multisystem PET imaging approach in patients with stable coronary artery disease and proposed a pathway of emotional stress causing increased haemopoietic activity, the release of macrophages, and increased plaque inflammation.4 Kim et al. performed 18F-FDG-PET/CT imaging in 45 patients within 45 days of their myocardial infarct, alongside 17 control patients of similar age. 18F-FDG activity was higher in acute MI patients than controls in the amygdala, bone marrow, and carotid artery, and these correlated moderately with each other (r values between 0.35 and 0.47). Ten MI patients were rescanned after 6 months when 18F-FDG levels in each organ system had returned to baseline and the levels observed in controls. The study therefore demonstrates the concordant up-regulation of glucose utilization across these organ systems following MI and their concurrent return to baseline with time. It therefore adds to our growing appreciation of the complex interdependence of the cardiovascular system with the rest of the body and the growing need to investigate cardiac disorders in that wider context. The authors conclude that their results suggest psychological stress is linked to plaque instability via macrophage activation and that this pathway could be the targeted to prevent MI. This is possible; however, this observational study cannot inform us as to the direction of the associations observed nor establish causality. Indeed, it would seem equally plausible that myocardial inflammation induces psychological stress, and haemopoeitic activity leading to the observation of increased plaque inflammation (Graphical abstract). A similar pathway has been established in mouse models5 and fits better with the delayed time points at which the initial 18F-FDG-PET scans were performed following MI. This classic chicken and egg conundrum is in truth difficult to disentangle. Ideally it would require 18F-FDG-PET scans performed both before and after MI, a highly challenging task given the unpredictable nature of plaque rupture events.6 One potential method would be to image patients before and after the predictable iatrogenic MI induced by alcohol septal ablation performed in patients with hypertrophic cardiomyopathy. Studies to this effect are currently underway. The study by Kim et al. has other limitations including the small sample size and relatively long delay between infarction and imaging, during which the anti-inflammatory effects of drugs such as statins may have had an effect. Moreover, the study did not investigate cardiac inflammation at the site of infarction, which may have provided additional insights as to the direction of the observed associations. Nevertheless, this study underlines the potential value of multisystem 18F-FDG-PET imaging as a method for interrogating the association of atherosclerotic inflammation with activity in other organ systems. Future studies should aim to elucidate the directionality of these associations and test the hypothesis that reductions in psychological stress may aid in the recovery from MI and in the prevention of future and recurrent cardiac events. Conflict of interest: none declared. References 1 Dweck MR , Chow MWL , Joshi NV , Williams MC , Jones C , Fletcher AM , Richardson H , White A , McKillop G , van Beek EJR , Boon NA , Rudd JHF , Newby DE. Coronary arterial 18F-sodium fluoride uptake . J Am Coll Cardiol 2012 ; 59 : 1539 – 1548 . Google Scholar Crossref Search ADS PubMed WorldCat 2 Jenkins WSA , Vesey AT , Stirrat C , Connell M , Lucatelli C , Neale A , Moles C , Vickers A , Fletcher A , Pawade T , Wilson I , Rudd JHF , van Beek EJR , Mirsadraee S , Dweck MR , Newby DE. Cardiac αVβ3 integrin expression following acute myocardial infarction in humans . Heart 2017 ; 103 : 607 – 615 . Google Scholar Crossref Search ADS PubMed WorldCat 3 Kang DO ., Eo JS, Park EJ, Nam HS, Song JW, Park YH, Park SY, Na JO, Choi CU, Kim EJ, Rha S-W, Park CG, Seo HS, Kim CK, Yoo H, Kim JW, X. Stress-associated neurobiological activity is linked with acute plaque instability via enhanced macrophage activity: a prospective serial 18F-FDG-PET/CT imaging assessment . Eur Heart J 2021 ;doi:10.1093/eurheartj/ehaa1095. Google Scholar OpenURL Placeholder Text WorldCat 4 Tawakol A , Ishai A , Takx RA , Figueroa AL , Ali A , Kaiser Y , Truong QA , Solomon CJ , Calcagno C , Mani V , Tang CY , Mulder WJ , Murrough JW , Hoffmann U , Nahrendorf M , Shin LM , Fayad ZA , Pitman RK. Relation between resting amygdalar activity and cardiovascular events: a longitudinal and cohort study . Lancet 2017 ; 389 : 834 – 845 . Google Scholar Crossref Search ADS PubMed WorldCat 5 Dutta P , Courties G , Wei Y , Leuschner F , Gorbatov R , Robbins CS , Iwamoto Y , Thompson B , Carlson AL , Heidt T , Majmudar MD , Lasitschka F , Etzrodt M , Waterman P , Waring MT , Chicoine AT , van der Laan AM , Niessen HWM , Piek JJ , Rubin BB , Butany J , Stone JR , Katus HA , Murphy SA , Morrow DA , Sabatine MS , Vinegoni C , Moskowitz MA , Pittet MJ , Libby P , Lin CP , Swirski FK , Weissleder R , Nahrendorf M. Myocardial infarction accelerates atherosclerosis . Nature 2012 ; 487 : 325 – 329 . Google Scholar Crossref Search ADS PubMed WorldCat 6 Joshi NV , Toor I , Shah ASV , Carruthers K , Vesey AT , Alam SR , Sills A , Hoo TY , Melville AJ , Langlands SP , Jenkins WSA , Uren NG , Mills NL , Fletcher AM , van Beek EJR , Rudd JHF , Fox KAA , Dweck MR , Newby DE. Systemic atherosclerotic inflammation following acute myocardial infarction: myocardial infarction begets myocardial infarction . J Am Heart Assoc 2015 ; 4 : e001956 . Google Scholar Crossref Search ADS PubMed WorldCat The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Radfar, Azar; Abohashem, Shady; Osborne, Michael T; Wang, Ying; Dar, Tawseef; Hassan, Malek Z O; Ghoneem, Ahmed; Naddaf, Nicki; Patrich, Tomas; Abbasi, Taimur; Zureigat, Hadil; Jaffer, James; Ghazi, Parastou; Scott, James A; Shin, Lisa M;

Suzuki, Hideaki; Yasuda, Satoshi; Shimokawa, Hiroaki

doi: 10.1093/eurheartj/ehab026pmid: 33532845

This editorial refers to ‘Stress-associated neurobiological activity associates with the risk for and timing of subsequent takotsubo syndrome’, by A. Radfar et al., doi:10.1093/eurheartj/ehab029. A brain–heart connection has been long proposed as a critical factor for development of Takotsubo syndrome (TTS), also known as ‘stress-induced cardiomyopathy’.1 As physical and mental stress preceded the majority of cases in TTS,2 stress-associated brain regions, such as the limbic system (the insula, the hippocampus, the amygdala, etc.), the ventromedial prefrontal cortex (vmPFC), and the brainstem have been hypothesized as neural substrates in TTS pathogenesis.3–10 This notion is also consistent with the catecholamine hypothesis for TTS1 because sympathetic activity is augmented by increased activity of the stress-associated regions, which largely overlap with brain autonomic centres.3 In a review of 569 consecutive patients who were admitted within 24 h after the onset of an acute ischaemic stroke, including seven TTS patients, insular damage was demonstrated as a predominant feature in TTS.4 Lesions of the brainstem, which has autonomic centres, such as the solitary nucleus and rostral ventromedial medulla, relate to TTS onset in relapses of multiple sclerosis.5,6 These neurological cases support the notion that damage of the limbic system and the brainstem is associated with development of TTS. Brain single-photon emission computed tomography shows that brain activity, including the hippocampus and the brainstem, is increased at 1–4 days after TTS onset.7 This abnormal brain activation is relieved but remains to some extent even after full recovery of cardiac wall motion abnormalities (28–39 days after onset).7 In contrast, activity of the vmPFC is reduced through both acute and chronic phases of TTS.7 Analysis of brain structural and functional magnetic resonance images demonstrate that atrophy of the insula and the amygdala and their altered connectivity with other brain regions, including the vmPFC and the hippocampus, are found in TTS patients as compared with controls even at 1 year after onset.8,9 These neuroimaging findings after TTS onset suggest a long-lasting psychological stress in TTS as well as the association of abnormal neural activity with development of TTS.8,9 The study by Radfar et al., published in this issue of the European Heart Journal,10 is the first to assess cerebral [18F]fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) prior to the onset of TTS. The amygdala activity (AmygA) was measured retrospectively and manually in 104 patients (median age 67.5 years, 72% female, 86% with malignancy) who underwent clinical 18F-FDG-PET/CT imaging, including 41 who subsequently developed TTS (median 2.2 years after imaging) and 63 matched controls. Patients with subsequent TTS had higher baseline AmygA after adjusting for TTS risk factors (P = 0.038). Higher AmygA was associated with greater odds for developing TTS in adjusted regression analyses [standardized odds ratio (OR) 1.64, 95% confidence interval (CI) 1.03–2.61, P = 0.036] and independently predicted subsequent onset of TTS after adjustment for TTS risk factors [standardized hazard ratio (HR) 1.643, 95% CI 1.189–2.270, P = 0.003]. Among the patients who developed TTS, those with higher AmygA (>mean 1 SD) developed TTS ∼2 years earlier compared with those with lower AmygA (β –2.72, 95% CI –5.12 to –0.32, P = 0.028). These relationships between AmygA and TTS were even robust after adjusting for activity of the vmPFC, which has an important role in reducing stress responses.3 Although having intrinsic limitations of retrospective and manual (not automated, not whole-brain) analysis, these findings by Radfar et al. shed light on the brain–heart connection representing a neurobiological mechanism of TTS development3–10 (Graphical abstract). Graphical abstract Open in new tabDownload slide Possible involvement of brain–heart connection for the onset of Takotsubo syndrome. Under abnormal activity and connectivity of the stress/autonomic brain regions, emotional and/or physical stressors may induce exaggerated systemic responses, leading to development of Takotsubo syndrome. The picture of the brain is from the magnetic resonance imaging template available in the free software SPM12. The left ventriculogram of a patient with Takotsubo syndrome is from Suzuki et al.7 vmPFC, ventromedial prefrontal cortex. Graphical abstract Open in new tabDownload slide Possible involvement of brain–heart connection for the onset of Takotsubo syndrome. Under abnormal activity and connectivity of the stress/autonomic brain regions, emotional and/or physical stressors may induce exaggerated systemic responses, leading to development of Takotsubo syndrome. The picture of the brain is from the magnetic resonance imaging template available in the free software SPM12. The left ventriculogram of a patient with Takotsubo syndrome is from Suzuki et al.7 vmPFC, ventromedial prefrontal cortex. The work by Radfar et al. raises the possibily of at least two future directions. First, it still remains unclear whether AmygA and/or activity of other stress/autonomic-associated brain regions are also associated with relapse of TTS. The rate of recurrence of TTS is 1.8% per patient-year, with a span of 25 days to 9.2 years after the first event.2 One interesting study reports that mental stress evokes regional cardiac wall motion changes (perfusion defects and/or wall motion abnormality) in 16 out of 22 TTS patients at 1 month after onset, while none of 11 controls has stress-induced abnormalities.11 Three patients who have abnormal cardiac response to mental stress experienced TTS recurrence at an interval of 6 ± 4 months.11 It would be worth examining whether patients with abnormal activity of stress/autonomic-associated brain regions have a higher recurrence rate of TTS. Second, no therapeutic option is currently available for the abnormal brain activity in TTS patients. Improvement in symptoms of post-traumatic stress disorder by cognitive behavioural therapy is associated with reduced AmygA,12 indicating that an intervention to stress and resultant improvement in abnormal activity of stress/autonomic-associated brain regions may be effective for decreasing the risk of TTS development. Finally, the heart–brain connection is not a specific phenomenon of TTS but is widely noted in patients with cardiovascular diseases. Increased AmygA may also predict the risk of other stress-related cardiovascular and metabolic diseases.13 The activity of the hippocampus, which is lower in patients with chronic heart failure, is associated with depression and cognitive impairment.14 Chronic heart failure patients with higher hippocampal activity may also experience more advanced cardiac remodelling as compared with those with lower hippocampal activity.15 Heightened stress-associated neural activity may represent a therapeutic target to reduce TTS as well as other stress-related cardiovascular diseases, including chronic heart failure. Funding This work was supported by grants from the Japan Society for the Promotion of Science (20K07776). Conflict of interest: H. Suzuki and H. Shimokawa have no conflicts of interest to declare. S.Y. reports grants from Takeda and Abbott, and personal fees from Daiichi-Sankyo and Bristol-Myers Squibb, outside the submitted work. The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology. References 1 Akashi YJ , Goldstein DS, Barbaro G, Ueyama T. Takotsubo cardiomyopathy: a new form of acute, reversible heart failure . Circulation 2008 ; 118 : 2754 – 2762 . 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Neural regulation of endocrine and autonomic stress responses . Nat Rev Neurosci 2009 ; 10 : 397 – 409 . Google Scholar Crossref Search ADS PubMed WorldCat 4 Yoshimura S , Toyoda K, Ohara T, Nagasawa H, Ohtani N, Kuwashiro T, Naritomi H, Minematsu K. Takotsubo cardiomyopathy in acute ischemic stroke . Ann Neurol 2008 ; 64 : 547 – 554 . Google Scholar Crossref Search ADS PubMed WorldCat 5 Kozu K , Suzuki H, Nishiyama S, Yaoita N, Yamamoto S, Tatebe S, Miura M, Aoki T, Hao K, Matsumoto Y, Sugimura K, Aoki M, Shimokawa H. Multiple sclerosis lesion in the medulla oblongata in a patient with takotsubo cardiomyopathy . Int J Cardiol 2016 ; 222 : 980 – 981 . Google Scholar Crossref Search ADS PubMed WorldCat 6 Androdias G , Bernard E, Biotti D, Collongues N, Durand-Dubief F, Pique J, Sanchez I, Delmas C, Ninet J, Marignier R, Vukusic S. Multiple sclerosis broke my heart . Ann Neurol 2017 ; 81 : 754 – 758 . Google Scholar Crossref Search ADS PubMed WorldCat 7 Suzuki H , Matsumoto Y, Kaneta T, Sugimura K, Takahashi J, Fukumoto Y, Takahashi S, Shimokawa H. Evidence for brain activation in patients with takotsubo cardiomyopathy . Circ J 2014 ; 78 : 256 – 258 . Google Scholar Crossref Search ADS PubMed WorldCat 8 Hiestand T , Hänggi J, Klein C, Topka MS, Jaguszewski M, Ghadri JR, Lüscher TF, Jäncke L, Templin C. Takotsubo syndrome associated with structural brain alterations of the limbic system . J Am Coll Cardiol 2018 ; 71 : 809 – 811 . Google Scholar Crossref Search ADS PubMed WorldCat 9 Templin C , Hänggi J, Klein C, Topka MS, Hiestand T, Levinson RA, Jurisic S, Lüscher TF, Ghadri JR, Jäncke L. Altered limbic and autonomic processing supports brain–heart axis in Takotsubo syndrome . Eur Heart J 2019 ; 40 : 1183 – 1187 . Google Scholar Crossref Search ADS PubMed WorldCat 10 Radfar A , Abohashem S, Osborne MT, Wang Y, Dar T, Hassan MZO, Ghoneem A, Naddaf N, Patrich T, Abbasi T, Zureigat H, Jaffer J, Ghazi P, Scott JA, Shin LM, Pitman RK, Neilan TG, Wood MJ, Tawakol A. Stress-associated neurobiological activity associates with the risk for and timing of subsequent takotsubo syndrome . Eur Heart J 2021 ;doi:10.1093/eurheartj/ehab029. Google Scholar OpenURL Placeholder Text WorldCat 11 Sciagrà R , Parodi G, Del Pace S, Genovese S, Zampini L, Bellandi B, Gensini GF, Pupi A, Antoniucci D. Abnormal response to mental stress in patients with Takotsubo cardiomyopathy detected by gated single photon emission computed tomography . Eur J Nucl Med Mol Imaging 2010 ; 37 : 765 – 772 . Google Scholar Crossref Search ADS PubMed WorldCat 12 Felmingham K , Kemp A, Williams L, Das P, Hughes G, Peduto A, Bryant R. Changes in anterior cingulate and amygdala after cognitive behavior therapy of posttraumatic stress disorder . Psychol Sci 2007 ; 18: 127 – 129 . Google Scholar Crossref Search ADS PubMed WorldCat 13 Tawakol A , Ishai A, Takx RA, Figueroa AL, Ali A, Kaiser Y, Truong QA, Solomon CJ, Calcagno C, Mani V, Tang CY, Mulder WJ, Murrough JW, Hoffmann U, Nahrendorf M, Shin LM, Fayad ZA, Pitman RK. Relation between resting amygdalar activity and cardiovascular events: a longitudinal and cohort study . Lancet 2017 ; 389 : 834 – 845 . Google Scholar Crossref Search ADS PubMed WorldCat 14 Suzuki H , Matsumoto Y, Ota H, Sugimura K, Takahashi J, Ito K, Miyata S, Furukawa K, Arai H, Fukumoto Y, Taki Y, Shimokawa H. Hippocampal blood flow abnormality associated with depressive symptoms and cognitive impairment in patients with chronic heart failure . Circ J 2016 ; 80 : 1773 – 1780 . Google Scholar Crossref Search ADS PubMed WorldCat 15 Suzuki H , Matsumoto Y, Sugimura K, Takahashi J, Miyata S, Fukumoto Y, Taki Y, Shimokawa H. Impacts of hippocampal blood flow on changes in left ventricular wall thickness in patients with chronic heart failure . Int J Cardiol 2020 ; 310 : 103 – 107 . Google Scholar Crossref Search ADS PubMed WorldCat Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)