Dyslipidaemias in stroke, chronic kidney disease, and aortic stenosis: the new frontiers for cholesterol loweringCrea, Filippo
doi: 10.1093/eurheartj/ehab295pmid: 34097728
For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue on dyslipidaemias contains a State of the Art Review article entitled ‘How low is safe? The frontier of very low (<30 mg/dL) LDL cholesterol’ by Angelos Karagiannis from Emory University School of Medicine in Atlanta, GA, USA, and colleagues.1 The authors note that LDL cholesterol (LDL-C) is a proven causative factor for developing atherosclerotic cardiovascular disease (CVD), and its reduction substantially reduces cardiovascular risk.2–4 Individuals with genetic conditions associated with lifelong very low LDL-C levels can be healthy. We now possess the pharmacological armamentarium [statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors] to reduce LDL-C to an unprecedented extent. Increasing numbers of patients are expected to achieve very low (<30 mg/dL) LDL-C. Cardiovascular event reduction increases log linearly in association with lowering LDL-C, without reaching any clear plateau even when very low LDL-C levels are achieved. It is still controversial whether lower LDL-C levels are associated with significant clinical adverse effects (e.g. new-onset diabetes mellitus and possibly haemorrhagic stroke), and long-term data are needed to address safety concerns. This review presents the familial conditions characterized by very low LDL-C, analyses trials with lipid-lowering agents where patients attained very low LDL-C, and summarizes the benefits and potential adverse effects associated with achieving very low LDL-C. Given the potential for cardiovascular benefit and the short-term safety profile of very low LDL-C, it may be advantageous to attain such low levels in specific high-risk populations. Further studies are needed to compare the net clinical benefit of non-LDL-C-lowering interventions with very low LDL-C approaches, in addition to comparing the efficacy and safety of very low LDL-C levels vs. current recommended targets (Figure 1). Figure 1 Open in new tabDownload slide Summary of all the potential benefits and side effects associated with very low LDL-C. (from Karagiannis AD, Mehta A, Dhindsa DS, Virani SS, Orringer CE, Blumenthal RS, Stone NJ, Sperling LS. How low is safe? The frontier of very low (<30 mg/dL) LDL cholesterol. See pages 2154–2169) Figure 1 Open in new tabDownload slide Summary of all the potential benefits and side effects associated with very low LDL-C. (from Karagiannis AD, Mehta A, Dhindsa DS, Virani SS, Orringer CE, Blumenthal RS, Stone NJ, Sperling LS. How low is safe? The frontier of very low (<30 mg/dL) LDL cholesterol. See pages 2154–2169) Chronic kidney disease (CKD) is associated with high cardiovascular risk.5,6 CKD patients exhibit a specific lipoprotein pattern termed ‘uraemic dyslipidaemia’, which is characterized by rather normal/low LDL-C, low HDL cholesterol (HDL-C), and high triglyceride plasma levels. In a second State of the Art Review article entitled ‘Lipoproteins in chronic kidney disease: from bench to bedside’, Thimoteus Speer from the Saarland University Hospital in Germany, and colleagues provide an update on uraemic dyslipidaemia.7 The authors indicate that several lipoprotein classes are involved in the pathogenesis of CKD-associated CVDs. Uraemia leads to several modifications of the structure of lipoproteins such as changes of the proteome and the lipidome, post-translational protein modifications (e.g. carbamylation), and accumulation of small molecular substances within the lipoprotein moieties, which affect their functionality. Lipoproteins from CKD patients interfere with lipid transport and promote inflammation, oxidative stress, endothelial dysfunction, as well as other features of atherogenesis, thus contributing to the development of CKD-associated CVD (Figure 2). While lipid-modifying therapies play an important role in the management of CKD patients, their efficacy is modulated by kidney function. Novel therapeutic agents to prevent the adverse remodelling of lipoproteins in CKD and to improve their functional properties are highly desirable and partially under development. Figure 2 Open in new tabDownload slide Cellular effects of HDL, LDL, and VLDL from patients with chronic kidney disease. SDMA, symmetric dimethylarginine; SAA, serum amyloid A; SAPK/JNK, protein kinase/Janus kinase; SCIMP, SLP adaptor and CSK interacting membrane protein; SDMA, symmetric dimethylarginine; TF, tissue factor; TLR2, toll-like receptor-2; TLR4, toll-like receptor-4; TrF, transcription factor (from Speer T, Ridker PM, von Eckardstein A, Schunk SJ, Fliser D. Lipoproteins in chronic kidney disease: from bench to bedside. See pages 2170–2185). Figure 2 Open in new tabDownload slide Cellular effects of HDL, LDL, and VLDL from patients with chronic kidney disease. SDMA, symmetric dimethylarginine; SAA, serum amyloid A; SAPK/JNK, protein kinase/Janus kinase; SCIMP, SLP adaptor and CSK interacting membrane protein; SDMA, symmetric dimethylarginine; TF, tissue factor; TLR2, toll-like receptor-2; TLR4, toll-like receptor-4; TrF, transcription factor (from Speer T, Ridker PM, von Eckardstein A, Schunk SJ, Fliser D. Lipoproteins in chronic kidney disease: from bench to bedside. See pages 2170–2185). Lipoprotein(a) [Lp(a)] is a recognized causal risk factor for atherosclerotic cardiovascular disease.8–10 Its role in acute ischaemic stroke (AIS), however, remains controversial. In a clinical research article entitled ‘Lipoprotein(a) is associated with large artery atherosclerosis stroke aetiology and stroke recurrence among patients below the age of 60 years: results from the BIOSIGNAL study’, Markus Arnold from the University Hospital Zurich in Switzerland, and colleagues evaluated the association of Lp(a) with large artery atherosclerotic (LAA) stroke and risk of recurrent cerebrovascular events in AIS patients.11 For this analysis of the prospective, observational, multicentre BIOSIGNAL cohort study, the authors measured Lp(a) levels in plasma samples of >1700 primarily Caucasian AIS patients, collected within 24 h after symptom onset. Primary outcomes were LAA stroke aetiology and recurrent cerebrovascular events (ischaemic stroke or transient ischaemic attack) within 1 year. Arnold et al. showed that Lp(a) levels were independently associated with LAA stroke aetiology [adjusted odds ratio (adj OR) 1.48, per unit log 10 Lp(a) increase] and identified age as a potent effect modifier of this association (P for interaction = 0.031). The adj OR for LAA stroke in patients aged <60 years was 3.64. The authors did not find a significant association in the whole cohort for 152 recurrent cerebrovascular events. However, Lp(a) levels ≥100 nmol/L were associated with an increased risk for recurrent events among patients who were either <60 years (adj HR 2.40), had evident LAA stroke aetiology (adj HR 2.18), or had no known atrial fibrillation (adj HR 1.60). The authors conclude that elevated Lp(a) is independently associated with LAA stroke aetiology and risk of recurrent cerebrovascular events among primarily Caucasian individuals aged <60 years. The manuscript is accompanied by an Editorial by Sotirios Tsimikas from the University of California-San Diego in La Jolla, CA, USA.12 The author concludes that this study may provide useful data on whether the frequency of first or recurrent stroke events can be reduced by lowering plasma Lp(a). Familial hypercholesterolaemia (FH) and elevated Lp(a) are inherited disorders associated with premature atherosclerotic cardiovascular disease (ASCVD).13,14 Aortic valve stenosis (AVS) is the most prevalent valvular heart disease, and LDL-C and Lp(a) may be involved in its pathobiology. In a clinical research article ‘Lipoprotein(a), LDL-cholesterol, and hypertension: predictors of the need for aortic valve replacement in familial hypercholesterolaemia’ Leopoldo Pérez de Isla from the Universidad Complutense in Madrid, Spain, and colleagues investigated the frequency and predictors of severe AVS requiring aortic valve replacement (AVR) in molecularly defined patients with FH.15 The authors analysed the frequency and predictors of the need for AVR due to AVS in this cohort. More than 5000 were enrolled [3712 with FH; 1310 non-affected relatives (NARs)]. Fifty patients with FH (1.48%) and three NARs (0.27%) required AVR (OR 5.71) after a mean follow-up of 7.48 years. Cox regression analysis demonstrated an association between FH and AVR (HR 3.89), with older age, previous ASCVD, hypertension, and elevated Lp(a) being independently predictive of an event. Pérez de Isla and colleagues conclude that the need for AVR due to AVS is significantly increased in FH patients, particularly in those who are older and have previous ASCVD, hypertension, and elevated Lp(a). Reduction in LDL-C and Lp(a) together with control of hypertension could retard the progression of AVS in FH, but this needs testing in clinical trials. The article is accompanied by an Editorial by Florian Kronenberg from the Medical University of Innsbruck in Austria.16 The author concludes that we will need additional pieces of evidence to come to a definite conclusion considering that the incidence of aortic valve stenosis will markedly increase over the next decades due to increasing life expectancy. The issue is complemented by two Discussion Forum articles. In a contribution entitled ‘Neutrophil–lymphocyte ratio in the immune checkpoint inhibitors-related atherosclerosis’, Nan Zhang from the Second Hospital of Tianjin Medical University in Tianjin, China, and colleagues comment on the recent contribution entitled ‘The neutrophil–lymphocyte ratio and incident atherosclerotic events: analyses from five contemporary randomized trials’ by Nicholas H. Adamstein from the Brigham and Women’s Hospital in Boston, MA, USA, and colleagues.17,18 Adamstein et al. respond to this message in a separate contribution.19 The editors hope that readers of this issue of the European Heart Journal will find it of interest. With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article. References 1 Karagiannis AD , Mehta A , Dhindsa DS , Virani SS , Orringer CE , Blumenthal RS , Stone NJ , Sperling LS. How low is safe? The frontier of very low (<30 mg/dL) LDL cholesterol . Eur Heart J 2021 ; 42 :2154–2169. Google Scholar OpenURL Placeholder Text WorldCat 2 Ray KK. Changing the paradigm for post-MI cholesterol lowering from intensive statin monotherapy towards intensive lipid-lowering regimens and individualized care . Eur Heart J 2021 ; 42 : 253 – 256 . Google Scholar Crossref Search ADS PubMed WorldCat 3 Szarek M , Bittner VA , Aylward P , Baccara-Dinet M , Bhatt DL , Diaz R , Fras Z , Goodman SG , Halvorsen S , Harrington RA , Jukema JW , Moriarty PM , Pordy R , Ray KK , Sinnaeve P , Tsimikas S , Vogel R , White HD , Zahger D , Zeiher AM , Steg PG , Schwartz GG. Lipoprotein(a) lowering by alirocumab reduces the total burden of cardiovascular events independent of low-density lipoprotein cholesterol lowering: ODYSSEY OUTCOMES trial . Eur Heart J 2020 ; 41 : 4245 – 4255 . Google Scholar Crossref Search ADS PubMed WorldCat 4 Jaspers NEM , Blaha MJ , Matsushita K , van der Schouw YT , Wareham NJ , Khaw KT , Geisel MH , Lehmann N , Erbel R , Jöckel KH , van der Graaf Y , Verschuren WMM , Boer JMA , Nambi V , Visseren FLJ , Dorresteijn JAN. Prediction of individualized lifetime benefit from cholesterol lowering, blood pressure lowering, antithrombotic therapy, and smoking cessation in apparently healthy people . Eur Heart J 2020 ; 41 : 1190 – 1199 . Google Scholar Crossref Search ADS PubMed WorldCat 5 Marx N , Floege J. Dapagliflozin, advanced chronic kidney disease, and mortality: new insights from the DAPA-CKD trial . Eur Heart J 2021 ; 42 : 1228 – 1230 . Google Scholar Crossref Search ADS PubMed WorldCat 6 Rossignol P , Agarwal R , Canaud B , Charney A , Chatellier G , Craig JC , Cushman WC , Gansevoort RT , Fellström B , Garza D , Guzman N , Holtkamp FA , London GM , Massy ZA , Mebazaa A , Mol PGM , Pfeffer MA , Rosenberg Y , Ruilope LM , Seltzer J , Shah AM , Shah S , Singh B , Stefánsson BV , Stockbridge N , Stough WG , Thygesen K , Walsh M , Wanner C , Warnock DG , Wilcox CS , Wittes J , Pitt B , Thompson A , Zannad F. Cardiovascular outcome trials in patients with chronic kidney disease: challenges associated with selection of patients and endpoints . Eur Heart J 2019 ; 40 : 880 – 886 . Google Scholar Crossref Search ADS PubMed WorldCat 7 Speer T , Ridker PM , von Eckardstein A , Schunk SJ , Fliser D. Lipoproteins in chronic kidney disease: from bench to bedside . Eur Heart J 2021 ; 42 : 2170 – 2185 . Google Scholar OpenURL Placeholder Text WorldCat 8 Farukhi ZM , Mora S. Lifelong low Lp(a) levels: genetics give a green light? Eur Heart J 2021 ; 42 : 1157 – 1159 . Google Scholar Crossref Search ADS PubMed WorldCat 9 Langsted A , Nordestgaard BG , Kamstrup PR. Low lipoprotein(a) levels and risk of disease in a large, contemporary, general population study . Eur Heart J 2021 ; 42 : 1147 – 1156 . Google Scholar Crossref Search ADS PubMed WorldCat 10 Pirillo A , Catapano AL. The cardiovascular benefit of Lp(a) reduction: not there yet . Eur Heart J 2020 ; 41 : 4256 – 4258 . Google Scholar Crossref Search ADS PubMed WorldCat 11 Arnold M , Schweizer J , Nakas CT , Schütz V , Westphal LP , Inauen C , Pokorny T , Luft A , Leichtle A , Arnold M , Bicvic A , Fischer U , De Marchis GM , Bonati LH , Müller MD , Kahles T , Nedeltchev K , Cereda CW , Kägi G , Bustamante A , Montaner J , Ntaios G , Foerch C , Spanaus K , von Eckardstein A , Katan M. Lipoprotein(a) is associated with large artery atherosclerosis stroke aetiology and stroke recurrence among patients below the age of 60 years: results from the BIOSIGNAL study . Eur Heart J 2021 ; 42 : 2186 – 2196 . Google Scholar OpenURL Placeholder Text WorldCat 12 Tsimikas S. Elevated lipoprotein(a) and the risk of stroke in children, young adults, and the elderly , Eur Heart J 2021 ; 42 : 2197 – 2200 . Google Scholar OpenURL Placeholder Text WorldCat 13 Ademi Z , Norman R , Pang J , Liew D , Zoungas S , Sijbrands E , Ference BA , Wiegman A , Watts G. Health economic evaluation of screening and treating children with familial hypercholesterolemia early in life: many happy returns on investment? Eur Heart J 2020 ; 41 (Suppl_2):ehaa946.3535 Google Scholar OpenURL Placeholder Text WorldCat 14 Landmesser U , Chapman MJ , Stock JK , Amarenco P , Belch JJF , Borén J , Farnier M , Ference BA , Gielen S , Graham I , Grobbee DE , Hovingh GK , Lüscher TF , Piepoli MF , Ray KK , Stroes ES , Wiklund O , Windecker S , Zamorano JL , Pinto F , Tokgözoglu L , Bax JJ , Catapano AL. 2017 Update of ESC/EAS Task Force on practical clinical guidance for proprotein convertase subtilisin/kexin type 9 inhibition in patients with atherosclerotic cardiovascular disease or in familial hypercholesterolaemia . Eur Heart J 2018 ; 39 : 1131 – 1143 . Google Scholar Crossref Search ADS PubMed WorldCat 15 Pérez de Isla L , Watts GF , Alonso R , Díaz-Díaz JL , Muñiz-Grijalvo O , Zambón D , Fuentes F , de Andrés R , Padró T , López-Miranda J , Mata P. Lipoprotein(a), LDL-cholesterol, and hypertension: predictors of the need for aortic valve replacement in familial hypercholesterolaemia . Eur Heart J 2021 ; 42 : 2201 – 2211 . Google Scholar OpenURL Placeholder Text WorldCat 16 Kronenberg F. Aortic valve stenosis: the long and winding road . Eur Heart J 2021 ; 42 :2212–2214. Google Scholar OpenURL Placeholder Text WorldCat 17 Zhang N , Tse G , Liu T. Neutrophil–lymphocyte ratio in the immune checkpoint inhibitors-related atherosclerosis . Eur Heart J 2021 ; 42 : 2215 . Google Scholar OpenURL Placeholder Text WorldCat 18 Adamstein NH , MacFadyen JG , Rose LM , Glynn RJ , Dey AK , Libby P , Tabas IA , Mehta NN , Ridker PM. The neutrophil–lymphocyte ratio and incident atherosclerotic events: analyses from five contemporary randomized trials . Eur Heart J 2021 ; 42 : 896 – 903 . Google Scholar Crossref Search ADS PubMed WorldCat 19 Adamstein NH , Ridker PM. The neutrophil–lymphocyte ratio: considerations for clinical application . Eur Heart J 2021 ; 42 : 2216 – 2217 . Google Scholar Crossref Search ADS 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)
Jennifer A. Doudna and Emmanuelle CharpentierOzkan, Judy
doi: 10.1093/eurheartj/ehaa1054pmid: 34038533
In 2020, the Royal Swedish Academy of Sciences—the body with responsibility for the Nobel Prize in Chemistry—chose to honour Emmanuelle Charpentier, of the Max Planck Unit for the Science of Pathogens, Berlin, Germany and US scientist Jennifer A. Doudna, from the University of California, Berkeley, for ‘the development of a method for genome editing’. Their discovery of the CRISPR/Cas9 ‘genetic scissors’ was described as a revolution for basic science and acknowledged as one of the sharpest tools in existence to help find therapies for genetic diseases. The breakthrough, as published in Science magazine in 2012, has enabled researchers to rewrite the genetic code of humans, plants, and animals. Eight years later, when announcing the 2020 laureates to the world, Claes Gustafsson, chair of the Nobel Committee for Chemistry noted the rapid take up of the discovery and the way it was being used to find new therapies. He said: ‘This technology has had a revolutionary impact on the life sciences, is contributing to new cancer therapies and may make the dream of curing inherited diseases come true’. Very few discoveries, even at the Nobel level of achievement have been judged to have had such a major impact in such a short space of time as the CRISPR/Cas9 genetic scissors which enable changes to DNA to be made with unprecedented high precision and speed. Emmanuelle Charpentier PhD Laureate Emmanuelle Charpentier is a renowned expert in the regulatory mechanisms underlying processes of infection and immunity in bacterial pathogens. She was born in 1968, in Juvisy-sur-Orge, just outside Paris, France and later studied biochemistry, genetics, and microbiology at the University Pierre and Marie-Curie (now the Sorbonne University) in Paris. She gained her PhD in microbiology for research carried out at the Pasteur Institute and later spent 5 years in the United States at Rockefeller University, New York University Langone Medical Center and the Skirball Institute of Biomolecular Medicine, as well as the St Jude Children’s Research Hospital in Memphis. She returned to Europe in 2002 to lead her first independent research group at the Max F. Perutz Laboratories (now Max Perutz Labs), at the University of Vienna in Austria. Prior to her current appointment at the Max Planck Unit for the Science of Pathogens, where she is Scientific and Managing Director, Charpentier was Associate Professor at the Laboratory for Molecular Infection Medicine Sweden and visiting Professor at the Umeå Centre for Microbial Research (UCMR), Umeå University, Sweden where she did much of the work that led to the breakthrough. During Charpentier’s studies of Streptococcus pyogenes, she discovered a previously unknown molecule, tracrRNA. Her work showed that tracrRNA is part of bacteria’s ancient immune system, CRISPR/Cas, that disarms viruses by ‘cleaving’ their DNA. She published this discovery in 2011 in Nature, and the same year she met US-based Jennifer Doudna, an experienced biochemist and expert on RNA. After talking about their respective work, the pair decided to form a collaboration and together, they succeeded in recreating the bacteria’s genetic scissors in a test tube and simplifying and making the scissors easier to use. In their natural form, the scissors recognize DNA from viruses, but what Charpentier and Doudna proved was that they could be controlled to cut any DNA molecule at a predetermined site. The system was developed into a precise gene-editing tool that can correct defective DNA in a similar way to editing the text in a document. A year after their initial meeting and an ‘intense’ collaboration, details of the DNA targeting mechanism by the CRISPR-Cas9 system and guidelines on how to use it to modify the genome of cells and organisms, were published in the journal Science. Speaking on the day of the Nobel Prize announcement, Charpentier described how she had been involved in manipulating DNA since her earliest days working on infectious diseases at the Rockefeller University, she also described how her vision had always been to discover useful pathways to develop therapeutics. She said: ‘I am truly amazed at the speed at which CRISPR research and applications in so many diverse areas of the life sciences have developed in recent years and I look forward to seeing new developments in this genome editing and engineering technology, particularly as a gene-based medicine to treat serious human diseases’. Jennifer A. Doudna PhD Jennifer A. Doudna was born in 1964 in Washington, DC and raised and educated in Hawaii. She later enrolled to study biochemistry at Pomona College, Claremont, California and received her PhD from Harvard Medical School, Boston. She is currently the Li Ka Shing Chancellor’s Chair in Biomedical and Health Sciences, a Howard Hughes Medical Institute investigator at UC Berkeley, a Professor of Molecular and Cell Biology, and a Professor of Chemistry. She is the first woman from UC Berkley to be awarded a Nobel Prize and together with Charpentier, half of the first all-women collaboration to be honoured in the chemistry category. Speaking from UC Berkley shortly after being notified of her Nobel honour, she described how her work with CRISPR began: ‘After I had moved my lab from Yale to Berkeley, I had a conversation with a colleague at Berkeley, Jillian Banfield (a professor studying structure, functioning, and diversity of microbial communities in natural environments and the human microbiome), who said that CRISPR might be something I would like to investigate as a biochemist. I later met Emmanuelle at a conference in Puerto Rico in 2011 and realized that we had complementary scientific expertise, as she is a medical microbiologist and was doing a lot of work with a particular organism that had a kind of CRISPR system in the genome. We decided to work together and started to communicate regularly’. The pair formed a productive rapport as did their respective researchers Martin Jínek, PhD, a Czech postdoctoral Fellow in Doudna’s lab, and Krzysztof Chylinski, a Polish graduate in Charpentier’s group. Referring to the impact of the pair’s discovery Doudna says: ‘CRISPR opens the door to address some of the urgent problems humanity is facing. Genetic diseases and environmental problems such as global warming are being affected by CRISPR and we are already seeing some of the effects of this technology in the case of sickle cell disease’. She said that some of the area’s most likely to benefit in the future will be genetic diseases such as Multiple Sclerosis, Cystic Fibrosis, and neuro-degenerative diseases where scientists know a lot about the genes that cause the condition but are unable to provide remedies due to a lack of technology. She said ‘The field is moving so fast now that I don’t know where we will be 100 years from now or how people will look at the discovery, but the ability to rewrite the human code for all organisms is really quite extraordinary’. In 2014, Doudna founded the Innovative Genomics Institute (IGI) with Jonathan Weisman at the University of California San Francisco and the Gladstone Institutes to apply this technology to solve some of humanity’s greatest problems. IGI members and scientists have since launched dozens of research projects and published more than 100 papers related to their research. In addition to its scientific efforts, the IGI is committed to advancing public understanding of genome engineering and providing resources for the broader community. She says ‘We launched IGI with the vision of bringing genome editing to bear on problems facing humanity whether they be in biomedicine or in agriculture and importantly to do that with an eye towards accessibility, sustainability, and affordability that will make the technology go from a lab tool to a standard of care some day in genetic disease or a way to create the kind of changes in agricultural products to meet the challenges of climate change, and so much more’. The Nobel Prize was announced during an online ceremony in Stockholm. Claes Gustafsson reiterated the enormous implications—current and future of the discovery and said how it had revolutionized biomedical science and enabled the ‘dream to cure’ genetic diseases. He did, however, note with caution that the enormous power of this technology means it should be used with caution and great care must be taken regarding the ethical framework in which it is employed. The two women share the prize fund of KR 10 000, a place in scientific history and will receive their awards at a future date as the traditional Nobel Week celebrations which take place in Stockholm in the December following the prize announcements have been cancelled for 2020 due to the ongoing CV19 pandemic. Expert comment: Jeanette Erdmann PhD Jeanette Erdmann is Professor of Cardiogenetics and Director of the Institute for Cardiogenetics (ICG) at the University of Lübeck, Germany and is known for her investigative work into the underlying genetic factors of cardiovascular disease and myocardial infarction to develop novel therapeutic targets. ‘It’s not only in cardiovascular research that CRISPR has opened up a whole new avenue of applications. Experimentally, we can now systematically interrogate the influence of non-coding variants we have identified in the past decade by genome-wide association studies, for example, by generating cell culture models into which we introduce the variant under investigation using CRISPR and then study whether this change is functionally effective. Importantly, these studies can also be done in a large-scale setting allowing us to study thousands of variants simultaneously. But CRISPR plays an even more important role when it comes to possible therapies. Firstly, CRISPR allows the establishment of urgently needed disease models necessary for the development of novel therapeutics approaches. And secondly, in the not so far future, we might use CRISPR to tackle other cardiovascular risk genes apart from PCSK9 to reduce cholesterol’. Conflict of interest: none declared. Open in new tabDownload slide Open in new tabDownload slide Open in new tabDownload slide Open in new tabDownload slide Open in new tabDownload slide Open in new tabDownload slide Nobel Laureate series 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)
Antiplatelet and direct oral anticoagulation management after coronary artery bypass graft surgery: the Cinderella of current cardiovascular trials, please show me (some) evidenceSchoenrath, Felix; Just, Isabell Anna; Falk, Volkmar; Emmert, Maximilian Y
doi: 10.1093/eurheartj/ehab033pmid: 33615338
Introduction Even today, it remains unclear whether an intensification of platelet inhibition or anticoagulant therapy is beneficial when added to the standard therapy with acetylsalicylic acid (ASA) after coronary artery bypass graft (CABG) surgery. The literature shows clear evidence supporting dual antiplatelet therapy (DAPT) in patients with acute coronary syndrome (ACS), especially after coronary stent implantation or on medical treatment alone, as well as in patients with stable coronary artery disease (CAD) after coronary interventions, unless there is an indication for full-dose anticoagulation or an elevated bleeding risk. DAPT with ASA plus clopidogrel or ticagrelor after CABG surgery decreases the incidence of bypass graft failures and might protect against recurrent ischaemic events in off-pump surgical strategies or after coronary endarterectomy. Concerning graft patency, there is strong evidence that ASA prevents early occlusion and increases long-term graft survival. Based on some data from subgroup analyses of randomized controlled ACS trials, DAPT is associated with reduced mortality and improved vein graft patency.1,2 For decades, anticoagulation with vitamin K antagonists (VKA) was the therapy of choice in patients with coexisting atrial fibrillation (AF) and stable CAD due to its beneficial stroke prevention and anti-ischaemic potential comparable to combination therapy with ASA and VKA, but with a significantly lower bleeding risk.3 In recent years, an anticoagulation strategy with low-dose direct oral anticoagulants was tested in large-scale randomized trials, which confirmed that some patients with ACS or stable CAD benefit from dual pathway inhibition (DPI) by combining coagulation factor Xa inhibition and ASA (NCT00809965, NCT00831441, NCT01776424). It remains an important clinical question whether this strategy is applicable in patients after CABG surgery, and if so, whether the benefits outweigh the increased risk of bleeding. Moreover, it is desirable to define the clinical setting in which patients may benefit the most, especially with regard to patients in whom DAPT is indicated, according to the aforementioned scenarios. Although the European Medicines Agency (EMA) has approved a DPI regimen in patients who are at high risk of a recurrent thrombotic event after ACS, evidence from trials addressing a surgical cohort is scarce (EMEA/H/C/005279). Dual pathway inhibition pathophysiology The concept of combined antiplatelet and anticoagulant therapy was derived from molecular and cellular models of coronary atherogenesis. An atherosclerotic plaque rupture triggers platelet activation and an exposure of tissue factor, which is known to activate the coagulation cascade. Both mechanisms of arterial thrombus formation are medically addressed by the DPI strategy: ASA irreversibly inactivates the cyclooxygenase enzymes, leading to a reduced production of the prothrombotic thromboxane A2 and hereby inhibiting platelet activation, and the direct coagulation factor Xa inhibitor interrupts the coagulation cascade, consequently blocking thrombin and fibrin formation.4 Dual pathway inhibition trials In the ATLAS ACS2-TIMI51 trial, 15 526 patients received the direct factor Xa inhibitor rivaroxaban [2.5 or 5 mg twice daily (b.i.d.)] or placebo in addition to standard therapy with ASA alone (7%) or as add-on to a combination of ASA and clopidogrel (93%) within 1 week after ACS. None of the participants received a more potent P2Y12 inhibitor (ticagrelor, prasugrel) in a DAPT or DPI regimen. In the combined rivaroxaban groups, the composite of major adverse cardiovascular events (MACE), defined as cardiovascular death, myocardial infarction, and stroke, was reduced by 16% (P = 0.008) at the cost of an increase in major bleeding, but with no increase in fatal bleeding compared to placebo. The very low rivaroxaban dose (2.5 mg b.i.d.) also showed reduced mortality rates (P = 0.002) (NCT00809965). Approximately 60% of ACS patients underwent revascularization by either percutaneous coronary intervention (PCI) or CABG surgery. The proportion of patients with CABG surgery has not been published and no subgroup analysis addressing the efficacy of DPI in preventing primary graft failure has been performed yet. In the case of non-emergency indications and randomization before revascularization, the study drug (rivaroxaban or placebo) was stopped 12 h before CABG surgery and was restarted after postoperative recovery, when no ongoing bleeding risk was assumed.5 A previous, similar trial underlined the importance of administering a low dose of the anticoagulant in the DPI regimen: The direct factor Xa inhibitor apixaban at a full therapeutic dose of 5 mg b.i.d., as given in AF, led to excessive major bleeding including intracranial haemorrhage when combined with ASA in an early post-ACS cohort. The participants were mainly treated by medical therapy only (55.6%) or by PCI (43.8%). The trial was terminated early for safety reasons. There was no reduction in MACE or mortality in the 7392 participants recruited (NCT00831441). The combination of full-dose anticoagulation and a highly potent P2Y12 inhibitor (ticagrelor, prasugrel) has been studied in patients with AF undergoing PCI; dual or triple antithrombotic strategies with a vitamin K antagonist have been associated with significantly higher rates of clinically relevant haemorrhagic complications and should therefore be avoided according to the current guidelines.6 The combination of rivaroxaban and ticagrelor is currently under investigation (CAPITOL PCI AF trial, NCT03331484). In the COMPASS trial, more than 27 000 patients with stable cardiovascular diseases were randomized to ASA alone, rivaroxaban 5 mg b.i.d. alone, or rivaroxaban 2.5 mg b.i.d. combined with ASA. Compared to ASA alone, DPI was associated with a reduction in the composite of MACE by 24% (4.1% vs. 5.4%; P < 0.001) and a reduction in mortality (3.4% vs. 4.1%; P = 0.01) at the cost of an increase in major bleeding, defined as any bleeding that led to presentation to an acute care facility or to hospitalization (3.1% vs. 1.9%; P < 0.001). Fatal or critical organ bleeding was not increased (NCT01776424). Patients with a left ventricular ejection fraction (LV-EF) of less than 30% or New York Heart Association (NYHA) functional class III or IV symptoms were excluded from the investigation on the basis of the results of the COMMANDER-HF trial.7 Here, a very low dose of rivaroxaban (2.5 mg b.i.d.) in addition to standard antiplatelet therapy (ASA or DAPT) was not superior to placebo at preventing MACE (25.0% vs. 26.2%; P = 0.27) or mortality in 5022 patients with CAD and chronic heart failure (LV-EF ≤ 40%) who had not undergone concurrent revascularization (NCT01877915). A pre-planned sub-study of the COMPASS trial analysed whether DPI is effective in preventing graft failure and MACE after CABG surgery. A total of 1448 patients were randomized within 4–14 days after implantation of at least two bypass grafts. Compared to ASA alone the combined therapy reduced the composite of MACE (2.4% vs. 3.5%; P = 0.34) non-significantly, but in line with the results of the larger COMPASS trial. DPI failed to reduce graft failures (9.1% vs. 8.0%; odds ratio 1.13; 95% confidence interval 0.82–1.57; P = 0.45), which were diagnosed by a computed tomography angiogram (CTA) 1 year after surgery (NCT01776424). The authors discussed that this might be due to the low power of the sub-study, since the COMPASS trial was stopped early and not all patients underwent CTA. In concordance with these results, in a previous study from 1997, anticoagulation with low-dose warfarin (mean international normalized ratio 1.4) failed to reduce long-term graft failure.8 Conclusions The data on DPI after CABG surgery in patients with ACS or with stable CAD are limited: The size of the ACS cohort managed by surgical revascularization remained undefined and the time of starting or re-starting DPI after surgery was presumably too late to prevent early graft failures, since these commonly occur within the first days to weeks after surgery.9,10 Additionally, DPI has never been compared to a DAPT strategy with a more potent P2Y12 inhibitor than clopidogrel in either an ACS cohort or a stable CAD cohort. Furthermore, DPI after elective CABG surgery has not been investigated in patients with a reduced LV-EF <30% or NYHA functional class III or IV symptoms. Figure 1 summarizes the current state of evidence on DPI after cardiac surgery. Figure 1 Open in new tabDownload slide The current state of evidence on postoperative antiplatelet and anticoagulation therapy in coronary artery bypass graft surgery.1,3 ACS, acute coronary syndrome; ASA, acetylsalicylic acid; b.i.d., twice daily; CAD, coronary artery disease; DAPT, dual antiplatelet therapy; DPI, dual pathway inhibition; GFR, glomerular filtration rate; LV-EF, left ventricular ejection fraction. *Patients post-ACS and if DAPT was well tolerated for 12 months. Figure 1 Open in new tabDownload slide The current state of evidence on postoperative antiplatelet and anticoagulation therapy in coronary artery bypass graft surgery.1,3 ACS, acute coronary syndrome; ASA, acetylsalicylic acid; b.i.d., twice daily; CAD, coronary artery disease; DAPT, dual antiplatelet therapy; DPI, dual pathway inhibition; GFR, glomerular filtration rate; LV-EF, left ventricular ejection fraction. *Patients post-ACS and if DAPT was well tolerated for 12 months. Taking the available evidence, with all its limitations for a surgical cohort, and the promising underlying pathophysiological concept into account, we suggest carefully considering DPI treatment in patients after elective CABG surgery with an LV-EF >35%. This is valid under the assumption that the bleeding risk is low and the risk of recurrent ischaemic events is elevated, especially in patients with more severe atherosclerosis and diabetes. Overall, further in-depth research assessing the adequate and safe time of DPI initialization after CABG surgery and its potential to prevent early graft failure is urgently needed. Conflict of interest: F.S. receives remuneration, consultancy fees and/or travel support from Medtronic GmbH, Abbott GmbH & Co. KG, Cardiorentis AG. V.F. has relevant (institutional) financial activities outside the summited work with following commercial entities: Medtronic GmbH, Biotronik SE & Co., Abbott GmbH & Co. KG, Boston Scientific, Edwards Lifesciences, Berlin Heart, Novartis Pharma GmbH, JOT EC GmbH and Zurich Heart in relation to educational grants (including travel support), fees for lectures and speeches, fees for professional consultation and research and study funds. Open in new tabDownload slide Open in new tabDownload slide References 1 Valgimigli M , Bueno H , Byrne RA , Collet J-P , Costa F , Jeppsson A , Jüni P , Kastrati A , Kolh P , Mauri L , Montalescot G , Neumann F-J , Petricevic M , Roffi M , Steg PG , Windecker S , Zamorano JL , Levine GN ; ESC Scientific Document Group; ESC Committee for Practical Guidelines (CPG); ESC National Cardiac Societies . 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: the task force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Throacic Surgery (EACTS ). 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Google Scholar Crossref Search ADS PubMed WorldCat Author notes The first two authors Felix Schoenrath and Isabell Anna Just contributed equally to this work. 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)
Introduction to the Department of Cardiology in West China Hospital of Sichuan UniversityZhao, Zhen-Gang; He, Jing-Jing; Feng, Yuan; Chen, Mao
doi: 10.1093/eurheartj/ehab032pmid: 33550414
History and current status of West China Hospital The history of West China Hospital (WCH), situated at the city of Chengdu and affiliated with Sichuan University, can be traced back to the Renji and Cunren Hospital founded by missionaries from America and Canada in 1892. It became an epicentre for thriving of academic excellence and nurturing of medical talents in China during World War II, when renowned universities and colleges in war-afflicted area moved to take cover in the west. WCH has now become a leading medical centre in China, with 4300 beds and 5.7 million outpatient visits annually (Figure 1). WCH ranks No. 2 in the Best Hospital in China Rankings (2009–2019), and ranks No. 1 in the Science and Technology Evaluation Metrics (STEM) Rankings for Chinese Hospitals (2014–2019). Figure 1 Open in new tabDownload slide Panoramic view of West China Hospital, Sichuan University. Figure 1 Open in new tabDownload slide Panoramic view of West China Hospital, Sichuan University. The Department of Cardiology, founded by Professor Luo Decheng in 1954, is now designated as a state key clinical specialty and the only state-qualified training centre for cardiac interventional therapeutics in Sichuan Province. The Department has 185 beds, one coronary care unit, and nine Cath Labs. The Department performs many percutaneous procedures to treat patients in need. Acknowledging the great potential of transcatheter valve interventions, the Department was devoted to promoting the technique in China during the past decade. Currently, the Department has developed as a leading centre of transcatheter aortic valve implantation (TAVI) in China, in terms of both quality of care and academic reputation. The heart valve team The multidisciplinary heart valve team of WCH strives to provide patient-oriented care (Figure 2). The team was founded by Professor Mao Chen in 2012, when TAVI had gained worldwide acceptance. However, promoting TAVI in China was encountered with enormous challenges, primarily due to the different aortic valve anatomy and the lack of commercially available devices. Approximately 40% of TAVI candidates in China have a bicuspid aortic valve (BAV) and 10∼20% have non-calcific leaflets, both had been considered as relative contraindications for TAVI. Besides, many patients in China are in critical status when sought care, making the procedure even more challenging. By cooperating with leading valve centres and domestic manufacturers, the team was able to help solve some key problems that had impeded TAVI development in China. Figure 2 Open in new tabDownload slide The heart valve team at West China Hospital, Sichuan University. Figure 2 Open in new tabDownload slide The heart valve team at West China Hospital, Sichuan University. Clinical research on transcatheter aortic valve implantation in bicuspid anatomy BAV is frequently associated with eccentric annulus, ‘volcano-shaped’ leaflet configuration, and asymmetrical valve calcification. These unfavourable anatomical features pose significant challenges for TAVI, with increased risk of elliptical deployment and prosthetic valve dysfunction. However, given the high incidence, BAV is an inevitable problem for TAVI implanters in China. To date, the team has treated approximately 500 patients with BAV by TAVI. Incorporating their preliminary experience, the team comprehensively reviewed the safety and efficacy of TAVI in BAV in a paper published in Nature Reviews Cardiology in 2014. The paper proposed technical strategies for optimal outcomes and pointed out the knowledge gap for future research. To optimize patient selection, the team cooperated with Professor Hasan Jilaihawi from NYU Langone Medical Center and proposed a simplified and novel classification of BAV for TAVI which categorized BAV as tricommissural, bicommissural raphe type, and bicommissural non-raphe type. Such classification better reflects the interaction between prosthesis and the aortic-valvular complex and provides informative guidance for procedural workup. Another tricky issue was prosthetic valve sizing for BAV. The team proposed a novel sizing technique widely known as supra-annular sizing along with Professor Nicolo Piazza from McGill University Health Center, Canada. The concept derived from an observation of the multi-level interference between the prosthesis and bicuspid anatomy (Figure 3). In a computed tomography imaging-based study involving patients treated with the straight cylindrical Lotus Valve, the team demonstrated the existence of supra-annulus and the feasibility of supra-annular sizing in BAV. Figure 3 Open in new tabDownload slide Central illustration of supra-annular sizing for bicuspid aortic valve stenosis. From Xiong, T.-Y. et al. JACC Cardiovasc Interv 2019;12(12):1164–1171. Reproduced with permission from Elsevier. Figure 3 Open in new tabDownload slide Central illustration of supra-annular sizing for bicuspid aortic valve stenosis. From Xiong, T.-Y. et al. JACC Cardiovasc Interv 2019;12(12):1164–1171. Reproduced with permission from Elsevier. While reducing the risk associated with excessive oversizing, such as leaflet distortion and valve migration, supra-annular sizing sometimes results in the implant of a too small valve and suboptimal haemodynamic improvement, especially in severely calcified BAV. Therefore, the team launched a pilot study examining the feasibility of reshaping technique in significantly calcified BAV. The technique aims to better prepare BAV anatomy for TAVI by inflating an hourglass-shaped valvuloplasty balloon prior to valve implant. Initial clinical experience displayed encouraging results with less paravalvular leak or requirement for rescue valve-in-valve. The prospective international multicentre trial of the reshaping technique is coming soon. Clinical research on transcatheter aortic valve implantation in non-calcific aortic stenosis Non-calcific aortic stenosis (AS) is deemed as a relative contraindication due to concerns on the stability of prosthetic valve anchorage. However, a significant proportion of AS patients in China manifest isolated leaflet thickening with minimal or no calcium deposition. The underlying pathology was unclear but could be rheumatic heart disease or a unique disease process of non-calcific aortic valve degeneration. TAVI outcomes remained largely unknown in these patients. To address this knowledge gap, the team compared the procedural, echocardiographic, and clinical results of TAVI between non-calcific and senile calcific AS. The study confirmed the feasibility, safety, and effectiveness of TAVI in this unique subset of patients and brought forward pertinent procedural strategies. Clinical research on new transcatheter aortic valve implantation device Based on in-depth imaging studies and practical experience, the team was able to help design and modify the first domestic TAVI valve in China (Venus A-Valve, Venus MedTech Inc., Hangzhou, China) which is tailored according to the anatomy of Chinese patients. Compared with other self-expandable valves, Venus A-Valve has stronger radial force which enables it to cope with bicuspid and severely calcified aortic valve. As one of the leading investigators of the pre-market trial, the team helped to confirm the safety and efficacy of the Venus A-Valve. Since its commercialization in 2017, Venus A-Valve has benefited thousands of Chinese patients to date. During TAVI, valve preparation is time-consuming and may delay the rescue of patients with volatile haemodynamics. The pre-packaged dry-tissue Venibri Valve (Venus MedTech Inc., Hangzhou, China) is designed for simplified and safer TAVI. The valve has been pre-mounted and pre-packaged at manufacturer, thus does not need on-site preparation. The team successfully performed the first-in-man implantation in 2016. Thus, rapid wait-free TAVI, which could be life-saving under emergent circumstances, was demonstrated possible. Besides, as the device can be easily transported and stored, it may facilitate TAVI dissemination to resource-poor regions. Promotion of transcatheter aortic valve implantation development in China The building of a qualified TAVI heart team requires considerable training and guidance. Before 2015, only three centres in mainland China had an experience of TAVI in over 50 cases. To make TAVI available in more parts of the country, the Department organized the PCR-CIT China Chengdu Valves (PCCV) course in collaboration with Paris Course on Revascularisation (PCR). The mission of the course is in line with that of PCR, which is to serve the needs of each individual patient by helping the cardiovascular community to share knowledge, experience and practice. PCCV provides TAVI training for the heart teams through the mixture of various of formats, including live demonstration, step-by-step learning session, hands-on practice, case discussion and lectures (Figure 4). The course also introduces the latest update in transcatheter therapy for mitral and tricuspid valve. Since its birth in 2015, PCCV grows rapidly in parallel with the booming development of TAVI in China. Each fall, participants gathered in Chengdu to learn from leading experts in the field. In 2019, the course attracted over 1100 registered participants. Besides, many physicians benefited from the course by watching online lively or retrospectively. According to the webcast data, there were 17 735 views during the meeting. In the past 5 years, PCCV has become an influential valve course in the Asia-Pacific region and serves as an interactive academic exchange platform between Asian and Western physicians. Figure 4 Open in new tabDownload slide Providing TAVI training via LIVE demonstration at PCR-CIT China Chengdu Valves. Figure 4 Open in new tabDownload slide Providing TAVI training via LIVE demonstration at PCR-CIT China Chengdu Valves. Conflict of interest: none declared. Open in new tabDownload slide Open in new tabDownload slide Open in new tabDownload slide Open in new tabDownload slide Open in new tabDownload slide Open in new tabDownload slide Open in new tabDownload slide Open in new tabDownload slide Author notes Zhen-Gang Zhao and Jing-Jing He contributed equally to this paper. 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)
Modulating the gut microbiome with dietary interventions to reduce cardiometabolic disease riskLiuzzo, Giovanna; Galiuto, Leonarda
doi: 10.1093/eurheartj/ehab261pmid: 34097727
Comment on ‘The gut microbiome modulates the protective association between a Mediterranean diet and cardiometabolic disease risk’ published in Nature Medicine (https://doi.org/10.1038/s41591-020-01223-3) Key Points To assess whether the effects of different diets on cardiometabolic disease (CMD) risk could be modified by individual gut microbiome, the longitudinal microbiome data of 307 generally healthy men enrolled in the long-running Health Professionals Follow-Up Study (HPFS)1 were collected in the period 2011–2013 (two paired stool samples per participant were collected 6 months apart). The microbiome data were analysed alongside long-term dietary information [validated semiquantitative food-frequency questionnaires (SFFQs) were obtained every 4 years, as well as 3 months before and after the biospecimens] and hallmarks of CMD risk (biomarkers of glucose homeostasis, lipid metabolism, and inflammation were measured two times 6 months apart). The primary goal was to understand whether the association between adherence to a healthy Mediterranean-style dietary (MedDiet) pattern and CMD risk varies in individuals with different gut microbial profiles. The secondary goal was to understand MedDiet’s influence on the gut microbiome. A MedDiet index was applied to quantify each participant’s adherence to a MedDiet pattern with a possible range from 0 (non-adherence) to 9 (perfect adherence). To evaluate each participant’s CMD risk, a composite risk score was calculated that summarized the levels of measured biomarkers, with a higher score indicating a higher CMD risk. The microbiome analysis yielded 925 shotgun metagenomes and 340 shotgun metatranscriptomes. Taxonomic profiling using MetaPhlAn2 quantified a total of 468 microbial species across all participants. HUMAnN2 was used to perform functional profiling that is the enzymes and pathways encoded and transcribed by gut bacteria. A healthy MedDiet pattern had a small but significant effect on the overall gut microbiome profile and was associated with specific functional and taxonomic components of the gut microbiome. The MedDiet index accounted for the third largest proportion of variation in taxonomy. It was associated with a higher percentage of variation in taxonomy than several covariables previously reported to have strong influences on the gut microbial communities, such as antibiotic use. A higher adherence to MedDiet was positively associated with the abundance in the gut microbiomes of major dietary fibre metabolizers and short-chain fatty acid producers, as well as their functions that break down specific dietary fibres (particularly pectin). Conversely, a lower adherence to MedDiet was associated with enrichment of the secondary bile acid biosynthesis potential. Furthermore, the gut microbiome composition modulated the protective association between MedDiet and CMD risk (P-value for interaction = 0.02). In particular, the protective association was significantly stronger in participants with gut microbiomes depleted of Prevotella copri (P. copri). The interactions between the MedDiet index and both the CMD risk score and P. copri carriage (above 20th percentile) were statistically significant (P for interaction = 0.001 and 0.046, respectively). Comment The role of the microbiome in cardiometabolic health is difficult to define in large human populations,2–4 probably due to the complexity of habitual diets, the difficulty of measuring them and disentangling them from other lifestyle variables, and the personalized nature of the microbiome.5 Long-term dietary intake seems to be the dominant force that shapes the structure and activity of the gut microbiome in humans.6 MedDiet, characterized by high intake of fruits, vegetables, nuts, legumes and olive oil, low intake of red meats and refined grains, and low-to-moderate wine consumption, has been consistently recognized as beneficial for the prevention and management of several diseases, and for overall health and well-being. Higher adherence to MedDiet has been associated with reduced incidence of several chronic diseases, such as obesity, type-2 diabetes, gastrointestinal cancer, and cardiovascular disease.7 Although the underlying mechanisms remain largely undetermined, recent evidence suggests modulation of the gut microbiome and microbial metabolites as one of the possible factors mediating the health effects of MedDiet.6,8 The authors of the HPFS1 have taken the plunge, although with the limitations shared by other microbiome epidemiological investigations. The observational design of the HPFS might represent an important limitation. Although the authors adjusted for many potential confounders in the statistical models, specific prebiotic usage and most inter-individual variation in microbiome were not taken into account. Moreover, the study focused on biomarkers of CMD rather than hard clinical end points, limiting the clinical relevance of these findings. The nature of the interaction between diet and P. copri carriage is also not clear. The study design does not allow distinguishing between two hypotheses: (i) in individuals who do not carry P. copri, the gut microbiome may metabolize components of the MedDiet more efficiently, producing higher amounts of cardioprotective metabolites; (ii) individuals who adhere to the MedDiet may be less likely to acquire or retain P. copri. Furthermore, the study did not establish a significant association between the MedDiet and the P. copri carriage, but only an interaction between diet and P. copri carriage with CMD risk. Nevertheless, these findings supports the hypothesis that dietary interventions for CMD prevention could be tailored to an individual’s gut microbial profile, for example recommending healthy eating to individuals lacking P. copri, and reserving drugs, such as statins, for P. copri carriers. Interventional studies are needed to clarify the clinical relevance of such hypothesis, assessing changes in CMD risk in individuals with and without P. copri after a MedDiet intervention, as well as changes in microbiome composition. In conclusion, this study represents a major step forward in personalized nutritional guidance. Even though not all the potential confounders have been considered, it provides new and compelling evidence that a Mediterranean-style diet has long-term effects on the gut microbiome composition and that the gut microbiome in turn modulates the protective association between diet and CMD risk. Thus, manipulating the composition of the gut microbiome through dietary interventions might represent a useful preventive and therapeutic strategy. Conflict of interest: G.L. received grant support (to the institution) for investigator-initiated research from American Heart Association, Italian National Health Service and Italian Minister of Education, University and Research. She is currently involved in the Research Programs of the Italian Cardiovascular Network. L.G. has nothing to disclose. References 1 Wang DD , Nguyen LH , Li Y , Yan Y , Ma W , Rinott E , Ivey KL , Shai I , Willett WC , Hu FB , Rimm EB , Stampfer MJ , Chan AT , Huttenhower C. The gut microbiome modulates the protective association between a Mediterranean diet and cardiometabolic disease risk . Nat Med 2021 ; 27 : 333 – 343 . Google Scholar Crossref Search ADS PubMed WorldCat 2 Brown JM , Hazen SL. Microbial modulation of cardiovascular disease . Nat Rev Microbiol 2018 ; 16 : 171 – 181 . Google Scholar Crossref Search ADS PubMed WorldCat 3 Kurilshikov A , van den Munckhof ICL , Chen L , Bonder MJ , Schraa K , Rutten JHW , Riksen NP , de Graaf J , Oosting M , Sanna S , Joosten LAB , van der Graaf M , Brand T , Koonen DPY , van Faassen M , Slagboom PE , Xavier RJ , Kuipers F , Hofker MH , Wijmenga C , Netea MG , Zhernakova A , Fu J ; LifeLines DEEP Cohort Study, BBMRI Metabolomics Consortium . Gut microbial associations to plasma metabolites linked to cardiovascular phenotypes and risk . Circ Res 2019 ; 124 : 1808 – 1820 . Google Scholar Crossref Search ADS PubMed WorldCat 4 Anselmi G , Gagliardi L , Egidi G , Leone S , Gasbarrini A , Miggiano GAD , Galiuto L. Gut microbiota and cardiovascular diseases: a critical review . Cardiol Rev 2020 ;doi:10.1097/CRD.0000000000000327. Google Scholar OpenURL Placeholder Text WorldCat 5 Pasolli E , Asnicar F , Manara S , Zolfo M , Karcher N , Armanini F , Beghini F , Manghi P , Tett A , Ghensi P , Collado MC , Rice BL , DuLong C , Morgan XC , Golden CD , Quince C , Huttenhower C , Segata N. Extensive unexplored human microbiome diversity revealed by over 150,000 genomes from metagenomes spanning age, geography, and lifestyle . Cell 2019 ; 176 : 649 – 662.e20 . Google Scholar Crossref Search ADS PubMed WorldCat 6 Asnicar F , Berry SE , Valdes AM , Nguyen LH , Piccinno G , Drew DA , Leeming E , Gibson R , Le Roy C , Khatib HA , Francis L , Mazidi M , Mompeo O , Valles-Colomer M , Tett A , Beghini F , Dubois L , Bazzani D , Thomas AM , Mirzayi C , Khleborodova A , Oh S , Hine R , Bonnett C , Capdevila J , Danzanvilliers S , Giordano F , Geistlinger L , Waldron L , Davies R , Hadjigeorgiou G , Wolf J , Ordovás JM , Gardner C , Franks PW , Chan AT , Huttenhower C , Spector TD , Segata N. Microbiome connections with host metabolism and habitual diet from 1,098 deeply phenotyped individuals . Nat Med 2021 ; 27 : 321 – 332 . Google Scholar Crossref Search ADS PubMed WorldCat 7 Estruch R , Ros E , Salas-Salvadó J , Covas MI , Corella D , Arós F , Gómez-Gracia E , Ruiz-Gutiérrez V , Fiol M , Lapetra J , Lamuela-Raventos RM , Serra-Majem L , Pintó X , Basora J , Muñoz MA , Sorlí JV , Martínez JA , Fitó M , Gea A , Hernán MA , Martínez-González MA ; PREDIMED Study Investigators . Primary prevention of cardiovascular disease with a mediterranean diet supplemented with extra-virgin olive oil or nuts . N Engl J Med 2018 ; 378 : e34 . Google Scholar Crossref Search ADS PubMed WorldCat 8 Meslier V , Laiola M , Roager HM , De Filippis F , Roume H , Quinquis B , Giacco R , Mennella I , Ferracane R , Pons N , Pasolli E , Rivellese A , Dragsted LO , Vitaglione P , Ehrlich SD , Ercolini D. Mediterranean diet intervention in overweight and obese subjects lowers plasma cholesterol and causes changes in the gut microbiome and metabolome independently of energy intake . Gut 2020 ; 69 : 1258 – 1268 . 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)
How low is safe? The frontier of very low (<30 mg/dL) LDL cholesterolKaragiannis, Angelos D; Mehta, Anurag; Dhindsa, Devinder S; Virani, Salim S; Orringer, Carl E; Blumenthal, Roger S; Stone, Neil J; Sperling, Laurence S
doi: 10.1093/eurheartj/ehaa1080pmid: 33463677
Low-density lipoprotein cholesterol (LDL-C) is a proven causative factor for developing atherosclerotic cardiovascular disease. Individuals with genetic conditions associated with lifelong very low LDL-C levels can be healthy. We now possess the pharmacological armamentarium (statins, ezetimibe, PCSK9 inhibitors) to reduce LDL-C to an unprecedented extent. Increasing numbers of patients are expected to achieve very low (<30 mg/dL) LDL-C. Cardiovascular event reduction increases log linearly in association with lowering LDL-C, without reaching any clear plateau even when very low LDL-C levels are achieved. It is still controversial whether lower LDL-C levels are associated with significant clinical adverse effects (e.g. new-onset diabetes mellitus or possibly haemorrhagic stroke) and long-term data are needed to address safety concerns. This review presents the familial conditions characterized by very low LDL-C, analyses trials with lipid-lowering agents where patients attained very low LDL-C, and summarizes the benefits and potential adverse effects associated with achieving very low LDL-C. Given the potential for cardiovascular benefit and short-term safe profile of very low LDL-C, it may be advantageous to attain such low levels in specific high-risk populations. Further studies are needed to compare the net clinical benefit of non-LDL-C-lowering interventions with very low LDL-C approaches, in addition to comparing the efficacy and safety of very low LDL-C levels vs. current recommended targets.
Lipoproteins in chronic kidney disease: from bench to bedsideSpeer, Thimoteus; Ridker, Paul M; von Eckardstein, Arnold; Schunk, Stefan J; Fliser, Danilo
doi: 10.1093/eurheartj/ehaa1050pmid: 33393990
Chronic kidney disease (CKD) is associated with high cardiovascular risk. CKD patients exhibit a specific lipoprotein pattern termed ‘uraemic dyslipidaemia’, which is characterized by rather normal low-density lipoprotein cholesterol, low high-density lipoprotein cholesterol, and high triglyceride plasma levels. All three lipoprotein classes are involved in the pathogenesis of CKD-associated cardiovascular diseases (CVDs). Uraemia leads to several modifications of the structure of lipoproteins such as changes of the proteome and the lipidome, post-translational protein modifications (e.g. carbamylation) and accumulation of small-molecular substances within the lipoprotein moieties, which affect their functionality. Lipoproteins from CKD patients interfere with lipid transport and promote inflammation, oxidative stress, endothelial dysfunction as well as other features of atherogenesis, thus contributing to the development of CKD-associated CVD. While, lipid-modifying therapies play an important role in the management of CKD patients, their efficacy is modulated by kidney function. Novel therapeutic agents to prevent the adverse remodelling of lipoproteins in CKD and to improve their functional properties are highly desirable and partially under development.
Elevated lipoprotein(a) and the risk of stroke in children, young adults, and the elderlyTsimikas, Sotirios
doi: 10.1093/eurheartj/ehab251pmid: 34000000
Graphical AbstractThe lipoprotein(a) [Lp(a)] particle may impact cardiovascular risk through antifibrinolytic, proinflammatory, and proatherogenic mechanisms, through the apolipoprotein(a), oxidized phospholipids (OxPLs), and LDL components, respectively. Because it is difficult to separate these effects out in vivo, they probably contribute to various but different extents in all age groups. However, it is proposed that specific properties may predominate and manifest clinically in different age groups, with antifibrinolytic effects mainly in children, proinflammatory effects in young adults, and proatherogenic effects in the elderly.