Wednesday 24 May
Gene therapy in lipid metabolism and CVD
Sekar Kathiresan is co-founder, chief executive officer and a member of the company’s board of directors of Verve Therapeutics. Prior to joining Verve, he served as Director of the Massachusetts General Hospital (MGH) Center for Genomic Medicine and was the Ofer and Shelly Nemirovsky MGH Research Scholar. He also served as Director of the Cardiovascular Disease Initiative at the Broad Institute and was Professor of Medicine at Harvard Medical School. His research focused on understanding the inherited basis for blood lipids and myocardial infarction (MI) and using these insights to improve preventive cardiac care. Among his scientific contributions, Dr. Kathiresan helped to highlight new biological mechanisms underlying MI, discovered mutations that protect against MI risk, and developed a genetic test for personalized MI prevention. He received a Distinguished Scientist Award from the American Heart Association and the 2018 Curt Stern Award from the American Society of Human Genetics.
Dr. Kathiresan completed a Bachelor of Arts in history from the University of Pennsylvania and a medical degree from Harvard Medical School. He undertook clinical training in internal medicine and cardiology at MGH and postdoctoral research training in human genetics at the Framingham Heart Study and the Broad Institute.
Gene-based therapies to address dyslipidemia will undoubtedly lead to a paradigm shift in lipid management. These approaches include gene silencing methods (such as antisense or siRNA therapies), which act at specific targets of lipid metabolism. Their high specificity and efficacy, low dosing frequency and relatively predictable adverse event profile are key advantages over conventional lipid lowering treatments. Although at an earlier stage of development, gene replacement and gene-editing strategies offer potential for the management of severe, monogenic forms of dyslipidemia. Somatic gene editing has application for the treatment of severe forms of dyslipidemia, and, subject to demonstration of efficacy and safety, may offer therapeutic opportunities in a wider patient population at risk of cardiovascular disease .
The development of clustered-regularly-interspaced-short-palindromic-repeats/CRISPR-associated 9 (CRISPR/Cas9), which produces double-stranded DNA-breaks at precise sites, has been a key driver of practical application of gene editing. Among the first of these novel treatments is VERVE-101, an investigational in vivo CRISPR base editing therapy which is designed to alter a single DNA base in the PCSK9 gene, permanently turn off hepatic protein production, and thus durably lower low-density lipoprotein cholesterol (LDL-C) levels. Studies in non-human primates and a murine model showed that the LDL-C lowering response was durable, and that treatment was well tolerated. These findings provided a basis for progression to the first-in-human clinical trial in patients with heterozygous familial hypercholesterolemia and atherosclerotic cardiovascular disease. Such ‘one treatment’ approaches offer the real possibility for lifelong reduction in cardiovascular risk in individuals with this common inherited dyslipidemia.
Lee RG, Mazzola AM, Braun MC, Platt C, Vafai SB, Kathiresan S, Rohde E, Bellinger AM, Khera AV. Efficacy and Safety of an Investigational Single-course CRISPR base editing therapy targeting PCSK9 in non-human primate and mouse models. Circulation 2022. doi: 10.1161/CIRCULATIONAHA.122.062132
Khera AV, Wang M, Chaffin M, Emdin CA, Samani NJ, Schunkert H, Watkins H, McPherson R, Elosua R, Boerwinkle E, Ardissino D, Butterworth AS, Di Angelantonio E, Naheed A, Danesh J, Chowdhury R, Krumholz HM, Sheu WH, Rich SS, Rotter JI, Chen YI, Gabriel S, Lander ES, Saleheen D, Kathiresan S. Gene sequencing identifies perturbation in nitric oxide signaling as a nonlipid molecular subtype of coronary artery disease. Circ Genom Precis Med 2022; 10:101161CIRCGEN121003598.
Musunuru K, Chadwick AC, Mizoguchi T, Garcia SP, DeNizio JE, Reiss CW, Wang K, Iyer S, Dutta C, Clendaniel V, Amaonye M, Beach A, Berth K, Biswas S, Braun MC, Chen HM, Colace TV, Ganey JD, Gangopadhyay SA, Garrity R, Kasiewicz LN, Lavoie J, Madsen JA, Matsumoto Y, Mazzola AM, Nasrullah YS, Nneji J, Ren H, Sanjeev A, Shay M, Stahley MR, Fan SHY, Tam YK, Gaudelli NM, Ciaramella G, Stolz LE, Malyala P, Cheng CJ, Rajeev KG, Rohde E, Bellinger AM, Kathiresan S. In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates. Nature 2021;593:429-34.
Sek Kathiresan, USA
Imaging and reclassification & risk stratification
Khurram Nasir is Professor of Cardiology, Academic Institute, Chief, Division of Cardiovascular Prevention and Wellness, Department of Cardiology and Co-director, Center for Health Data Science and Analytics, Houston Methodist and Weill Cornell Medical College, USA. His research aims to identify the at-risk population to enable treatments to better targeted.
Dr. Nasir completed his medical degree in Pakistan, followed by a Master of Public Health degree at John Hopkins University. He undertook a residency at Boston Medical Center, a cardiology fellowship at Yale University, postdoctoral research training at the Division of Cardiology, Johns Hopkins Hospital, a fellowship in cardiac imaging at Massachusetts General Hospital, and a Master’s degree in Health Economics and Policy Management from the London School of Economics & Political Science, UK. Dr Nasir was the recipient of the Johns Hopkins Distinguished Alumnus Award in 2013. He is Associate Editor for Circulation: Quality of Care and Outcomes, an editorial board member for Circulation, and is on the board of directors for the American Society of Preventive Cardiology.
Cardiovascular disease is the leading cause of death globally. To reduce this burden of disease, identification of individuals at high risk is essential to early implementation of risk factor modifying therapies. Imaging modalities offer precise risk assessment and identification of individuals who are likely to derive the most benefit from treatment.
Coronary artery calcium (CAC) is recognised as a mainstay in personalized risk assessment in primary prevention, supported by extensive evidence for the association between CAC burden, total coronary plaque, and incident coronary heart disease and atherosclerotic cardiovascular disease events. CAC has increasingly been used for stratification of cardiovascular disease risk, and also improves discrimination and cardiovascular risk reclassification beyond traditional risk factors in asymptomatic individuals. Coronary computed tomography angiography (CCTA) has utility in identifying complex plaque morphology and assessing plaque characteristics. Although the evidence for CCTA for risk assessment on top of CAC in primary prevention is limited, this modality may have a role in clinical decision making for adjunctive therapies on top of statin treatment. Assessment of plaque burden may add incremental prognostic value over established CCTA measures in individuals with suspected coronary artery disease and a high prevalence of risk-factors.
Application of artificial intelligence to non-invasive cardiovascular imaging modalities will undoubtedly improve risk stratification and patient-tailored risk prediction.
Nasir K, Cainzos-Achirica M, Valero-Elizondo J, Ali SS, Harvesting R, Lakshman S, Blaha MJ, Blankstein R, Shapiro MD, Arias L, Saxena A, Feldman T, Budoff MJ, Ziffer JA, Fialkow J, Cury RC. Coronary Atherosclerosis in an asymptomatic U.S. population: Miami Heart Study at Baptist Health South Florida. JACC Cardiovasc Imaging 2022;15:1604-18.
Agha AM, Pacor J, Grandhi GR, Mszar R, Khan SU, Parikh R, Agrawal T, Burt J, Blankstein R, Blaha MJ, Shaw LJ, Al-Mallah MH, Brackett A, Cainzos-Achirica M, Miller EJ, Nasir K. The prognostic value of CAC zero among individuals presenting with chest pain: a meta-analysis. JACC Cardiovasc Imaging 2022;15:1745-57.
Cainzos-Achirica M, Quispe R, Mszar R, Dudum R, Al Rifai M, Erbel R, Stang A, Jöckel KH, Lehmann N, Schramm S, Schmidt B, Toth PP, Rana JS, Lima JAC, Doria de Vasconcellos H, Lloyd-Jones D, Joshi PH, Ayers C, Khera A, Blaha MJ, Greenland P, Nasir K. Coronary artery calcium score to refine the use of PCSK9i in asymptomatic individuals: a multicohort study. J Am Heart Assoc 2022;11(16):e025737.
Khurram Nasir, USA
Single-cell and spatial transcriptomics dissection of coronary artery disease
Manolis Kellis is Professor of Computer Science at Massachusetts Institute of Technology (MIT), a member of the Broad Institute of MIT and Harvard, and a member of the Computer Science and Artificial Intelligence Laboratory at MIT where he directs the MIT Computational Biology Group (compbio.mit.edu). A major focus of his work is understanding the effects of genetic variation on various human diseases, including obesity, diabetes, Alzheimer’s disease and cancer. Specifically, his research focuses on i) genome interpretation, aiming to develop comparative genomics methods to identify genes and regulatory elements in the human genome; ii) gene regulation; iii) epigenomics, aiming to understand the chromatin signatures associated with distinct activity states, and the changes in these states across different cell types and during differentiation; and iv) evolutionary genomics, aiming to understand the dynamics of gene phylogenies across complete genes.
Single-cell RNA sequencing (scRNA-seq) has been instrumental to understanding cellular heterogeneity and to defining the pathophysiological processes underlying cardiovascular disease. Using this approach, researchers have been able to trace cells during their differentiation, elucidate the activation and deactivation of specific genes required in this process, as well as gain insights into cell signalling and gene expression patterns relevant to cardiovascular disease pathogenesis. Increasing the depth of cellular resolution has enabled identification of specialized subpopulations of immune cells, offering insights into vascular inflammation and potential therapeutic targets.
The combination of scRNA-seq and spatial transcriptomics enables evaluation of the spatial distribution of different cell populations, and local networks of intercellular communication. Recent studies using these approaches to assess cardiac tissues have helped to elucidate the diversity of cardiac cell populations, and identify expression of the SARS-CoV-2 receptors in different cardiovascular cells. Importantly, scRNA-seq provides a tool to investigate responses to myocardial injury and remodelling at the cellular level, as well as to profile heart failure. Future insights may help in discerning the pathophysiology of complex cardiac disease, and lead to identification of novel therapeutic targets.
Blanchard JW, Akay LA, Davila-Velderrain J, von Maydell D, Mathys H, Davidson SM, Effenberger A, Chen CY, Maner-Smith K, Hajjar I, Ortlund EA, Bula M, Agbas E, Ng A, Jiang X, Kahn M, Blanco-Duque C, Lavoie N, Liu L, Reyes R, Lin YT, Ko T, R’Bibo L, Ralvenius WT, Bennett DA, Cam HP, Kellis M, Tsai LH. APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes. Nature 2022:doi: 10.1038/s41586-022-05439-w.
Yang J, Vamvini M, Nigro P, Ho LL, Galani K, Alvarez M, Tanigawa Y, Renfro A, Carbone NP, Laakso M, Agudelo LZ, Pajukanta P, Hirshman MF, Middelbeek RJW, Grove K, Goodyear LJ, Kellis M. Single-cell dissection of the obesity-exercise axis in adipose-muscle tissues implies a critical role for mesenchymal stem cells. Cell Metab 2022;34:1578-93.
Xiong X, Hou L, Park YP, Molinie B; GTEx Consortium, Gregory RI, Kellis M. Genetic drivers of m6A methylation in human brain, lung, heart and muscle. Nat Genet 2021;53:1156-65.
Manolis Kellis, USA
Update on targeting PCSK9 vis a vis GLP1R agonist / SGLT2i
Pam R. Taub, MD is Professor of Medicine at the University of California (UC) San Diego School of Medicine in the Division of Cardiovascular Medicine. She is the Founding Director of the Step Family Foundation Cardiac Rehabilitation and Wellness Center. Her ongoing research focuses on the impact of daily fasting on cardiometabolic parameters and on mitochondrial function; biomarkers for cardiovascular risk factor stratification; wearable/mobile devices for improving cardiovascular outcomes; and the impact of epicatechin (compound in dark chocolate) on mitochondrial function/cellular bioenergetics and exercise capacity.
Dr. Taub completed her medical degree from Boston University School of Medicine, her residency at the University of Washington Medical Center in Seattle and her fellowship in cardiovascular medicine at UC San Diego. She is a fellow of the American College of Cardiology and a fellow and board member for the American Society of Preventive Cardiology.
Individuals with type 2 diabetes mellitus (T2DM) are at high risk of cardiovascular mortality, and this risk is doubled for those who also have established cardiovascular disease. Recent cardiovascular outcomes studies have demonstrated cardiovascular benefits for two classes of antiglycemic agents, sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists. In summary, SGLT-2 inhibitors were superior to GLP-1 receptor agonists for improving cardiovascular outcomes such as myocardial infarction and heart failure-related outcomes, as well as renal outcomes, whereas GLP-1 receptor agonists were superior for stroke outcomes.
The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, which substantially lower low-density lipoprotein cholesterol (LDL-C), also reduce cardiovascular events in diabetes patients. Although Mendelian randomization studies showed that PCSK9 genetic variants associated with lower LDL-C levels correlated with a higher incidence of T2DM, data from randomized controlled trials suggest no detrimental effect of PCSK9 monoclonal antibody therapy on glucose homeostasis.
To date there is no cardiovascular outcomes trial offering direct comparisons of these drug classes and nor is one likely. As patients with T2DM are at risk of a range of cardiovascular and renal events, treatment needs to be targeted according to the patient profile. In addition to cardiovascular benefits, SGLT-2 inhibitors and GLP-1 receptor agonists have benefits on glycaemia and body weight, as well as moderate effects on blood pressure and lipid levels; a PCSK9 inhibitor is needed to lower atherosclerotic risk.
Handelsman Y, Anderson JE, Bakris GL, Ballantyne CM, Beckman JA, Bhatt DL, Bloomgarden ZT, Bozkurt B, Budoff MJ, Butler J, Dagogo-Jack S, de Boer IH, DeFronzo RA, Eckel RH, Einhorn D, Fonseca VA, Green JB, Grunberger G, Guerin C, Inzucchi SE, Jellinger PS, Kosiborod MN, Kushner P, Lepor N, Mende CW, Michos ED, Plutzky J, Taub PR, Umpierrez GE, Vaduganathan M, Weir MR. DCRM Multispecialty Practice Recommendations for the management of diabetes, cardiorenal, and metabolic diseases. J Diabetes Complications 2022;36(2):108101.
Manoogian ENC, Zadourian A, Lo HC, Gutierrez NR, Shoghi A, Rosander A, Pazargadi A, Ormiston CK, Wang X, Sui J, Hou Z, Fleischer JG, Golshan S, Taub PR, Panda S. Feasibility of time-restricted eating and impacts on cardiometabolic health in 24-h shift workers: The Healthy Heroes randomized control trial. Cell Metab 2022;34:1442-56.e7.
Aroda VR, Taub PR, Stanton AM. Diabetes with cardiomyopathy: at the juncture of knowledge and prevention. J Am Coll Cardiol 2021;78:1599-602.
Pam Taub, San Diego, USA
Monday 22 May
Integrating the many players of cardiovascular risk
Fatty liver disease; the new kid on the block of cardio-metabolic disorders
Christos Mantzoros is Professor of Medicine at Harvard Medical School, Director of the Human Nutrition Unit, Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, and Chief of Endocrinology, VA Boston Healthcare System, Boston, Massachusetts. His research focuses on obesity, diabetes and adipokine biology. Basic research in his laboratory utilises genomics-bioinformatics, animal physiology, and molecular biology studies to elucidate the role of new molecules important in energy homeostasis. Current translational /clinical investigations focus mainly on the role of metabolically important hormones, including leptin, irisin and adiponectin as well as their downstream effectors, on energy homeostasis and metabolic abnormalities. Dr Mantzoros serves as the Editor-in-Chief of Metabolism, Clinical and Experimental. He is the recipient of numerous awards including the American Association of Clinical Endocrinology Frontiers in Science Award, the Novartis Award in Diabetes and Metabolic Diseases, the Lilly Award by the North American Association for the Study of Obesity, the American Society for Nutrition Mead Johnson Award, the HypoCCS award in Paris, France, the Wilhelm Friedrich Bessel Award by the Humboldt Foundation of Germany, The Hygeia Award of the New England Hellenic Medical and Dental Society, the Outstanding Investigator Award by the American Federation of Medical Research, and the Solomon Berson Award from the American Physiological Society and FASEB, He is the scientific co-founder of Intekrin Metabolic Therapeutics.
Previously referred to as Non-Alcoholic Fatty Liver Disease, Fatty Liver Disease (FLD) is highly prevalent, already affecting 25% of adults worldwide, and escalating in concert with global trends for obesity and diabetes. FLD – particularly its more severe presentation non-alcoholic steatohepatitis (NASH) – and cardiovascular disease shares several risk factors, such as obesity, metabolic syndrome, hypertension, dyslipidemia, type 2 diabetes, and chronic kidney disease. Whether FLD as an independent risk factor for the development of cardiovascular disease is the focus of ongoing research.
The pathology of FLD is complex and influenced by multiple factors. Metabolic dysfunction predisposes to liver pathology, and widespread abnormal peri-organ or intra-organ fat deposition may contribute to cardiovascular risk. Type 2 diabetes may represent the common link between FLD and cardiovascular disease, given evidence that FLD, insulin resistance and fat accumulation in the liver are strongly related.
Improved understanding of the pathophysiology of FLD is critical to better characterise the disease. For example, the incorporation of accurate, validated and specific non-invasive biomarkers would help in disease identification, staging, prognosis and follow-up, thereby allowing for a more individualised approach to management, as well as guiding response to treatment. Recent guidelines recommend lifestyle interventions, bariatric surgery, and pharmacotherapy, including glucagon-like peptide-1 receptor agonists, peroxisome proliferator-activated receptor-gamma agonists, and sodium-glucose cotransporter-2 inhibitors. In addition to personalised therapeutic approaches, however, public health policies that consider FLD together with relevant comorbidities are needed to impact the burden of this increasingly prevalent disease.
Angelidi AM, Kokkinos A, Sanoudou D, Connelly MA, Alexandrou A, Mingrone G, Mantzoros CS. Early metabolomic, lipid and lipoprotein changes in response to medical and surgical therapeutic approaches to obesity. Metabolism 2022;138:155346.
Larsson SC, Michaëlsson K, Mola-Caminal M, Höijer J, Mantzoros CS. Genome-wide association and Mendelian randomization study of fibroblast growth factor 21 reveals causal associations with hyperlipidemia and possibly NASH. Metabolism 2022;37:155329.
Kouvari M, Tsiampalis T, Kosti RI, Naumovski N, Chrysohoou C, Skoumas J, Pitsavos CS, Panagiotakos DB, Mantzoros CS. Quality of plant-based diets is associated with liver steatosis, which predicts type 2 diabetes incidence ten years later: Results from the ATTICA prospective epidemiological study. Clin Nutr 2022;41:2094-102.
Christos Mantzoros, USA
Lp(a) - Finding the right place
Florian Kronenberg is Professor and Head of the Institute of Genetic Epidemiology at the Medical University of Innsbruck, Austria. He completed his medical degree at the University of Innsbruck and training in Medical Genetics in Gerd Utermann’s laboratory, and then worked at the Department of Cardiovascular Genetics, University of Utah, USA. He subsequently was appointed Head of the Research Unit “Genetic Epidemiology” at the Institute of Epidemiology, Helmholtz Center Munich before taking up his current position in 2004. His research interests include genetic and clinical epidemiological studies on lipoprotein(a), as well as the genetics of atherosclerosis, lipid disorders, kidney diseases, diabetes mellitus and related intermediate phenotypes. He served as a working group member on several guideline and consensus initiatives in the field of kidney disease as well as lipid metabolism.
Current evidence supports elevated lipoprotein(a) [Lp(a)] as a causal cardiovascular risk factor, and also associated with increased risk for aortic valve stenosis. As elevated Lp(a) (≥50 mg/dL) is common, affecting more than one in five of the general population, even higher among Black individuals, renewed efforts are needed to ensure testing for Lp(a) becomes routine in clinical practice. Indeed, guidelines recommend that Lp(a) should be measured at least once during the lifetime.
There are, however, persistent challenges with measuring Lp(a) with the assays available in routine practice, as well as the management of high Lp(a) levels, given the absence of approved specific Lp(a)-lowering therapies. Given evidence that Lp(a) interacts with other risk factors to exacerbate global cardiovascular risk, the 2022 European Atherosclerosis Society consensus panel statement recommended personalised risk factor intervention to mitigate the risk associated with elevated Lp(a). As the impact of a high Lp(a) concentration is greater among individuals with higher than lower absolute cardiovascular risk, more intense risk factor modification is necessitated.
For clinicians, the take home message is to measure Lp(a), as for too long this has been neglected in the clinic, and to manage those individuals identified with (very) high Lp(a) concentration with intensive risk factor modification. Results from the ongoing Lp(a) HORIZON trial are critical to answering the key question: whether lowering elevated Lp(a) concentration reduces cardiovascular risk.
Kronenberg F, Mora S, Stroes ESG, Ference BA, Arsenault BJ, Berglund L, Dweck MR, Koschinsky M, Lambert G, Mach F, McNeal CJ, Moriarty PM, Natarajan P, Nordestgaard BG, Parhofer KG, Virani SS, von Eckardstein A, Watts GF, Stock JK, Ray KK, Tokgözoğlu LS, Catapano AL. Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement. Eur Heart J 2022;43:3925-46.
Kronenberg F. Measuring lipoprotein(a): do it without ifs and buts. Eur J Prev Cardiol 2022;29:766-8.
Kronenberg F. Lipoprotein(a) and aortic valve stenosis: work in progress. Eur Heart J 2022;43:3968-70.
Florian Kronenberg, Austria
Peter Libby, USA
Antonio Vidal-Puig, UK
Tuesday 23 May
Identifying new pathways/players in CVD
Stephanie Dimmeler is Director of the Institute of Cardiovascular Regeneration at Frankfurt University. Her research focuses on the basic mechanisms underlying cardiovascular disease and vessel growth, with ongoing studies directed to elucidating epigenetic mechanisms that control cardiovascular repair, specifically the function of histone modifying enzymes and non-coding RNAs. Professor Dimmeler completed undergraduate training at the University of Konstanz, and postdoctoral training at the Department of Experimental Surgery at the University of Cologne, and the Department of Molecular Cardiology the University of Frankfurt, before appointment as Head of the Department of Molecular Cardiology at Frankfurt University. She is the recipient of numerous awards, most recently the Science4life award, the GlaxoSmithKline Award and the Madrid Award for Stem Cell Therapy in 2014, and presented the Thomas W. Smith Memorial Lecture at the Scientific Sessions of the American Heart Association in 2015. Professor Dimmeler is editor of EMBO Molecular Medicine and associate editor of Circulation Research and the European Heart Journal.
Tissue ischemia induced by myocardial infarction results in changes in endothelial cell function. Studies show that endothelial cells undergo a transient mesenchymal activation, which may facilitate regeneration of the vasculature. This ability of endothelial cells to transiently respond and recover maintenance functions – endothelial cell resilience – represents successful adaptation to the combined effects of hypoxia, inflammation, metabolic changes and clonal expansion associated with myocardial injury.
Cross-talk within the cardiac microenvironment, for example via long coding RNA (lncRNA CALA), regulates endothelial cell function and influences cardiomyocyte renewal, inflammation and fibrosis. Studies using single-cell multi-omics and genetic lineage tracing have identified transcriptional and phenotypical adaptation to the injured endothelial microenvironment. Together with bioinformatics analysis of putative ligand–receptor interaction, these approaches could be used to better define the pathophysiology of heart failure. Added to this, mechanistic studies of transient endothelial plasticity may help to identify potential targets for increasing endothelial resilience. Integration of these novel technologies will be critical to understanding the mechanistic drivers of cardiovascular disease, as well as providing novel approaches to individualised therapy.
Speer T, Dimmeler S, Schunk SJ, Fliser D, Ridker PM. Targeting innate immunity-driven inflammation in CKD and cardiovascular disease. Nat Rev Nephrol 2022;18:762-78.
Abplanalp WT, Tucker N, Dimmeler S. Single-cell technologies to decipher cardiovascular diseases. Eur Heart J 2022;43:4536-47.
Heumüller AW, Jones AN, Mourão A, Klangwart M, Shi C, Wittig I, Fischer A, Muhly-Reinholz M, Buchmann GK, Dieterich C, Potente M, Braun T, Grote P, Jaé N, Sattler M, Dimmeler S. Locus-conserved circular RNA cZNF292 controls endothelial cell flow responses. Circ Res 2022;130:67-79.
Stefanie Dimmeler, Germany
Discovery of multi receptor drugs for metabolic diseases
Matthias Tschöp is Chief Executive Officer and Scientific Director of Helmholtz Zentrum München, Alexander von Humboldt Professor and Chair of Metabolic Diseases at Technical University of Munich, and serves as an adjunct professor at Yale University, USA. His research focuses on the molecular mechanisms of diabetes and obesity in order to discover new preventive and therapeutic approaches for the metabolic syndrome. Recent research includes investigation of gut-brain communication as a key circuitry that regulates adiposity, glucose homeostasis and energy metabolism, as well as novel strategies for the early detection, individualised characterisation, and personalised therapy of metabolic dysfunction. His contributions include discovery of the hunger hormone ghrelin and gut hormone polyagonists that target both weight reduction and glycaemic control. Professor Tschöp completed his undergraduate and PhD studies at LMU Munich, and held postdoctoral positions at Eli Lilly and the German Institute of Human Nutrition in Potsdam. At the University of Cincinnati, he was Professor of Endocrinology and Diabetes at the Metabolic Diseases Institute, held the Arthur Russell Morgan Endowed Chair of Medicine, and was Research Director of the Metabolism Center of Excellence for Diabetes and Obesity. Professor Tschöp is a member of the European Molecular Biology Organization, the Bavarian Academy of Sciences and Humanities, and Academia Europaea. He is the recipient of numerous awards, most recently in 2021, the Ernst Jung Prize for Medicine and the Berthold Medal, and in 2019, the Paul Langerhans Medal.
Dysregulation of interorgan communication contributes to obesity, diabetes, fatty liver disease (FLD) and atherosclerosis. Advances in ‘omics’ technologies have provided new insights into the complexity of systemic metabolic cross-talk, including the role of neuroimmune interactions involving the brain and peripheral nervous system (somatic or autonomous) in the control of energy balance. Response to different metabolic challenges can modulate the expression of genes involved in de novo lipogenesis or lipid transport in the hypothalamus, as well as the activity of peripheral organs, of relevance for the development of obesity and metabolic sequelae including dyslipidemia. Astrocytes have emerged as a potential player in hypothalamic control of energy balance, given that these are the main site of fatty acid β-oxidation within the central nervous system. Indeed, studies in knockdown animal models identified a role for astrocytic fatty acid metabolism in central control of body weight and glucose homeostasis, possibly mediated by adaptive mitochondrial changes within the astrocytes.
Dyslipidemia may also mediate the cross-talk between disease states in the liver and kidney. Dysregulation of lipid uptake, oxidation or de novo lipogenesis contribute to the adverse effects of ectopic lipids and promote the development and progression of fatty liver disease and chronic kidney disease.
Understanding the molecular mechanisms of interorgan crosstalk may help to identify novel targets and therapeutics that can address dysregulated interorgan communication and the associated secondary organ complications.
Müller TD, Tschöp MH. Gut-hormone triple agonists: clinical safety and metabolic benefits. Lancet 2022;400:1826-28.
Herrera Moro Chao D, Kirchner MK, Pham C, Foppen E, Denis RGP, Castel J, Morel C, Montalban E, Hassouna R, Bui LC, Renault J, Mouffle C, García-Cáceres C, Tschöp MH, Li D, Martin C, Stern JE, Luquet SH. Hypothalamic astrocytes control systemic glucose metabolism and energy balance. Cell Metab 2022;34:1532-47.e6.
Abuhattum S, Kotzbeck P, Schlüßler R, Harger A, Ariza de Schellenberger A, Kim K, Escolano JC, Müller T, Braun J, Wabitsch M, Tschöp M, Sack I, Brankatschk M, Guck J, Stemmer K, Taubenberger AV. Adipose cells and tissues soften with lipid accumulation while in diabetes adipose tissue stiffens. Sci Rep 2022;12:10325.
Matthias Tschöp, Germany
Stress and the immune system
Dr Swirski is the Arthur and Janet C. Ross Professor of Medicine (Cardiology) and Professor of Diagnostic, Molecular and Interventional Radiology at the Icahn School of Medicine at Mount Sinai, as well as Director of the Cardiovascular Research Institute. He obtained his PhD at McMaster University in Canada and undertook postdoctoral studies at Brigham and Women’s Hospital, Boston, before appointment as Professor at Harvard Medical School and Massachusetts General Hospital. His research focuses on innate immunity and inflammation in cardiovascular disease. He uses in vivo models of acute and chronic inflammation relevant to cardiovascular and metabolic diseases, with specific emphasis on cell development, communication, and function. Recently, his focus has expanded to include lifestyle factors such as sleep, diet, and stress as critical modulators of cardiovascular health and hematopoiesis.
Psychosocial stress is a risk factor for many diseases, including atherosclerosis. Cross-talk between the brain and immune system plays a role in the fight-or-flight response to acute stress, and influences hematopoietic stem cell activity during chronic stress.
Leukocytes communicate across organ systems to shape immunity and inflammation in the body. The mechanistic pathways linking stress networks in the brain to peripheral leukocytes, however, is less well understood. Recent studies in experimental models show that distinct brain regions influence the leukocyte landscape during acute psychological stress. In this scenario, motor circuits mobilise neutrophils to the blood where they infiltrate peripheral organs and play a role in inflammation. In addition, lymphocytes are prevented temporarily from moving to the lymph nodes, potentially limiting adaptive immunity. Chronic psychosocial stress also produces monocytosis and neutrophilia, and in animal models, increases hemopoietic stem and progenitor cell proliferation and release from the bone marrow into the circulation, thereby accelerating atherosclerosis and promoting plaque features associated with vulnerable lesions in humans. These findings support a stress-sensitive neuro-immune axis between the sympathetic nervous system and cardiovascular health.
Understanding the pro-inflammatory effects of psychosocial stress and how these may be mitigated via resilience mechanisms may offer future therapeutic potential.
McAlpine CS, Kiss MG, Zuraikat FM, Cheek D, Schiroli G, Amatullah H, Huynh P, Bhatti MZ, Wong LP, Yates AG, Poller WC, Mindur JE, Chan CT, Janssen H, Downey J, Singh S, Sadreyev RI, Nahrendorf M, Jeffrey KL, Scadden DT, Naxerova K, St-Onge MP, Swirski FK. Sleep exerts lasting effects on hematopoietic stem cell function and diversity. J Exp Med 2022;219(11):e20220081.
Rohde D, Vandoorne K, Lee IH, Grune J, Zhang S, McAlpine CS, Schloss MJ, Nayar R, Courties G, Frodermann V, Wojtkiewicz G, Honold L, Chen Q, Schmidt S, Iwamoto Y, Sun Y, Cremer S, Hoyer FF, Iborra-Egea O, Muñoz-Guijosa C, Ji F, Zhou B, Adams RH, Wythe JD, Hidalgo J, Watanabe H, Jung Y, van der Laan AM, Piek JJ, Kfoury Y, Désogère PA, Vinegoni C, Dutta P, Sadreyev RI, Caravan P, Bayes-Genis A, Libby P, Scadden DT, Lin CP, Naxerova K, Swirski FK, Nahrendorf M. Bone marrow endothelial dysfunction promotes myeloid cell expansion in cardiovascular disease. Nat Cardiovasc Res 2022;1:28-44.
Poller WC, Downey J, Mooslechner AA, Khan N, Li L, Chan CT, McAlpine CS, Xu C, Kahles F, He S, Janssen H, Mindur JE, Singh S, Kiss MG, Alonso-Herranz L, Iwamoto Y, Kohler RH, Wong LP, Chetal K, Russo SJ, Sadreyev RI, Weissleder R, Nahrendorf M, Frenette PS, Divangahi M, Swirski FK. Brain motor and fear circuits regulate leukocytes during acute stress. Nature 2022;607:578-84.
Filip Swirski, USA
The changing landscape of atherosclerosis
Renu Virmani is President of CVPath Institute, Gaithersburg, and Clinical Professor, Department of Pathology at Georgetown University; University of Maryland-Baltimore; George Washington University, and Vanderbilt University, USA. Dr Virmani has revolutionised understanding of coronary atherosclerotic plaques and their role in sudden coronary death. Dr. Virmani received her medical degree from Lady Hardinge Medical College, Delhi University, New Delhi, India. She is a member of the American Heart Association, and the US and Canadian Academy of Pathology, and is a Fellow of the American College of Cardiology. In 2021, Dr. Virmani was a recipient of the European Society of Cardiology Gold Medal.
Therapeutic approaches to atherosclerotic cardiovascular disease (ASCVD) have predominantly focused on management of the major cardiovascular risk factors, including low-density lipoprotein cholesterol, diabetes and hypertension. It is evident, however, that other targets need to be considered, including triglyceride-rich lipoproteins and inflammatory pathways in ASCVD. In the context of increasing obesity across the globe, increasing perivascular adipose tissue density has been associated with vessel inflammation, in turn a driver of progression of the lipid component of coronary atherosclerotic plaque. Attention has also focused on non-traditional risk factors, such as those associated with the environment and the microbiome. Moreover, there is recognition that characteristics of the atherosclerotic plaque, in particular plaque morphology and coronary artery calcification, differ between men and women.
While the presence of macrophages is undoubtedly a hallmark of atherosclerosis, emerging evidence also shows that the phenotypic heterogeneity and plasticity of macrophages are relevant to the atherosclerotic process. Signals derived from atherosclerotic lesions drive the differentiation of macrophages into complex subsets which differ in their ability to enhance, resolve and regress atherosclerotic lesions. The functionality of these macrophage phenotypes is influenced by the microenvironment, changing with the extent of lipid and cholesterol loading, as well as the metabolic state of the cell. Thus, targeting specific macrophage phenotypes may offer future therapeutic potential for preventing atherosclerosis progression.
Lee SE, Sung JM, Andreini D, Al-Mallah MH, Budoff MJ, Cademartiri F, Chinnaiyan K, Choi JH, Chun EJ, Conte E, Gottlieb I, Hadamitzky M, Kim YJ, Lee BK, Leipsic JA, Maffei E, Marques H, de Araújo Gonçalves P, Pontone G, Shin S, Kitslaar PH, Reiber JHC, Stone PH, Samady H, Virmani R, Narula J, Berman DS, Shaw LJ, Bax JJ, Lin FY, Min JK, Chang HJ. Association between changes in perivascular adipose tissue density and plaque progression. JACC Cardiovasc Imaging 2022;15:1760-7.
van den Hoogen IJ, Stuijfzand WJ, Gianni U, van Rosendael AR, Bax AM, Lu Y, Tantawy SW, Hollenberg EJ, Andreini D, Al-Mallah MH, Cademartiri F, Chinnaiyan K, Chow BJW, Conte E, Cury RC, Feuchtner G, Gonçalves PA, Hadamitzky M, Kim YJ, Leipsic J, Maffei E, Marques H, Plank F, Pontone G, Villines TC, Lee SE, Al’Aref SJ, Baskaran L, Danad I, Gransar H, Budoff MJ, Samady H, Virmani R, Berman DS, Chang HJ, Narula J, Min JK, Bax JJ, Lin FY, Shaw LJ; ICONIC Investigators. Early versus late acute coronary syndrome risk patterns of coronary atherosclerotic plaque. Eur Heart J Cardiovasc Imaging 2022;23:1314-23.
Sato Y, Kawakami R, Sakamoto A, Cornelissen A, Mori M, Kawai K, Ghosh S, Romero ME, Kolodgie FD, Finn AV, Virmani R. Sex differences in coronary atherosclerosis. Curr Atheroscler Rep 2022;24:23-32.
Renu Virmani, USA