Immunosuppressive therapy of myocarditis and inflammatory cardiomyopathy in the light of new dataOzieranski, Krzysztof; Tyminska, Agata; Caforio, Alida L P
doi: 10.1093/eurheartj/ehac500pmid: 36263783
This commentary refers to ‘Immunosuppressive therapy in virus-negative inflammatory cardiomyopathy: 20-year follow-up of the TIMIC trial’, by C. Chimenti et al., https://doi.org/10.1093/eurheartj/ehac348 and the discussion piece ‘Individualized immunosuppression in virus-negative inflammatory cardiomyopathy’, by A. Frustaci et al., https://doi.org/10.1093/eurheartj/ehac559. Figure 1 Open in new tabDownload slide Proposed scheme of study design of immunosuppressive treatment in myocarditis/inflammatory cardiomyopathy. We wish to comment on the study recently published in the European Heart Journal1 entitled: ‘Immunosuppressive therapy in virus-negative inflammatory cardiomyopathy: 20-year follow-up of the TIMIC (Tailored Immosuppression in Inflammatory Cardiomyopathy) trial’. The paper presents important long-term results of the randomized, placebo-controlled TIMIC trial initially published by Frustaci et al.2 in 2009. The previous study played a leading role in the current position of endomyocardial biopsy and immunosuppressive therapy in virus-negative myocarditis/inflammatory cardiomyopathy. However, it is important to note that the current ESC guidelines still do not unequivocally recommend this treatment.3 Further, there are still major gaps in our knowledge of immunosuppression that should be answered in future prospective randomized trials to generate data relevant for international recommendations. Here, we list a few emerging issues that should be answered: confirmation of treatment efficacy—i.e. improvement of left ventricular ejection fraction (LVEF) and positive myocardial remodelling, as well as improvement of symptoms and heart failure outcomes; confirmation of treatment safety—frequency of adverse events associated with immunosuppressive therapy i.e. serious infections; significant decrease in blood parameters; worsening kidney, pancreatic, and/or liver function; necessity for treatment discontinuation; required treatment duration—patients in the TIMIC trial were treated for 6 months, while clinical practice suggests that longer immunosuppressive therapy might be necessary; and persistence of treatment effects—particularly during the first year after treatment discontinuation. These issues should be assessed via a larger multicentre and homogenous population of patients with biopsy-proven virus negative myocarditis and/or inflammatory cardiomyopathy enrolled in a high-quality trial (i.e. adequately powered, randomized, double-blind, and placebo-controlled) (Figure 1). The design of and results from the TIMIC trial were the foundation of the currently ongoing multicentre, randomized, double-blind, placebo-controlled study to evaluate the efficacy of immunosuppression in biopsy-proven virus negative myocarditis or inflammatory cardiomyopathy (IMPROVE-MC) (ClinicalTrials.gov: NCT04654988 and EudraCT; 2020-003877-23).4 The study enrolls 100 patients with reduced LVEF (≤45%) in seven centres to a 12-month treatment with prednisone and azathioprine (dosage based on the TIMIC protocol) or to placebo on top of guideline-recommended medical therapy. In addition, the study will also assess the maintenance of therapy effects after a subsequent 12-month observation period. The primary endpoint is change from baseline in LVEF at 12-months. All key study assessments (i.e. biopsy and blood samples, echocardiographic and cardiac magnetic resonance images) are performed in CORE-LABs to ensure high data quality. In conclusion, the TIMIC trial showed that patients with biopsy-proven myocarditis/inflammatory cardiomyopathy may benefit from immunosuppressive therapy in short- and long-term, but several important clinical questions with high relevance for future clinical guidelines remain unanswered. Funding The primary investigator on the IMPROVE-MC trial is Professor Marcin Grabowski, the Head of the First Department of Cardiology, Medical University of Warsaw (MUW), Poland. K.O. and A.T. designed and coordinate the trial, while A.L.P.C. is the head of its Scientific Excellence Committee. The IMPROVE-MC trial is a non-commercial study. The trial sponsor is the MUW. The study is supported by a grant, worth∼3.5 m € awarded by the Polish Medical Research Agency (grant no.: 2019/ABM/01/00047-00). Data availability The data underlying this article are available in the article and in its online Supplementary material. References 1 Chimenti C , Russo MA, Frustaci A. Immunosuppressive therapy in virus-negative inflammatory cardiomyopathy: 20-year follow-up of the TIMIC trial . Eur Heart J 2022 : ehac348 . https://doi.org/10.1093/eurheartj/ehac348. Google Scholar OpenURL Placeholder Text WorldCat 2 Frustaci A , Russo MA, Chimenti C. Randomized study on the efficacy of immunosuppressive therapy in patients with virus-negative inflammatory cardiomyopathy: the TIMIC study . Eur Heart J 2009 ; 30 : 1995 – 2002 . https://doi.org/10.1093/eurheartj/ehp249 Google Scholar Crossref Search ADS PubMed WorldCat 3 Authors/Task Force Members , McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, et al. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: developed by the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). With the special contribution of the Heart Failure Association (HFA) of the ESC . Eur J Heart Fail 2022 ; 24 : 4 – 131 . https://doi.org/10.1002/ejhf.2333 Google Scholar PubMed OpenURL Placeholder Text WorldCat 4 Ozierański K , Tymińska A, Marchel M, Januszkiewicz Ł, Maciejewski C, et al. A multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy of immunosuppression in biopsy-proven virus-negative myocarditis or inflammatory cardiomyopathy (IMPROVE-MC) . Cardiol J . 2022 ; 29 : 329 – 341 . https://doi.org/10.5603/CJ.a2021.0166 Google Scholar Crossref Search ADS PubMed WorldCat Author notes Conflict of interest: The authors designed, coordinate and participate in the Scientific Excellence Committee of the IMPROVE-MC trial. © The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: [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) © The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: [email protected]
The RUHR Heart Failure Network: improved heart failure care in a metropolitan areaLuedike, Peter; Heusch, Gerd; Rassaf, Tienush
doi: 10.1093/eurheartj/ehac480pmid: 36053222
Heart failure (HF) remains the leading cause of hospitalizations and readmissions in Europe and the USA, and its prevalence and costs continue to rise, making it a significant population health issue. Despite tremendous progress in therapy and improving HF care, the quality of HF care varies between countries and regions. Recognizing that structured care of HF patients improves patient outcomes,1,2 in 2016 the German Cardiac Society (GCS) and the German Society for Thoracic and Cardiovascular Surgery (GSTCS) published an interdisciplinary joint recommendation for the structure and organization of HF-networks (NETs) and HF units (HFUs) to optimize treatment of acute and chronic HF.3 It was the first description of the requirements that must be met by the modules of a HF-NET to be eligible for certification as a HFU adopted to the German healthcare system. The West German Heart and Vascular Center (WHGZ) at the University Hospital Essen became the first certified supra-regional HFU in the Ruhr area in 2018 according to these society recommendations.4 These considerations further served as the basis for the development concept of the RUHR-HF-network in 2020 that constitutes the first certified HF-network in the Ruhr area (the biggest metropolitan area in Germany with 53 cities, 5.100.000 inhabitants, 4.438 square kilometres) (Figure 1). This development concept comprises essential components and aims to lay the foundation for a supra-regional, independent benchmark system including validated quality indicators (QIs) that enables healthcare organizations to measure quality, improve care, and it provides a basis for value-based health care (VBHC). The basic principle of the RUHR-HF-NET development plan is combining the conceptual framework of the dimensions of health care based on the Donabedian model (structure, process, outcome) with regional peculiarities and infrastructural requirements. Figure 1 Open in new tabDownload slide The RUHR-HF-network was founded in 2020 and constitutes the first certified HF-network in the Ruhr area (the biggest metropolitan area in Germany). The aim of the network is to establish a structure of board-certified institutions with standardized, contract-based communication pathways and close interactions to create the framework for transparent and independent quality evaluation. Different elements according to the Donabedian model have been identified and clearly defined components of networking implemented. The long-term objective of this concept is to build a solid platform for value-based health care. ECLS, extracorporeal life support; MCS, mechanical circulatory support; HF, heart failure; HFU, heart failure unit; GP, general practitioner; QIs, quality indicators; AHF, advanced heart failure. Structural elements To meet formal requirements, a new interdisciplinary (cardiology and cardiothoracic surgery) HF ward was installed, and both MDs as well as nurses underwent specific HF curricula certified by the GCS/GSTCS. To further warrant guideline-directed discharge management, an outpatient clinic was implemented that covers both disease management as well as patient education. These local changes of infrastructure were paralleled by the establishment of a supra-regional acute HF service according to the widely accepted ‘Spoke-and-Hub model’ that comprises 24/7 availability of extracorporeal life support (ECLS) as well as all available interventional and surgical approaches for mechanical circulatory support (MCS). RUHR-HF-NET members without local opportunity for ECLS/MCS are equipped with one-call-access connection to the WHGZ and standardized shock-protocols ensure timely remote support from a dedicated mobile shock team. To date, the network consists of nine cardiology departments and four general cardiology offices throughout the Ruhr area, each of which aims to be certified as regional HFU and building a local HF network to accommodate the regional peculiarities (e.g. interaction with general practitioners, GPs). Additionally, a rehabilitation hospital, dedicated to cardiovascular conditions is integrated in the network to ensure timely and standardized discharge management also after long-term intensive care hospitalization, left ventricular assist device (LVAD) implantation or heart transplantation (HTX). These components constitute the structural foundation of the RUHR-HF-NET. Procedural elements While definition of structural and educational demands can set the minimum standards for HF facilities and staff, communication pathways, and trans-sectoral interactions are poorly defined. To overcome this shortcoming in a metropolitan area with juxtaposition of different healthcare providers and different individual expertize, interests and liabilities, collaboration within the RUHR-HF-NET is contract-based and implies mandatory participation in a standardized communication scheme. A weekly, digital, interdisciplinary HF board for case discussions and therapy planning is the key element to facilitate and ensure interaction and standardized therapy across the network. This weekly exchange is paralleled by a quarterly meeting of representatives of each network member to discuss problems, inform about innovations and to develop further collaboration. The third pillar is an annual HF meeting (‘Essen Heart Failure’) with participation of all members to cover latest science and to improve interaction. Future process elements are a quarterly education (HF grand rounds) programme that is available online and an advanced HF task force with members from all network partners that meets twice a year and that ensures timely and accurate treatment of patients with advanced HF or cardiogenic shock. Regular patient education events and local training of GPs are further components that must be covered from each partner. Outcome measures The European Society of Cardiology as well as other national and international cardiovascular societies have developed QIs for the care and outcomes of adults with HF, to enable healthcare providers to develop valid and feasible metrics to quantify and improve the quality of cardiovascular care.5–8 While current benchmark systems in healthcare focus rather on certain index procedures such as the total number of LVADs implanted, HTXs, or certain numbers of structural interventions than on outcomes that reflect VBHC, networking should aim to address this imbalance. To establish an overriding organization structure for the management of QIs, the RUHR-HF-NET closely integrates a telemedicine centre that meets the highest requirements of the German Federal Joint Committee (G-BA) and that closely interacts with the Cardiac Trial Unit (CTU), a core facility for clinical research at the WHGZ. A pilot study was started to test the feasibility of this collaboration aiming to measure and monitor QIs such as quality of life and therapy optimization in LVAD recipients (NCT04613401). This approach will constitute the framework for a network overriding structure that enables an independent monitoring of QIs to improve care and to guide network development. General considerations Healthcare providers worldwide are not only confronted with medical challenges from HF but also with economical burdens and demands, irrespectively of underlying reimbursement systems. Collaborations such as HF networks need therefore to consider the individual situation of each member to respect regional peculiarities. For this reason, it should be the goal of each network initiative that infrastructural demands are specified, controlled, and certified by national cardiac societies to prevent hierarchies between network members and to enable focus on VBHC. Data Availability No new data were generated or analysed in support of this research. References 1 McDonagh TA , Gardner RS, Lainscak M, Nielsen OW, Parissis J, Filippatos G, et al. Heart failure association of the European society of cardiology specialist heart failure curriculum . Eur J Heart Fail 2014 ; 16 : 151 – 162 . Google Scholar Crossref Search ADS PubMed WorldCat 2 McDonagh TA , Blue L, Clark AL, Dahlstrom U, Ekman I, Lainscak M, et al. European society of cardiology heart failure association committee on patient C. European society of cardiology heart failure association standards for delivering heart failure care . Eur J Heart Fail 2011 ; 13 : 235 – 241 . Google Scholar Crossref Search ADS PubMed WorldCat 3 Ertl G , Angermann CE, Bekeredjian R, Beyersdorf F, Güder G, Gummert J, et al. Aufbau und Organisation von Herzinsuffizienz-Netzwerken (HF-NETs) und Herzinsuffizienz-Einheiten („Heart Failure Units“. HFUs) zur Optimierung der Behandlung der akuten und chronischen Herzinsuffizienz . Der Kardiologe 2016 ; 10 : 222 – 235 . Google Scholar Crossref Search ADS WorldCat 4 Rassaf T , Heusch G. The West German heart and vascular center at university medicine Essen . Eur Heart J 2021 ; 42 : 963 – 964 . Google Scholar Crossref Search ADS PubMed WorldCat 5 Burns DJP , Arora J, Okunade O, Beltrame JF, Bernardez-Pereira S, Crespo-Leiro MG, et al. International consortium for health outcomes measurement (ICHOM): standardized patient-centered outcomes measurement set for heart failure patients . JACC Heart Fail 2020 ; 8 : 212 – 222 . Google Scholar Crossref Search ADS PubMed WorldCat 6 Heidenreich PA , Fonarow GC, Breathett K, Jurgens CY, Pisani BA, Pozehl BJ, et al. 2020 ACC/AHA clinical performance and quality measures for adults with heart failure . Circ Cardiovasc Qual Outcomes 2020 ; 13 : e000099 . Google Scholar Crossref Search ADS PubMed WorldCat 7 Aktaa S , Batra G, Wallentin L, Baigent C, Erlinge D, James S, et al. European society of cardiology methodology for the development of quality indicators for the quantification of cardiovascular care and outcomes . Eur Heart J Qual Care Clin Outcomes 2022 ; 8 : 4 – 13 . Google Scholar Crossref Search ADS PubMed WorldCat 8 Aktaa S , Polovina M, Rosano G, Abdin A, Anguita M, Lainscak M, et al. European society of cardiology quality indicators for the care and outcomes of adults with heart failure. Developed by the working group for heart failure quality indicators in collaboration with the heart failure association of the European society of cardiology . Eur J Heart Fail 2022 ; 24 : 132 – 142 . Google Scholar Crossref Search ADS PubMed WorldCat Author notes Conflict of interest: None declared. © The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: [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) © The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: [email protected]
Toward personalized medicine for cardiovascular pharmacotherapyTamargo, Juan; Hasegawa, Koji; Agewall, Stefan
doi: 10.1093/eurheartj/ehac413pmid: 35924414
Graphical AbstractGraphical Abstract(A) Role of some of the genetic loci associated with angiotensin-converting enzyme inhibitor discontinuation due to cough. (B) The authors hypothesized that genetic variants could partly share pathophysiological pathways, so that genetic susceptibility to ACEIAC could in part be driven by an innate cough sensitization, which progresses into cough after exposure to a trigger (e.g. ACEI, GERD, or allergens). Abbreviations: ACE, angiotensin-converting enzyme; ACEI, ACE inhibitor; ACEIAC: ACEI-associated cough; GERD, gastro-oesophageal reflux disease; GWAS, genome-wide association study; NTR1, neurotensin receptor 1.
Fusion imaging in preoperative planning of mitral valve surgery to prevent injury of the left circumflex arteryMan, Jelle Piet; Bouma, Berto Jorrit; Schuuring, Mark Johan
doi: 10.1093/eurheartj/ehac566pmid: 36271810
Open in new tabDownload slide A 66-year-old woman with severe mitral regurgitation was referred to our heart team to assess eligibility for mitral valve (MV) surgery (MVS). In MVS, injury to the left circumflex artery (LCX) is estimated to occur in up to 2.7% of the patients.1 The distance of the LCX to the MV (on average 3.1 ± 1.3 mm) is highly variable and is likely to determine the prevalence of this complication.1 Transesophageal echocardiography (TEE) is the modality of choice for MVS planning (Panel A and B).2 Computed tomography (CT) has been proposed as standard screening tool for MVS to determine the risk of LCX injury.3 We aimed to fuse the CT-derived LCX identification (Panel C) with TEE-derived MV views to improve the surgical planning of MVS in patients at high risk of injury. Using Meshmixer (Autodesk), 3D Slicer (Slicer) and Elastix toolbox, TEE (General Electric) and CT scans (Siemens) were prealigned using the Procrustes algorithm, cropped, and subsequently aligned using Mutual information registration with an adaptive gradient descent optimizer.4,5 The LCX is segmented on CT and a MV reconstruction is made on TEE. This initiative is the first to fuse CT and a TEE of the MV for the purpose MVS planning. The fused image (Panel D) provides synergistic information derived from both TEE and CT modalities. If, in routine screening on CT, the distance of the MV to the LCX is close, fusion of the LCX to TEE could be helpful to devise a surgical strategy for MVS.. We would like to thank F. Meijerink and S.A.J. Chamuleau for their support. This study was approved by the local Human Research Ethics Committee (Amsterdam UMC). Informed consent was obtained. Supplementary data is available at European Heart Journal online. The data underlying this article will be shared on reasonable request to the corresponding author. 1 Ender J , Selbach M, Borger MA, Krohmer E, Falk V, Kaisers UX, Mohr FW, Mukherjee C. Echocardiographic identification of iatrogenic injury of the circumflex artery during minimally invasive mitral valve repair . Ann Thorac Surg 2010 ; 89 : 1866 – 1872 . Google Scholar Crossref Search ADS PubMed WorldCat 2 Vahanian A , Beyersdorf F, Praz F, Milojevic M, Baldus S, Bauersachs J, Capodanno D, Conradi L, De Bonis M, De Paulis R, Delgado V, Freemantle N, Gilard M, Haugaa KH, Jeppsson A, Jüni P, Pierard L, Prendergast BD, Sádaba JR, Tribouilloy C, Wojakowski W; ESC/EACTS Scientific Document Group . 2021 ESC/EACTS guidelines for the management of valvular heart diseaseDeveloped by the task force for the management of valvular heart disease of the European society of cardiology (ESC) and the European association for cardio-thoracic surgery (EACTS) . Eur Heart J Oxford Academic 2022 ; 43 : 561 – 632 . Google Scholar Crossref Search ADS WorldCat 3 Pingpoh C . Should pre-operative computer tomography with post-processed three-dimensional images become the benchmark in mitral valve surgery? Eur J Cardio-Thoracic Surg Oxford Academic 2022 ; 61 : 684 – 684 . Google Scholar Crossref Search ADS WorldCat 4 Man J , Maessen J, Sardari Nia P. The development of a flexible heart model for simulation-based training. Interact Cardiovasc Thorac Surg Oxford University Press ; 2021 ; 32 : 182 . Crossref Search ADS PubMed 5 Pluim JPW , Maintz JBA, Viergever MA. Mutual-information-based registration of medical images: a survey . IEEE Trans Med Imaging 2003 ; 22 : 986 – 1004 . Google Scholar Crossref Search ADS PubMed WorldCat Author notes Conflict of interest: None declared. © The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected] © The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.
Highly malignant disease in childhood-onset arrhythmogenic right ventricular cardiomyopathySmedsrud, Marit Kristine; Chivulescu, Monica; Forså, Marianne Inngjerdingen; Castrini, Isotta; Aabel, Eivind Westrum; Rootwelt-Norberg, Christine; Bogsrud, Martin Prøven; Edvardsen, Thor; Hasselberg, Nina Eide; Früh, Andreas; Haugaa, Kristina Hermann
doi: 10.1093/eurheartj/ehac485pmid: 36036653
AimsThis study aimed to explore the incidence of severe cardiac events in paediatric arrhythmogenic right ventricular cardiomyopathy (ARVC) patients and ARVC penetrance in paediatric relatives. Furthermore, the phenotype in childhood-onset ARVC was described.MethodsConsecutive ARVC paediatric patients and genotype positive relatives ≤18 years of age were followed with electrocardiographic, structural, and arrhythmic characteristics according to the 2010 revised Task Force Criteria. Penetrance of ARVC disease was defined as fulfilling definite ARVC criteria and severe cardiac events were defined as cardiac death, heart transplantation (HTx) or severe ventricular arrhythmias. Childhood-onset disease was defined as meeting definite ARVC criteria ≤12 years of age.ResultsAmong 62 individuals [age 9.8 (5.0–14.0) years, 11 probands], 20 (32%) fulfilled definite ARVC diagnosis, of which 8 (40%) had childhood-onset disease. The incidence of severe cardiac events was 23% (n = 14) by last follow-up and half of them occurred in patients ≤12 years of age. Among the eight patients with childhood-onset disease, five had biventricular involvement needing HTx and three had severe arrhythmic events. Among the 51 relatives, 6% (n = 3) met definite ARVC criteria at time of genetic diagnosis, increasing to 18% (n = 9) at end of follow-up.ConclusionsIn a paediatric ARVC cohort, there was a high incidence of severe cardiac events and half of them occurred in children ≤12 years of age. The ARVC penetrance in genotype positive paediatric relatives was 18%. These findings of a high-malignant phenotype in childhood-onset ARVC indicate a need for ARVC family screening at younger age than currently recommended.
Eggs and the heartMesserli, Franz H; Vongpatanasin, Wanpen; Messerli, Adrian W
doi: 10.1093/eurheartj/ehac473pmid: 36282734
Affordable and accessible in most countries, eggs are a source of good-quality nutrients and commonly recommended as part of a healthy diet. The American Egg Board in the introductory summary on Egg Nutrition states: ‘Eggs are a naturally nutrient-rich food, containing eight essential nutrients. Eggs provide an excellent source of vitamin B12, biotin (B7), iodine, selenium, and choline; a good source of high-quality protein, riboflavin (B2) and pantothenic acid (B5); as well as the carotenoids lutein and zeaxanthin (252 mcg), all for only 70 calories’.1 Of note, the term ‘cholesterol’ is nowhere to be found in this promotional excerpt. Cholesterol However, eggs are a conspicuous source of dietary cholesterol, containing more than 200 mg per large egg. Not surprisingly therefore, health benefits have been debated, and the association between egg intake and risk of mortality from cardiovascular disease (CVD) continues to be scrutinized. A thorough meta-analysis, published recently, of 28 prospective studies provocatively suggested that associations between egg consumption and CVD risk were population-specific: in Asian cohorts only, but not in Western cohorts, an inverse association was observed.2 More recently, in their prospective ATBC (Alpha-Tocopherol, Beta-Carotene Cancer Prevention) study of 27 078 men and their systematic review and meta-analysis of cohort studies, Zhao et al.3 state that their ‘findings support the hypothesis that it is the increased cholesterol intake from eggs that plays a key role and accounts for the elevated mortality associations’. In the subgroup analysis of geographical regions, the authors conclude that ‘the results from this updated meta-analysis provide compelling evidence for the association between increased egg consumption and elevated risk of CVD, especially in the US and possibly Europe, but not in Asia’. Surprisingly, the authors did not elaborate on the possible cause of these conspicuous geographic differences in their paper. Traditional egg breakfast We decided to scrutinize the egg consumption pattern in the three continents by analyzing on Google the first consecutive 20 images of the traditional Asian or European or American egg breakfast (accessed June 22. 2022). The egg images were subdivided into four categories (Table 1): Table 1 Traditional egg breakfast pattern in Asia, Europe, and America . Simple eggs: poached, boiled, steamed, sunny side up, Shakshuka . Processed eggs: scrambled, fried, omlette, or Benedict . Simple eggs with bacon, ham, or sausage . Processed eggs with bacon, ham, or sausage . Asian 14 6 0 0 European 7 6 4 3 American 0 1 14 5 . Simple eggs: poached, boiled, steamed, sunny side up, Shakshuka . Processed eggs: scrambled, fried, omlette, or Benedict . Simple eggs with bacon, ham, or sausage . Processed eggs with bacon, ham, or sausage . Asian 14 6 0 0 European 7 6 4 3 American 0 1 14 5 Analyzed by the first consecutive 20 images on Google (accessed on 22 April 2022). Open in new tab Table 1 Traditional egg breakfast pattern in Asia, Europe, and America . Simple eggs: poached, boiled, steamed, sunny side up, Shakshuka . Processed eggs: scrambled, fried, omlette, or Benedict . Simple eggs with bacon, ham, or sausage . Processed eggs with bacon, ham, or sausage . Asian 14 6 0 0 European 7 6 4 3 American 0 1 14 5 . Simple eggs: poached, boiled, steamed, sunny side up, Shakshuka . Processed eggs: scrambled, fried, omlette, or Benedict . Simple eggs with bacon, ham, or sausage . Processed eggs with bacon, ham, or sausage . Asian 14 6 0 0 European 7 6 4 3 American 0 1 14 5 Analyzed by the first consecutive 20 images on Google (accessed on 22 April 2022). Open in new tab A. Plain or minimally processed (boiled, poached, sunny side up, or Shakshuka). B. Processed and/or enriched (scrambled, fried, omelet, or Benedict) C. Plain with side dishes (bacon, ham, corned beef, or sausage) and D. Processed with side dishes. For Asia, the number of images were 14 for A, 6 for B, 0 for C, 0 for D; in Europe 7 for A, 6 for B, 4 for C, 3 for D, and in the US 0 for A, 1 for B, 14 for C, 5 for D (Table 1). Thus, in Asia, breakfast eggs are predominantly consumed unadulterated, whereas in the USA, breakfast eggs most often either are scrambled, fried, and/or accompanied by bacon, ham, or sausage. In Europe, breakfast egg consumption shows a mixed pattern. Could it be that not the eggs per se but rather the ingredients of their preparation and their accompanying dishes exerted the detrimental outcome observed in the paper of Zhao et al.?3 In the large cohort study of Qin et al.4 among Chinese adults, a moderate level of egg consumption was even associated with a significantly lower risk of CVD and stroke, largely independent of other risk factors. Of note, despite high per capita intake, most Asian studies documented either no effect or a J-shaped curve between outcome and egg consumption. Egg preparation When specifically looking at cooking methods in a study of 8241 healthy Chinese adults Wu et al.5 documented a positive association between fried egg consumption and odds of metabolic syndrome, (odds ratio 1.22, 95% CI 1.08–1.39: P trend <001 for comparing the highest category of more than 1/2 fried egg/per day with the lowest category of about 1 egg per week). In contrast, nonfried egg intake was not associated with metabolic syndrome odds (P trend = 0.08). Supporting the observation of Wu et al.5 are experimental data suggesting that frying or certain ways of food processing may transform dietary cholesterol in egg or meat products to potentially more atherogenic forms known as cholesterol oxidation products (COPs).6 When eggs are boiled instead of fried, COPs can be avoided. More investigation is needed to clarify the role of egg preparation, beyond its inherent cholesterol content. Munavoi As to Finland where the ATBC Study3 was conducted, a traditional egg breakfast consists of Munavoi (egg butter) with Karelian pie, called Karjalanpiirakka (Figure 1). The customary Munavoi recipe calls for one tablespoon (15 g) of butter per egg. Zhao et al.3 indicate that their multivariable models were further adjusted for numerous potential confounders including saturated fatty acids, monounsaturated fatty acids, and polyunsaturated fatty acids. We wonder whether such adjustment did extend to the excessive butter content in Munavoi. Figure 1 Open in new tabDownload slide Karjalanpiirakka (Karelian pie with Munavoi). Guidelines and clinical implications Before attempting to issue guidelines on modifications of egg consumption, we should consider possible clinical implications. Let us simply assume that patients and physicians could be convinced about the harmful effects of eggs and were willing to substitute a whole grain carbohydrate breakfast for a traditional egg breakfast. In the USA, such a substitution for eggs with bacon, ham, and sausage is likely to improve lipid profiles and to possibly confer cardiovascular benefits. In Finland, Munavoi without butter may well create frustration and unhappiness, which has its own cardiovascular risk. And in Asia, where per capita egg consumption is highest in the world, exceeding 300 eggs per year in China and Japan, carbohydrate substitution is prone to deprive people of an affordable and accessible source of good quality nutrients which may well exert detrimental effects. Association fallacy Based on the above continental differences of traditional egg breakfasts as evaluated by Google pictures, we submit that in the USA and to a lesser extent in Europe, egg consumption merely seems to be a marker of associated unhealthy food intake. Thus, many studies on egg consumption and outcome have been falling into the trap of association fallacy; eggs are judged guilty by being associated with some well-known malefactors such as butter, bacon, ham, and sausage. However, as documented in Asia, egg consumption in moderation may by itself be little more than an innocent bystander for the risk of CVD disease. We should consider however, that for many people, the gustatory appeal of a naked egg on a breakfast buffet does ill compare to it being buttered, fried, and decorated with crispy ham and bacon. While stage coaching through the Rockies in the 1860ties, Mark Twain reflected in his notebook: ‘Nothing helps the scenery like ham and eggs … ham and eggs and scenery, a downgrade, a flying coach, a fragrant pipe and a contended heart—these make happiness. It is what all the ages have struggled for’.7 We whole heartedly agree, as long as ham is added to eggs only to enhance the scenery and then only on the occasion of stage coaching. Data availability Data underlying this article were collected from Google picture accessed on June 22, 2022. References 1 https://www.incredibleegg.org/professionals/foodservice/egg-and-egg-products/egg-composition-nutrition#:∼:text=Eggs%20provide%20an%20excellent%20source,all%20for%20only%2070%20calories (29 April 2022, date at last accessed). 2 Drouin-Chartier J-P , Chen S, Li Y et al. Egg consumption and risk of cardiovascular disease: Three large prospective US cohort studies, systematic review, and updated meta-analysis . BMJ 2020 ; 368 : m513 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 3 Zhao B , Gan L, Graubard BI et al. Associations of dietary cholesterol, serum cholesterol, and egg consumption with overall and cause-specific mortality, and systematic review and updated meta-analysis . Circulation 2022 ; 145 : 1506 – 1520 . Google Scholar Crossref Search ADS PubMed WorldCat 4 Qin C , Lv J, Guo Y et al. Associations of egg consumption with cardiovascular disease in a cohort study of 0.5 million Chinese adults . Heart 2018 ; 104 : 1756 – 1763 . Google Scholar Crossref Search ADS PubMed WorldCat 5 Wu F , Zhuang P, Zhan C et al. Egg and dietary cholesterol consumption and the prevalence of metabolic syndrome: findings from a population-based nationwide cohort . J Acad Nutr Diet 2022 ; 122 : 758 – 770.e5 . Google Scholar Crossref Search ADS PubMed WorldCat 6 Staprans I , Pan XM, Rapp JH, Grunfeld C, Feingold KR. Oxidized cholesterol in the diet accelerates the development of atherosclerosis in LDL receptor- and apolipoprotein E-deficient mice . Arterioscler Thromb Vasc Biol 2000 ; 20 : 708 – 714 . Google Scholar Crossref Search ADS PubMed WorldCat 7 Beahrs A . Mark Twain: Writer, Humorist, Locavore. The Atlantic 2010, July 14 Author notes Conflict of interest: None declared. © The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: [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) © The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: [email protected]