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This Focus Issue on imaging contains a Special Article co-published with JACC entitled ‘Valve Academic Research Consortium 3: updated endpoint definitions for aortic valve clinical research’, authored by Martin Leon from the Columbia University Medical Center in New York, USA, and colleagues.1 The authors note that the Valve Academic Research Consortium (VARC), founded in 2010, was intended to identify appropriate clinical endpoints and standardize definitions of these endpoints for transcatheter and surgical aortic valve clinical trials. Rapid evolution of the field, including the emergence of new complications, expanding clinical indications, and novel therapy strategies, has mandated further refinement and expansion of these definitions to ensure clinical relevance.2–5 Thus, several years after the publication of the VARC-2 manuscript,6 an in-person meeting was held involving >50 independent clinical experts representing several societies, academic research organizations, the US Food and Drug Administration (FDA), and industry representatives to evaluate utilization of VARC endpoint definitions in clinical research, discuss the scope of this focused update, and review and revise specific clinical endpoint definitions. A writing committee of independent experts was convened and subsequently met to further address outstanding issues. There were ongoing discussions with the FDA and many experts to develop a new classification schema for bioprosthetic valve dysfunction and failure. Overall, this multidisciplinary process has resulted in important recommendations for data reporting, clinical research methods, and updated endpoint definitions. New definitions or modifications of existing definitions are being proposed for repeat hospitalizations, access site-related complications, bleeding events, conduction disturbances, cardiac structural complications, and bioprosthetic valve dysfunction and failure (including valve leaflet thickening and thrombosis). A more granular five-class grading scheme for paravalvular regurgitation (PVR) is being proposed to help refine the assessment of PVR. Finally, more specific recommendations on quality-of-life assessments have been included, which have been targeted to specific clinical study designs (Figure 1). The adoption of these updated and newly proposed VARC-3 endpoints and definitions will ensure homogenous event reporting, accurate adjudication, and appropriate comparisons of clinical research studies involving devices and new therapeutic strategies.
Bioprosthetic valve dysfunction and Bioprosthetic valve failure. BMI, body mass index; BVD, bioprosthetic valve dysfunction; BVF, bioprosthetic valve failure; HALT, hypo-attenuated leaflet thickening; RLM, reduced leaflet motion (from VARC-3 WRITING COMMITTEE: Généreux P, Piazza N, Alu MC, Nazif T, Hahn RT, Pibarot P, Bax JJ, Leipsic JA, Blanke P, Blackstone EH, Finn MT, Kapadia S, Linke A, Mack MJ, Makkar R, Mehran R, Popma JJ, Reardon M, Rodes-Cabau J, Van Mieghem NM, Webb JG, Cohen DJ, Leon MB. Valve Academic Research Consortium 3: updated endpoint definitions for aortic valve clinical research. See pages 1825–1857).
In another Special Article entitled ‘Coronavirus disease 2019 in adults with congenital heart disease: a position paper from the ESC working group of adult congenital heart disease, and the International Society for Adult Congenital Heart Disease’, Gerhard-Paul Diller from the University Hospital Münster in Germany, and colleagues note that we are witnessing an unparalleled pandemic caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) associated with coronavirus disease 2019 (COVID-19).7 Current data show that SARS-CoV-2 results in mild flu-like symptoms in the majority of healthy and young patients affected. The severity of COVID-19 respiratory syndrome and the risk of adverse or catastrophic outcomes are increased in patients with pre-existing cardiovascular disease.8 Adult congenital heart disease (ACHD) patients—by definition—have underlying cardiovascular disease.9 Many ACHD patients are also afflicted with residual haemodynamic lesions such as valve dysfunction, diminished ventricular function, arrhythmias, or cyanosis, have extracardiac comorbidities, and face additional challenges regarding pregnancy. Currently, there are emerging data of the effect of COVID-19 on ACHD patients, but many aspects, especially risk stratification and treatment considerations, remain unclear.10 In this contribution, the authors discuss the broad impact of COVID-19 on ACHD patients, focusing specifically on pathophysiology, risk stratification for work, self-isolation, hospitalization, impact on pregnancy, psychosocial health, and longer term implications for the provision of ACHD care.
Troponin elevation is common in hospitalized COVID-19 patients, but underlying aetiologies are ill defined.11–13 In a clinical research article entitled ‘Patterns of myocardial injury in recovered troponin-positive COVID-19 patients assessed by cardiovascular magnetic resonance’, Tushar Kotecha from the University College London, UK, and colleagues used multiparametric cardiovascular magnetic resonance (CMR) to assess myocardial injury in 148 patients (64 ± 12 years, 70% male) with severe COVID-19 infection (all requiring hospital admission, 32% requiring ventilatory support) and troponin elevation.14 CMR (including adenosine stress perfusion if indicated) was carried out at a median follow-up of 68 days. Left ventricular function was normal in 89% of patients. Late gadolinium enhancement (LGE) and/or ischaemia were found in 54% of patients. This comprised myocarditis-like scar in 26%, infarction and/or ischaemia in 22%, and dual pathology in 6% (Figure 2).
Spectrum of CMR pathology in patients with COVID-19 infection with associated troponin rise (from Kotecha T, Knight DS, Razvi Y, Kumar K, Vimalesvaran K, Thornton G, Patel R, Chacko L, Brown JT, Coyle C, Leith D, Shetye A, Ariff B, Bell R, Captur G, Coleman M, Goldring J, Gopalan D, Heightman M, Hillman T, Howard L, Jacobs M, Jeetley PS, Kanagaratnam P, Min Kon O, Lamb LE, Manisty CH, Mathurdas P, Mayet J, Negus R, Patel N, Pierce I, Russell G, Wolff A, Xue H, Kellman P, Moon JC, Treibel TA, Cole GD, Fontana M. Patterns of myocardial injury in recovered troponin-positive COVID-19 patients assessed by cardiovascular magnetic resonance. See pages 1866–1878).
The authors conclude that during convalescence after severe COVID-19 infection with troponin elevation, about half of patients present subclinical evidence of myocarditis, myocardial infarction, and myocardial ischaemia at CMR. Whether these alterations represent pre-existing clinically silent disease or de novo COVID-19-related changes remains undetermined. The manuscript is accompanied by an Editorial by Leslie Cooper from the Mayo Clinic in Jacksonville, Florida, USA and Matthias Friedrich from McGill University Health Centre in Montreal, Canada.15 The authors note that this is an important study as it shows that abnormalities of myocardial tissue characterized by magnetic resonance imaging (MRI) are common during COVID-19 recovery, while causal relationships of these tissue changes to future cardiac events remain to be established. In particular, the association with fibrosis, clinical heart failure, and arrhythmia risk over a meaningful span of years needs to be studied in diverse groups to develop a predictive risk model for the management of chronic COVID-19 cardiac injury. Several studies are ongoing and will deliver answers: COVID-HEART (NIHR 285147), PHOSP-COVID (NIHR 285439), MOIST (NCT04525404), MYOCOVID (NCT04375748), MIIC-MI (NCT04412369), CARDOVID (NCT04455347), and CISCO-19 (NCT04403607).
Emotional stress is associated with cardiovascular events.16,17 However, the mechanistic linkage of brain emotional neural activity with acute plaque instability is not fully elucidated. Activity in the amygdala, a brain centre involved in the perception of and response to stressors, is associated with heightened sympathetic nervous system and inflammatory output, as well as risk of cardiovascular disease. In a clinical research article entitled ‘Stress-associated neurobiological activity is linked with acute plaque instability via enhanced macrophage activity: a prospective serial 18F-FDG-PET/CT imaging assessment’, Dong Oh Kang from the Korea University Guro Hospital in the Republic of Korea, and colleagues sought to prospectively estimate the relationship between brain amygdalar activity, arterial inflammation, and macrophage haematopoiesis in acute myocardial infarction (AMI) as compared with controls.18 [18F]Fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) imaging was performed within 45 days of the index episode in 62 patients. In 10 patients of the AMI group, serial 18F-FDG-PET/CT imaging was performed after 6 months to estimate the temporal changes. The signals were compared using a customized 3D-rendered PET reconstruction. Amygdalar activity, carotid arterial inflammation, and macrophage haematopoiesis were significantly higher in AMI patients compared with controls. Amygdalar activity correlated significantly with those of the carotid arteries, aorta, and bone marrow. Psychological stress scales and amygdalar activity correlated well (P < 0.001). Six months after AMI, amygdalar activity, carotid arterial inflammation, and macrophage haematopoiesis decreased to a level comparable with that of the controls.
Kang et al. conclude that amygdalar activity, arterial inflammation, and macrophage haematopoiesis were concordantly enhanced in patients with AMI, showing concurrent dynamic changes over time. These results raise the possibility that stress-associated neurobiological activity is linked with acute plaque instability via augmented macrophage activity and could be a potential therapeutic target for plaque inflammation in AMI. The manuscript is accompanied by an Editorial by Marc Dweck from the University of Edinburgh in the UK.19 The author concludes that despite its limitations, 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.
In a clinical research article entitled ‘Stress-associated neurobiological activity associates with the risk for and timing of subsequent Takotsubo syndrome’, Azar Radfar from the Massachusetts General Hospital and Harvard Medical School, USA, and colleagues addressed the role of amygdalar activity in Takotsubo syndrome (TTS) known to be preceded by intense emotional or physical stress in ∼80% of cases.20,21 They hypothesized that the amygdalar activity is heightened among individuals who develop TTS, a heart failure syndrome often triggered by acute stress.22 The authors tested the hypotheses that: (i) heightened amygdalar activity precedes development of TTS; and (ii) those with the highest amygdalar activity develop the syndrome earliest. A total of 104 individuals who underwent clinical 18F-FDG-PET/CT imaging were retrospectively identified: 41 who subsequently developed TTS (median follow-up 2.5 years after imaging) and 63 matched controls. Amygdalar activity was measured using validated methods. Individuals with those without subsequent TTS had higher baseline amygdalar activity (P = 0.038) after adjusting for TTS risk factors. Further, amygdalar activity was associated with the risk for subsequent TTS after adjustment for risk factors. Among the subset of individuals who developed TTS, those with the highest amygdalar activity developed TTS ∼2 years earlier after imaging vs. those with lower amygdalar activity (P = 0.028).
The authors conclude that pre-exisiting amygdalar activity is associated with an increased risk for TTS . This heightened neurobiological activity is present years before the onset of TTS and may impact the timing of the syndrome. Accordingly, heightened stress-associated neural activity may represent a therapeutic target to reduce stress-related diseases, including TTS. The manuscript is accompanied by an Editorial by Hiroaki Shimokawa from the Tohoku University Graduate School of Medicine in Sendai, Japan, and colleagues.23 The authors note that the heart–brain connection is not a specific phenomenon of TTS but is widely noted in patients with cardiovascular diseases. Increased amygdalar activity may also predict the risk of other stress-related cardiovascular and metabolic diseases. They concur that 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.
Our understanding of the complexities of valvular heart disease (VHD) has evolved in recent years, primarily because of the increased use of multimodality imaging.24,25 In a State of the Art review article entitled ‘Multimodality imaging in valvular heart disease: how to use state-of-the-art technology in daily practice’, Anna Reid from the University of British Columbia in Vancouver, Canada, and colleagues note that whilst echocardiography remains the primary imaging technique, the contemporary evaluation of patients with VHD requires comprehensive analysis of the mechanism of valvular dysfunction, accurate quantification of severity, and active exclusion of extravalvular consequences.26 Furthermore, advances in surgical and percutaneous therapies have driven the need for meticulous multimodality imaging to aid in patient and procedural selection. Fundamental decision-making regarding who, when, and how to treat patients with VHD has become more complex. There has been rapid technological advancement in multimodality imaging; many techniques are now available in routine clinical practice, and their integration has the potential to truly individualize management strategies. This review provides an overview of the current evidence for the use of multimodality imaging in VHD, and how various techniques within each modality can be used practically to answer clinical conundrums.
The issue is complemented by a stand-alone Discussion Forum article: in a contribution entitled ‘The impact of minimally invasive technique on the outcomes of isolated tricuspid valve surgery’, Jinmiao Chen from Fudan University in Shanghai, China, and colleagues comment on the contribution ‘Isolated tricuspid valve surgery: impact of aetiology and clinical presentation on outcomes’ by Julien Dreyfus from the Centre Cardiologique du Nord in Saint-Denis, France, and colleagues.27,28
The editors hope that this issue of the European Heart Journal will be of interest to its readers.
With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article.
References
Généreux P, Piazza N, Alu MC, Nazif T, Hahn RT, Pibarot P, Bax JJ, Leipsic JA, Blanke P, Blackstone EH, Finn MT, Kapadia S, Linke A, Mack MJ, Makkar R, Mehran R, Popma JJ, Reardon M, Rodes-Cabau J, Van Mieghem NM, Webb JG, Cohen DJ, Leon MB; VARC-3 WRITING COMMITTEE. Valve Academic Research Consortium 3: updated endpoint definitions for aortic valve clinical research. Eur Heart J 2021;42:1825–1857.
