European Heart Journal

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Too hot to handle? The truth about the effects of extreme heat on cardiovascular health

2022 European Heart Journal

doi: 10.1093/eurheartj/ehac554pmid: 36254664

All correspondence relating to this article should be sent to [email protected] If you enjoyed a post-pandemic summer holiday during 2022, you may have become concerned by the intensity of the heatwave and the extreme temperatures across Europe. Those working in the health sector may have registered excessive numbers of patients seeking treatment for cardiovascular and respiratory ailments exacerbated by the hot weather. One physician who believes that the risk of environmental factors to our health is vastly under-stated is cardiologist Thomas Münzel MD, Chief of the Department of Cardiology at the University Medical Centre, Johannes Gutenberg University in Mainz, Germany. Prof. Münzel and his team have been focusing on environmental risk factors for cardiovascular disease (CVD) since 2011, initially in relation to aircraft noise and air pollution, and more recently in relation to excessive temperatures. With rising temperatures set to continue due to climate change, Prof. Münzel believes the threat of environmental factors on heart health is bigger than previously thought and needs to be highlighted. Over a series of articles in CardioPulse, he will explore the impact of rising temperatures on cardiovascular health and look at some possible solutions or mitigating actions (Figure 1). Figure 1 Open in new tabDownload slide Prof. Dr. Thomas Münzel. Prof. Münzel has showed how air pollution is much more dangerous than anticipated for health and currently surpasses tobacco smoking as a hazard for CVD. He also found that noise is a major risk factor as it stimulates stress in the brain, activates the sympathetic nervous system, and may trigger major adverse cardiovascular events. Concern about the effects of heatwaves and rising temperatures builds on this earlier work and shows how exceptionally hot weather and the issues that accompany it, exacerbates the problems. He says: ‘I’ve previously worked on the impact of noise and demonstrated how many deaths occur due to atmospheric pollution, but it’s not about one single factor, you often have a co-exposure of noise and air pollution, much of it traffic-related, and accompanying heat extremes.’ A heatwave is defined as an extended period of weather which exceeds expected conditions in a particular area relative to the time of year and persists for days or possibly weeks. The 2003 heatwave was memorable in Europe for its effects in London and Paris in particular. It is estimated to have caused in excess of 70 000 deaths across Europe. More recently, in 2022, the countries worst hit by the heatwave included the United Kingdom where temperatures of 40.2°C were recorded and Spain where the country’s Ministry of Health reported that 679 people had lost their lives in the first eight days (July 10–17) of the heatwave. Spain experienced two similarly severe heatwave events this year and in Portugal, dangerous forest fires broke out endangering life and adding to atmospheric pollution. Much of Southern Europe experienced extreme heat which scientists say is a result of the world’s changing climate. The effects of excess heat on the human body and the implications for cardiovascular health are many. Direct impacts include the following: dehydration, heat cramps, and heatstroke, resulting in fatalities attributable to respiratory, cardiovascular, or other chronic diseases. Indirect impacts include the transmission of water and food borne diseases, contamination of water supplies and in some cases damage to infrastructure through drought or wildfires. Heatwaves also put a strain on hospitals and health services. Physiological heat stress responses are necessary to limit a rise in core temperature and can affect people differently based on pre-existing medical conditions. Increased blood flow to the skin increases cardiac demand while decreasing the heart’s filling pressure. The heart is required to pump harder and faster, increasing oxygen demand. For people with pre-existing heart conditions, this response can lead to a mismatch between a high cardiac oxygen demand and a compromised cardiac oxygen delivery, resulting in cardiac ischaemia, infarction, and ultimately, cardiovascular collapse. Elevated cardiovascular strain from heat stress is a primary health concern during heat extremes for older adults in particular. All-cause cardiovascular illness is the primary cause of death during heatwaves, and as almost half a billion people are estimated to have CVD globally, any densely populated area affected by heat extremes will be at risk for increased cardiovascular-related mortality (Figure 2). Figure 2 Open in new tabDownload slide Burning fossil fuels contributes to air pollution. Whilst he is a cardiologist and not a climate change specialist, Prof. Münzel has taken up the challenge of raising awareness of the implications of heatwaves and rising temperatures amongst his colleagues and peers. He warns that the crisis is happening now, and action needs to be taken immediately. He says: ‘This year we’ve all seen how desert storms from the Sahara brought sand and dust from Africa to the Alps which covered the mountain range and caused the ice to melt and the temperature to rise. We also know that these desert storms are killing half a million people a year, adding to air pollution, and amplifying heatwaves. Many people with CVD are already greatly in danger because of increased heat and we will see more deaths amongst these patients from myocardial infarction and stroke.’ While environmental threats to health are well-documented, solutions are complex. Prof. Münzel says: ‘The problem lies with fossil fuel burning like oil, coal and gas and of course car emissions. If we stopped using them, it would both significantly decrease the temperature and pollution but that’s currently not straightforward or realistic. The problem is that people are dying at a rate of 5 million per year due to excess heat. Air pollution is killing around 8 million people each year.’ Importantly, most of the excess deaths are due to ischaemic heart disease and stroke but also caused by diabetes and arterial hypertension. These figures he points out are bigger than deaths caused by the COVID-19 pandemic. A study published in the Lancet showed that a mere 1°C increase in temperature was associated with CVD-related mortality across all considered diagnoses.1 The overall risk of CVD-related mortality increased by 2.1% specifically related to stroke and coronary heart disease. A 1°C, temperature rise was also associated with a significant increase in morbidity due to arrhythmias, cardiac arrest, and coronary heart disease. These findings strengthen the evidence that the rise in hot temperatures, in conjunction with an increase of older people in the population, may result in a significant rise in CVD. The Lancet review concluded that prevention measures are needed to lower the worldwide threat of the heat-related burden of CVD-related morbidity and death. The issue of air pollution which national governments worldwide are continuing to struggle with, is an important consideration in the heat debate. The World Health Organization has outlined how air pollution threatens health and contributes to millions of deaths a year. Excess heat and heatwaves add to pollution by increasing pollutants and their toxicity, as well as creating a stagnant layer of air above the ground. This increases emissions as people use air conditioning in cars and buildings, furthermore wild fires triggered by dry weather can add to pollution and contribute to a vicious circle. Sun and heat transform—and worsen—air pollution due to chemical reactions that cause ozone. Heatwaves and poor air quality often go hand-in-hand because lingering high pressure creates a stagnant environment, and a lack of rain means that pollutants remain in the air. By any standards, Prof. Münzel says, it all adds up to a major public health concern, the causes of which are beyond our prevention. ‘It’s too late to stop the sort of environmental damage that is causing some of these problems but not perhaps to mitigate some of the worst effects on cardiovascular health.’ Although solutions are complex and demanding, there is a lot of interest in this area which Prof. Münzel hopes can be translated into positive and immediate action. Some of the ways forward will be explored in a future article. Reference 1 Zhao Q , Guo Y, Ye T, Gasparrini A, Tong S, Overcenco A, et al. Global, regional, and national burden of mortality associated with non-optimal ambient temperatures from 2000 to 2019: a three-stage modelling study . Lancet Planet Health 2021 ; 5 : e415 – e425 . Google Scholar Crossref Search ADS PubMed WorldCat Author notes Conflict of interest: None declared. © The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: [email protected] This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) © The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: [email protected]

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Young at heart: a DNA methylation's tale

Mongelli, Alessia; Farsetti, Antonella; Gaetano, Carlo

2022 European Heart Journal

doi: 10.1093/eurheartj/ehac654pmid: 36380726

Aging is an incessant and unavoidable process that affects all organisms from birth to death. However, behavioural and economic conditions, lifestyle, diet, and physical activity, as well as genetic and epigenetic variables, play a pivotal role in its progression. Several strategies have been considered to interfere with the aging process—for example, caloric restriction, food integrators, and senolytic and senomorphic drugs. More recently, genetically based interventions, including the Yamanaka’s protocol of staminalization, have been applied in vivo to revert the aging process in mouse models.1 While the long-term effect of these interventions remains unclear, the difficulty in assessing their effect on the biological age represents a further significant limitation of these studies. Getting old and healthy is the consequence of a complex biological process modulated, during the lifetime, by multiple intrinsic and extrinsic factors, including hereditary, environmental, dietary, lifestyle, and stochastic factors, among others. At the molecular level, the consequence of aging is also complex and multifaceted and includes loss of proteostasis, genomic instability, telomere attrition, and various epigenetic alterations, such as changes in genomic DNA methylation. The introduction of this DNA modification is mediated by DNA methyltransferases which add a methyl group from the precursor S-adenosyl methionine to the carbon in the fifth position of cytosine (5mC), often in cytosine-guanine dinucleotides (CpG).2 This is a dynamic process: the loss of global 5mC, which occurs during aging, is in some cases associated with the increase of hydroxymethylcytosine (5hmC)3 determined by the ketoglutarate-dependent dioxygenases named ten-eleven-translocation proteins (TETs), which in turn can convert the 5mC into 5hmC and, further, into formyl and carboxylcytosine (5fC; 5caC, respectively). Finally, the 5caC is converted in an abasic site and restored to the naïve unmethylated Cytosine form by a DNA repair mechanism.2 It is worth noting here that DNA methylation status at particular CpG sites has been unequivocally associated with aging, up to the point of being used in accurate age-predictive models.4 DNA methylation and the biological age determination In 2013, Steve Horvath developed the first human multi-tissue epigenetic clock, screening thousands of methylated CpG sites on a microchip to finally find the 353 CpGs most suitable to assess the human biological age4 in multiple organs, including the heart. On the other hand, several blood-specific methods have also been developed based on a variable number of CpGs.5 Interestingly, all these methods turned out helpful in addressing the human age in forensic analyses, establishing the risk of developing cancer or cardiovascular diseases, or determining the probability of having a longer and healthier lifespan. Notably, in a peculiar case, it has been possible to demonstrate that monozygotic twins with different lifestyles had a divergent aging speed at the biological level. In recent years, determining the mammalian biological age has become even more accessible and facilitated by the development of dedicated portable devices. The result of this determination is known as the ‘DNA methylation-based age’ or DNAmAge alias ‘epigenetic age’. This novel parameter is calculated by applying specific algorithms in which some coefficients are multiplied by the percentage of CpG methylation. In most studies, the primary source of DNA has been the peripheral blood, which is easy to obtain, not invasively. The unprecedented DNAmAge potential In clinical practice, the awareness that patients can be biologically older or younger could be crucial in designing the appropriate therapeutic strategy. Therefore, the DNAmAge should be considered for the choice of therapeutic intervention and estimation of therapeutic success. For example, in breast and colorectal cancer, it has been demonstrated that patients’ DNAmAge is increased compared to the chronological one.4 Furthermore, an acceleration of biological age has also been observed in infectious diseases such as HIV, cytomegalovirus (CMV), and the severe acute respiratory syndrome Corona virus-2 (SARS-CoV-2). In cardiovascular disease (CVD), although it is well known that a specific pathophysiological condition might influence the epigenetic landscape of an organ, little is known about cues that might drive the heart and vessels into acquiring an accelerated or decelerated DNAmAge. Remarkably, a few works report that the heart could be consistently younger than the blood. These studies have been realized by applying blood-based multi-tissue algorithms.6 Although the observation is undoubtedly provocative, intrinsic differences occur among tissues, particularly between the heart and blood, and in specific pathophysiological conditions. For example, a study evaluating DNA methylation in the heart and blood of Fallot tetralogy patients detected a much higher level of DNA methylation in the heart.7 Likewise, in mice, the heart has been found prone to accumulate methylated DNA at a level higher than blood.8 Moreover, the human cardiac telomeres result significantly longer in the heart than in blood. Post-natal enriched oxygenation activates the DNA damage response that inhibits the cardiomyocyte’s cell cycle, possibly causing a slower telomere length shortening than leucocytes.9 In addition, the post-natal metabolism is quite different among the two cell types. In adult cardiomyocytes, long-chain fatty acids predominantly undergo β-oxidation, while T cells almost exclusively rely on glycolysis.10 These observations suggest that the cardiac epigenetic landscape might be exposed to particular environmental signals, raising the question of whether the cardiac biological age should be evaluated using tools specifically developed for the heart. Figure 1 Open in new tabDownload slide Chronological aging is an unchangeable process progressing constantly over time. Lifestyle cannot change our chronological age, dictated by the date of birth. However, several environmental variables and life habits modulate the bespoken biological age. Acute and chronic diseases or pathophysiological conditions such as cancers, infections, diabetes, and inflammation have been demonstrated to influence this parameter. Remarkably, recent advances suggest that the site-specific methylation of genomic cytosine-guanine dinucleotides and its intensity may be used to develop algorithms for defining the epigenetic clock and the DNA methylation-dependent age or DNA methylation-based age, which tells us whether an individual is younger (decelerated) or older (accelerated) compared to his/her chronological age. These clocks are frequently based on information obtained from blood DNA. However, further evidence indicates that, in consequence of their intrinsic features, organ-specific formulas should be necessary to accurately assess the age of an internal organ such as the heart. Perspectives and conclusions In a perspective view, more accurate biological clocks, customized for specific diseases or stage of disease or tissue will be certainly defined and optimized. As depicted in Figure 1, a small piece of cardiac tissue might be collected during surgery or biopsies for other non-surgical conditions, and the patients’ DNAmAge is easily estimated. If a significant acceleration of the heart aging process is detected, the physician will evaluate whether the patient is at higher risk of cardiac accidents or developing after-surgery complications. The appropriate actions could be considered, including a more frequent and accurate follow-up, a specific pharmacological treatment, or a tailored rehabilitation programme. On the other hand, if the heart is younger than the patient’s chronological age, the prescription might be milder or similar to that of subjects at lower risk. In conclusion, such molecular methods would soon make it possible to investigate the age-related epigenetic changes occurring in different heart diseases, such as coronary artery disease and chronic ischaemia, valvular defects, arrhythmias, heart failure, or congenital cardiac defects, and to know whether other non-cardiac-specific pathophysiological conditions, such as cancer or infectious diseases, would change the cardiac biological age faster than others might also be helpful for prognosis and treatment. If any correlation between cardiac DNAmAge and the disease severity will emerge, it would be exciting to investigate whether a specific and successful treatment will, for instance, decelerate the aging process by rejuvenating the heart. Data availability This manuscript is based on data available in literature. No raw data have been generated writing this article, however the authors are willing to discuss about any arising question related to their interpretations. References 1 Ocampo A , Reddy P, Martinez-Redondo P, Platero-Luengo A, Hatanaka F, Hishida T, et al. In vivo amelioration of age-associated hallmarks by partial reprogramming . Cell 2016 ; 167 : 1719 – 1733. e12 . https://doi.org/10.1016/j.cell.2016.11.052 Google Scholar Crossref Search ADS PubMed WorldCat 2 Moore LD , Le T, Fan G. DNA methylation and its basic function . Neuropsychopharmacology 2013 ; 38 : 23 – 38 . https://doi.org/10.1038/npp.2012.112 Google Scholar Crossref Search ADS PubMed WorldCat 3 López V , Fernández AF, Fraga MF. The role of 5-hydroxymethylcytosine in development, aging and age-related diseases . Ageing Res Rev 2017 ; 37 : 28 – 38 . https://doi.org/10.1016/j.arr.2017.05.002 Google Scholar Crossref Search ADS PubMed WorldCat 4 Horvath S . DNA methylation age of human tissues and cell types . Genome Biol 2013 ; 14 : R115 . Epub ahead of print 2013 . https://doi.org/10.1186/gb-2013-14-10-r115. Google Scholar Crossref Search ADS PubMed WorldCat 5 Daunay A , Baudrin LG, Deleuze J-F, How-Kit A. Evaluation of six blood-based age prediction models using DNA methylation analysis by pyrosequencing . Sci Rep 2019 ; 9 : 8862 . https://doi.org/10.1038/s41598-019-45197-w Google Scholar Crossref Search ADS PubMed WorldCat 6 Pavanello S , Campisi M, Fabozzo A, Cibin G, Tarzia V, Toscano G, et al. The biological age of the heart is consistently younger than chronological age . Sci Rep 2020 ; 10 : 10752 . https://doi.org/10.1038/s41598-020-67622-1 Google Scholar Crossref Search ADS PubMed WorldCat 7 Nelson JS , Kwok C, Braganca NE, Lopez DL, Espina Rey AP, Robinson M, et al. Comparison of DNA methylation patterns across tissue types in infants with tetralogy of Fallot . Birth Defects Res 2022 ; 114 : 1101 – 1111 . https://doi.org/10.1002/bdr2.2090 Google Scholar Crossref Search ADS PubMed WorldCat 8 Bachman M , Uribe-Lewis S, Yang X, Williams Mi, Murrell A, Balasubramanian S. 5-Hydroxymethylcytosine is a predominantly stable DNA modification . Nat Chem 2014 ; 6 : 1049 – 1055 . https://doi.org/10.1038/nchem.2064 Google Scholar Crossref Search ADS PubMed WorldCat 9 Benetos A , Toupance S, Gautier S, Labat C, Kimura M, Rossi PM, et al. Short leukocyte telomere length precedes clinical expression of atherosclerosis: the blood-and-muscle model . Circ Res 2018 ; 122 : 616 – 623 . https://doi.org/10.1161/CIRCRESAHA.117.311751 Google Scholar Crossref Search ADS PubMed WorldCat 10 MacIver NJ , Michalek RD, Rathmell JC. Metabolic regulation of T lymphocytes . Annu Rev Immunol 2013 ; 31 : 259 – 283 . doi: 10.1146/annurev-immunol-032712-095956 . Google Scholar Crossref Search ADS PubMed WorldCat Author notes Conflict of interest: The authors declare that they have no financial interests or connections, direct or indirect, or other situations that might raise the question of bias in the work reported or the conclusions, implications or opinions stated – including pertinent commercial or other sources of funding for the individual author(s) or for the associated department(s) or organization(s), personal relationships, or direct academic competition. © The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: [email protected] This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) © The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: [email protected]

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Coronary interventions 2021: insights from the National Societies of Cardiology Journals of the European Society of Cardiology

Monsuez, Jean-Jacques; Gatzov, Plamen; Ferreira-Gonzalez, Ignacio; Alfonso, Fernando; ,

2022 European Heart Journal

doi: 10.1093/eurheartj/ehac679pmid: 36478051

Several challenging issues with regards to the very large amount of percutaneous coronary interventions (PCIs) performed and the numerous clinical settings they apply have been addressed by studies published in National Societies of Cardiology Journals (NSCJs). A large Spanish study showed that survival of patients discharged from hospital after primary PCI for ST-elevation myocardial infarction (STEMI) is quite similar to an age-adjusted population life expectancy.1 However, several differences in success of PCIs and subsequent outcomes have been observed across selected populations. Women included in a Polish nationwide registry have more procedural-related complications after rotational atherectomy and a higher mortality rate.2 A large multinational survey of patients with acute coronary syndrome (ACS) found similar differences. Women were older than men, with more co-morbidities, and were less often revascularized. Compared with men, a higher percentage of women died during follow-up.3 Failure and complications of PCI also worsen clinical outcomes of patients, as reported in another large multinational study. Among patients with a non-ST elevation ACS, 5% experienced at least one complication. Procedural complications were associated with early mortality, acute myocardial infarction (AMI), or stroke.4 More reassuringly, neurological complications following AMI decreased overtime, as reported by the Swedish myocardial infarction registry. Within 10 years the relative risk of ischaemic stroke was reduced by 20% at 1-year post AMI. The reduction coincides with the shift of reperfusion therapy from thrombolysis to primary PCI for STEMI and the increased use of evidence-based secondary preventive therapy according to the ESC guidelines.5 Invasive physiological assessment of coronary lesions with fractional flow reserve, which is increasingly used, remains a subject of concern. A retrospective analysis of PCI performed in two large volume centres in Portugal showed that it was performed in few patients with either stable coronary artery disease (CAD) or ACS only. However, the release of the 2014 ESC guidelines on myocardial revascularization was followed by two-fold increase in its adoption.6 The usefulness of instantaneous wave-free ratio (iFR) was assessed using the newly developed Syncvision software to guide the iFR-pullback study and the final decision-making process in long, diffuse, or sequential lesions. Similar results with regards to outcomes of patients, including mortality, AMI, stent thrombosis, and target vessel revascularization (TVR), confirmed the safety of this approach too.7 Distal radial access for PCI is more difficult than conventional radial access. A Turkish study among patients with ACS found no difference between the success rate of both approaches, but distal access was associated with fewer rates of radial spasm and radial occlusion.8 According to the 2018 ESC guidelines, PCI for left main (LM) stenosis is increasingly performed after careful staging of lesions using the SYNTAX score. In a study from Bulgaria showing real world results, successful maximal revascularization was obtained after unprotected PCI of LM in all patients with only few unfavourable clinical outcomes during follow up.9 Percutaneous coronary intervention of LM bifurcation lesions carries a harmful risk of side-branch closure. Two different strategies for provisional side branch interventions have been compared in another study. For non-true bifurcation lesions, a one-stent technique with (aggressive strategy) or without (conservative strategy) mandatory kissing balloon inflation was applied. For true bifurcation lesions, an elective two-stent technique (aggressive strategy) was compared to a one-stent approach followed by a stepwise additional balloon inflation/stenting depending on the residual stenosis of the side branch (conservative strategy). Aggressive and conservative strategies for a side branch provisional stenting had similar results with regards to 1-year TVR.10 An Egyptian study of patients with STEMI and totally occluded culprit-lesion artery by a heavy thrombus burden compared outcomes of patients in whom thrombus aspiration was performed or not. Thrombus aspiration was associated with better TIMI flow, myocardial blush grade and ST-segment resolution and with reduced 1-month mortality rates.11 According to the 2018 ESC guidelines on myocardial revascularization, PCI for chronic total occlusions (CTOs) has increasingly been performed using the recommended calculation of the SYNTAX score. This increased rate was clearly seen in a multicenter study from Belgium and Luxembourg in which procedures achieved technical success in 80% of cases. High-volume centres progressively tackled more complex CTOs while keeping success rates stable overtime.12 Another issue of concerns pertains to aorto-ostial CTOs since they are often associated with unfavourable anatomic characteristics and unclear vessel course. Procedural success was achieved in 78% PCI of aorto-ostial CTOs among patients included in a large multinational study. There were only few procedural complications. During follow-up, subsequent TVR and cardiovascular mortality rate remained very low.13 Treatment of in-stent restenosis is another challenging anatomic scenario. In a 3-year clinical follow-up of patients presenting with bare-metal stent in-stent restenosis, a study from Czech Republic showed more favourable outcomes in patients treated with iopromide paclitaxel-coated balloons as compared with those treated with seal-wing paclitaxel-eluting balloons. Major cardiac adverse events and the need for TVR were seen in two- and three-fold fewer patients, respectively.14 A single centre study from Turkey reported the results on concomitant PCI or not in transaortic valve implantation (TAVI). Postprocedural complications including pericardial effusion, stroke, major vascular complications, bleeding, and emergency arrhythmias were similar in patients in whom coronary revascularization was performed simultaneously or performed as a staged procedure before or after TAVI. Although 30-day mortality was higher in simultaneously performed than in staged coronary revascularization, 1-year mortality rates were not statistically different.15 Another new field for percutaneous procedures relates to patients with refractory angina in whom revascularization is not suitable. The coronary sinus reducer is intended to relief these disabling symptoms. Among patients in whom the device was implanted in a 5-year Dutch experience, two third of them showed improvements of at least one Canadian Cardiovascular Society (CCS) class and about one half in at least two CCS class.16 As metoprolol was recently shown to reduce progression of ischaemic injury in a pig model of STEMI, this effect was assessed in patients with ongoing STEMI. Compared with controls, those who received intravenous (IV) metoprolol before reperfusion had narrower QRS, a lower prevalence of QRS distortion, and a lower sum of ST-elevation, suggesting that IV metoprolol may reduce ischaemic injury. The improvement by metoprolol in the electrocardiogram parameters correlated with improvement in magnetic resonance imaging parameters of infarct size, coronary microvascular obstruction, and left ventricular function.17 Publications on PCI released by NSCJs provide real-world insights on the current evolving challenges in management of patients with CAD across countries whose national cardiac societies are affiliated to the ESC. They highlight the advancements taking place in this dynamic field with ongoing procedural improvements and how ESC guidelines are progressively adopted and implemented in a real-world setting. Funding All authors declare no funding for this contribution. Conflict of interest All authors declare no conflict of interest for this contribution. Data availability We confirm that any required link or identifiers for our data are present in the manuscript. Appendix Jean-Jacques Monsuez (Editor-in-Chief of Archives des Maladies du Cœur et des Vaisseaux Pratique), France; Plamen Gatzov (Editor-in-Chief of Forum for Interventional Cardiology Journal), Bulgaria; Michael Aschermann (Editor-in-Chief of Cor et Vasa), Czech Republic; Hala Mahfouz Badran (Editor-in-Chief of Egyptian Heart Journal), Egypt; Nuno Cardim (Editor-in-Chief Revista Portuguesa de Cardiologia), Portugal; Ariel Cohen (Editor-in-Chief of Archives of Cardiovascular Diseases), France; Jose M De La Torre Hernandez (Editor-in-Chief REC Interventional Cardiology), Spain; Cetin Erol (Editor-in-Chief Anatolian Journal of Cardiology ), Turkey; Claes Held (Editor-in-chief Svensk Cardiologi), Sweden; Gerd Heusch (Editor-in-Chief of Basic Resarch in Cardiology), Germany; Patrizio Lancellotti (Editor-in-chief Acta Cardiol), Belgium; Jan Piek (Editor-in-chief Neth Heart J), Netherland; Juan Sanchis (Editor-in-Chief of Revista Española de Cardiología), Spain; Anetta Undas (Editor-in-Chief Kardiologia Polska), Poland; Dilek Ural (Editor-in-Chief of Archives of The Turkish Society of Cardiology), Turkey; Fernando Alfonso (past- Chairman of the Editors’ Network of the European Society of Cardiology), Spain; Ignacio Ferreira-Gonzalez (past-Chairman of the Editors’ Network of the European Society of Cardiology), Spain. References 1 Pascual I , Avanzas P, Almandarez M, Lorca R, Vigil-Escalera M, Arboine L, et al. STEMI, primary percutaneous intervention and recovering of life expectancy: insights from the SurviTEMI study . Rev Esp Cardiol 2021 ; 74 : 829 – 837 . https://doi.org/10.1016/j.recesp.2020.08.006 Google Scholar Crossref Search ADS PubMed WorldCat 2 Sabatowski K , Malinowsli K, Siudak Z, Reczuch K, Dobrzycki S, Lesiak M, et al. Sex-related differences and rotational atherectomy: analysis of 5177 percutaneous coronary interventions based on a large national registry from 2014 to 2020 . Kardiol Pol 2021 ; 79 : 1320 – 1327 . https://doi.org/10.33963/KP.a2021.0131 Google Scholar Crossref Search ADS PubMed WorldCat 3 Rossello X , Mas-Llado C, Pocock C, Vicent L, Van de Werf F, Chin CT, et al. Sex differences in mortality after an acute coronary syndrome increase with lower country wealth and a higher income inequality . Rev Esp Cardiol 2022 ; 75 : 392 – 400 . https://doi.org/10.1016/j.recesp.2021.05.009 Google Scholar Crossref Search ADS PubMed WorldCat 4 Abtan G , Wiviott SD, Sorbets E, Popovic B, Elbez Y, Mehta SR, et al. Prevalence, clinical determinants and prognostic implications of coronary interventions in non ST-segment myocardial infarction: insights from the contemporary multinational TAO trial . Arch Cardiovasc Dis 2021 ; 114 : 187 – 196 . https://doi.org/10.1016/j.acvd.2020.09.005 Google Scholar Crossref Search ADS PubMed WorldCat 5 Svensk HC . Cardiologi: Informatioskrift för Svenska Cardiologföreningen . Vol. 3 . Swedish Society of Cardiology ; 2021 : 32 – 34 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC 6 Raposo L , Gonçalves M, Roque D, Gonçalves PA, Magno P, Brito J, et al. Adoption and patterns of use of invasive physiological assessment of coronary artery disease in a large cohort of 40821 real-world procedures over a 12 year period . Portuguese J Cardiol 2021 ; 40 : 771 – 781 . https://doi.org/10.1016/j.repc.2021.01.010 Google Scholar Crossref Search ADS WorldCat 7 Pericet-Rodriguez C , Hidalgo-Lesmes FG, Gonzalez-Manzanares R, Ojeda-Pineda S, Luque-Moreno A, Suárez de Lezo J, et al. Usefulness of physiological coronary assessment with iFR in daily practice and all-comer patients: immediate and follow up results . REC Interv Cardiol 2021 ; 3 : 182 – 189 . https://doi.org/10.24875/RECICE.M21000206 Google Scholar OpenURL Placeholder Text WorldCat 8 Erdem K , Kurtoglu E, Kucuk MA, Ilgenli TF, Kizmaz. Distal transradial versus conventional access in acute coronary syndrome . Turk Kardiyol Dern Ars 2021 ; 49 : 257 – 265 . https://doi.org/10.5543/tkda.2021.64000 Google Scholar Crossref Search ADS PubMed WorldCat 9 Gelev V , Zheleva-Kyuchukova I. Percutaneous coronary interventions of unprotected left main stenosis . Forum Interv Cardiol J 2021 ; 1 : 25 – 35 . https://doi.org/10.3897/icf.1.e76246 Google Scholar OpenURL Placeholder Text WorldCat 10 Kim J , Lee JM, Park TK, Yang JH, Hahn J-Y, Choi J-H, et al. Optimal strategy for side branch treatment in patients with left main coronary bifurcation lesions . Rev Esp Cardiol 2021 ; 74 : 691 – 699 . https://doi.org/10.1016/j.recesp.2020.06.012 Google Scholar Crossref Search ADS PubMed WorldCat 11 Elfekky EM , Penjameen MN, Nassar AI, Elias RR. Outcome of manual thrombus aspiration for patients undergoing primary PCI for acute STEMI showing large thrombus burden . Egypt Heart J 2021 ; 73 : 8 . https://doi.org/10.1186/s43044-020-00122-9 Google Scholar Crossref Search ADS PubMed WorldCat 12 Eertsman W , Kayaert P, Bennet J, Ungureanu C, Bataille Y, Saad G, et al. The evolution of the CTO-PI landscape in Belgium and Luxembourg: a four year appraisal . Acta Cardiol 2021 ; 76 : 1043 – 1051 . https://doi.org/10.1080/00015385.2020.1801197 Google Scholar PubMed OpenURL Placeholder Text WorldCat 13 Ojeda S , Luque A, Pan M, Bellini B, Xenogiannis I, Lostalo A, et al. Percutaneous coronary intervention in aorto-ostial coronary chronic total occlusion: outcomes and technical considerations in a multicenter registry . Rev Esp Cardiol 2020 ; 73 : 1011 – 1017 . https://doi.org/10.1016/j.recesp.2020.01.018 Google Scholar Crossref Search ADS PubMed WorldCat 14 Pleva L , Kukla P, Zapletalova J, Hlinomaz O. In stent restenosis treatment with seal-wing paclitaxel drug-eluting balloon catheter . Cor Vasa 2021 ; 63 : 442 – 447 . https://doi.org/10.33678/cor.2021.013 Google Scholar Crossref Search ADS WorldCat 15 Karaduman BD , Ayhan H, Keles T, Bozkurt E. Impact of coronary revascularization on outcomes of transcatheteraortic valve implantation . Anatol J Cardiol 2021 ; 25 : 225 – 235 . https://doi.org/10.14744/AnatolJCardiol.2020.42728 Google Scholar PubMed OpenURL Placeholder Text WorldCat 16 Silvis MJM , Dekker M, Zivelonghi C, Agostoni P, Stella PR, Doevendans PA, et al. The coronary sinus reducer: 5-year Dutch experience . Neth Heart J 2021 ; 29 : 215 – 223 . https://doi.org/10.1007/s12471-020-01525-8 Google Scholar Crossref Search ADS PubMed WorldCat 17 Diaz-Munoz R , Valle-Caballero MJ, Sanchez-Gonzales J, et al. Intravenous metoprolol during ongoing STEMI ameliorates markers of ischemic injury; a METOCARD-CNIC trial electrocardiographic study . Basic Res Cardiol 2021 ; 116 : 45 . https://doi.org/10.1007/s00395-021-00884-6 Google Scholar Crossref Search ADS PubMed WorldCat Author notes † Listed of the authors provided in the Appendix section. © The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: [email protected] This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) © The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: [email protected]

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Protection and delay of aortic complications in the Marfan syndrome: a new indication for angiotensin receptor blockers on top of β blockers

Pedicino, Daniela; Volpe, Massimo

2022 European Heart Journal

doi: 10.1093/eurheartj/ehac685pmid: 36453082

Comment on ‘Angiotensin receptor blockers and β blockers in Marfan syndrome: an individual patient data meta-analysis of randomised trials’ which was published in the Lancet; https://doi.org/10.1016/S0140-6736(22)01534-3. Key Points In this individual patient data meta-analysis,1 a systematic search was performed using Embase, MEDLINE, and CENTRAL from database inception until November 2021. Seven relevant randomized trials (RCTs) assessing the effects of angiotensin receptor blockers (ARBs) vs. control or ARBs vs. β blockers (BB) in patients with Marfan syndrome were identified. The study focused on Marfan patients with no prior aortic root surgery, in order to estimate the effects of ARBs and BB on the annual rate of change in aortic root dimension, adjusted for body surface area (aortic root Z score) as the primary endpoint of the intervention. Of the seven eligible RCTs (1442 patients), four trials (676 patients) compared ARBs with controls, and three trials (766 patients) compared ARBs with BBs. For the first group of studies, the mean age of participants was 29 years [Standard Deviation (SD), 14], with 54% female and 75% receiving BB at baseline (in all trials patients were allowed to remain on BB). Moreover, of 630 genotyped individuals, 83% had a fibrillin-1 (FBN1) pathogenic variant that causes progressive enlargement of the aortic root. As for the second group of trials, the mean age of participants was 14 years (SD 10), with 44% female and 86% of genotyped individuals (327 patients) having a pathogenic variant in FBN1. During a median follow-up of 3 years, when compared with controls, ARB use was associated with half the annual rate of change in aortic root Z score [mean annual increase 0.07 for ARBs, standard error (SE) 0.02; vs. 0.13 for control, SE 0.02; absolute difference, −0.07; 95% confidence interval (CI), −0.12 to −0.01; P = 0.012], with larger effects for those patients with FBN1 pathogenic variant compared with those without the variant (P for heterogeneity = 0.005), and similar results irrespective of whether or not patients were on BB at baseline (P for heterogeneity = 0.54). These results were statistically significant for all specified aortic root measurement methods. Over a similar follow-up, the annual change in the aortic root Z score was similar in the ARB and BB groups (−0.08 in ARBs vs. −0.11 in BBs, P = 0.48). Moreover, by combining the results of the RCTs of ARBs vs. control with RCTs of ARBs vs. BB to indirectly assess BB vs. control, a difference in mean absolute annual change in the aortic root Z score between BB and control of −0.09 (95% CI, −0.18 to 0.00; P = 0.042) was estimated, similar to the direct estimate for the comparison of ARBs vs. control. Comment Marfan syndrome is a genetically determined disease and is one of the most common systemic disorders of the connective tissue affecting about 1.6 million people. Its incidence ranges between 2 and 3 cases per 10 000 individuals. It is caused by pathogenic variants in the FBN1 gene leading to multiorgan abnormalities with prominent involvement of the cardiovascular system.2 Aortic complications, such as progressive aortic dilatation and dissection, are the leading causes of premature death and disability of Marfan patients. Moreover, high morbidity and mortality are associated with the only effective therapeutic approach, i.e. the prophylactic surgical aortic replacement, to be considered in case of a large or rapidly expanding aortic aneurysm with an imminent risk of dissection.3 Since transforming growth factor β (TGFβ) is involved in the pathogenesis of some aortic aneurysms, previous studies in animal models have focused on the role of the ARB losartan in modulating/blocking aortic growth, in view of a dampening effect of this drug on TGFβ activity.4 In spite of the promising results in animal models and in small observational studies suggesting a delay in the development of aortic wall abnormalities,4,5 RCTs testing drug options for Marfan disease failed to show relevant effects in the prevention of aortic complications.6–9 Furthermore, previous meta-analyses were not able to define the effects of ARBs, by relying only on published data and being limited in scope by high data heterogeneity.10 In the current meta-analysis, individual patient data from eligible RCTs were used in a study protocol designed to overcome data heterogeneity.1 Following this approach, the authors were able to show that the increase in the annual Z score with ARBs compared with control was approximately halved, with the greatest benefit being observed among those patients with a pathogenic FBN1 variant.1 A similar reduction was documented for ARBs and BB in a limited number of head-to-head comparisons. However, given the young age of the patients in the two groups of RCTs (mean age of 29 years in the ARB vs. control subgroup and 14 years in the ARB vs. BB subgroup), the indirect comparison of BB vs. controls is poorly informative and the generalisability of the findings to older adults with Marfan syndrome is somewhat uncertain, as only 11% of the randomly assigned patients were aged 40 years or older and only 6% were aged 50 years or older.1 Moreover, the present study does not clarify whether the protective effect of ARBs is linked to specific agents or reflects a class effect. In addition, it cannot address the question of whether higher doses of ARBs may produce better results than BB or the combination of the two. On the other hand, the finding of no significant heterogeneity of the effects of ARBs depending on concomitant use of BB might suggest that the mechanisms of action of these drugs are independent of each other and potentially additive, thus leading to a greater benefit in decreasing the rate of progression in aortic root dilation, when used in combination. Additional relevant information comes from a sample size calculation performed by the Pediatric Heart Network investigators that suggests that a reduction in the annual rate of change of the Z score from 0.20 to 0.12 (i.e. an annual reduction of 0.08, similar to the effect size of both ARBs and BB) would lead to a delay of about 10 years in the need for aortic surgery.11 By considering that both ARBs and BB are easily accessible, inexpensive drugs, and are safe and well tolerated, the clinical relevance of the data provided in this meta-analysis strongly supports this combination therapy as the standard of care for patients with Marfan syndrome, especially those with FBN1 pathogenic variants. Funding All authors declare no funding for this contribution. Data availability No new data were generated or analysed in support of this research. References 1 Pitcher A , Spata E, Emberson J, Davies K, Halls H, Holland L, et al. Angiotensin receptor blockers and β blockers in marfan syndrome: an individual patient data meta-analysis of randomised trials . Lancet 2022 ; 400 : 822 – 831 . https://doi.org/10.1016/S0140-6736(22)01534-3 Google Scholar Crossref Search ADS PubMed WorldCat 2 The Marfan Foundation . Marfan syndrome . https://marfan.org/conditions/marfan-syndrome. 3 Erbel R , Aboyans V, Boileau C, Bossone E, Bartolomeo RD, Eggebrecht H, et al. 2014 ESC guidelines on the diagnosis and treatment of aortic diseases: document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult. The task force for the diagnosis and treatment of aortic diseases of the European society of cardiology (ESC) . Eur Heart J 2014 ; 35 : 2873 – 2926 . https://doi.org/10.1093/eurheartj/ehu281 Google Scholar PubMed OpenURL Placeholder Text WorldCat 4 Habashi JP , Judge DP, Holm TM, Cohn RD, Loeys BL, Cooper TK, et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of marfan syndrome . Science 2006 ; 312 : 117 – 121 . https://doi.org/10.1126/science.1124287 Google Scholar Crossref Search ADS PubMed WorldCat 5 Brooke BS , Habashi JP, Judge DP, Patel N, Loeys B, Dietz HC III. Angiotensin II blockade and aortic-root dilation in marfan's syndrome . N Engl J Med 2008 ; 358 : 2787 – 2795 . https://doi.org/10.1056/NEJMoa0706585 Google Scholar Crossref Search ADS PubMed WorldCat 6 Milleron O , Arnoult F, Ropers J, Aegerter P, Detaint D, Delorme G, et al. Marfan sartan: a randomized, double-blind, placebo-controlled trial . Eur Heart J 2015 ; 36 : 2160 – 2166 . https://doi.org/10.1093/eurheartj/ehv151 Google Scholar Crossref Search ADS PubMed WorldCat 7 Groenink M , den Hartog AW, Franken R, Radonic T, de Waard V, Timmermans J, et al. Losartan reduces aortic dilatation rate in adults with marfan syndrome: a randomized controlled trial . Eur Heart J 2013 ; 34 : 3491 – 3500 . https://doi.org/10.1093/eurheartj/eht334 Google Scholar Crossref Search ADS PubMed WorldCat 8 Möberg K , De Nobele S, Devos D, Goetghebeur E, Segers P, Trachet B, et al. The Ghent marfan trial–a randomized, double-blind placebo controlled trial with losartan in marfan patients treated with β-blockers . Int J Cardiol 2012 ; 157 : 354 – 358 . https://doi.org/10.1016/j.ijcard.2010.12.070 Google Scholar Crossref Search ADS PubMed WorldCat 9 Forteza A , Evangelista A, Sánchez V, Teixidó-Turà G, Sanz P, Gutiérrez L, et al. Efficacy of losartan vs. Atenolol for the prevention of aortic dilation in marfan syndrome: a randomized clinical trial . Eur Heart J 2016 ; 37 : 978 – 985 . https://doi.org/10.1093/eurheartj/ehv575 Google Scholar Crossref Search ADS PubMed WorldCat 10 Al-Abcha A , Saleh Y, Mujer M, Boumegouas M, Herzallah K, Charles L, et al. Meta-analysis examining the usefulness of angiotensin receptor blockers for the prevention of aortic root dilation in patients with the marfan syndrome . Am J Cardiol 2020 ; 128 : 101 – 106 . https://doi.org/10.1016/j.amjcard.2020.04.034 Google Scholar Crossref Search ADS PubMed WorldCat 11 Lacro RV , Dietz HC, Sleeper LA, Yetman AT, Bradley TJ, Colan SD, et al. Atenolol versus losartan in children and young adults with marfan's syndrome . N Engl J Med 2014 ; 371 : 2061 – 2071 . https://doi.org/10.1056/NEJMoa1404731 Google Scholar Crossref Search ADS PubMed WorldCat Author notes Conflict of interest: D.P. received speaker’s fees from Daiichi-Sankyo, outside the submitted work. M.V. reports personal fees for speaker bureau and/or consulting in Advisory Boards from Amgen, Astra Zeneca, Daiichi-Sankyo, Menarini Int, MSD, Novartis Pharma, and Novo Nordisk, outside the submitted work. © The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: [email protected] This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) © The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: [email protected]

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Acute, periprocedural and longterm antithrombotic therapy in older adults

Andreotti, Felicita; Geisler, Tobias; Collet, Jean-Philippe; Gigante, Bruna; Gorog, Diana A; Halvorsen, Sigrun; Lip, Gregory Y H; Morais, Joao; Navarese, Eliano Pio; Patrono, Carlo; Rocca, Bianca; Rubboli, Andrea; Sibbing, Dirk; Storey, Robert F; Verheugt, Freek W A; Vilahur, Gemma

2022 European Heart Journal

doi: 10.1093/eurheartj/ehac515pmid: 36477865

Graphical AbstractGraphical AbstractAntithrombotic therapy in older adults: challenges and selected consensus points. AC, anticoagulant; ACS, acute coronary syndrome; AF, atrial fibrillation; AP, antiplatelet; APT, antiplatelet therapy; ARC HBR, Academic Research Consortium High Bleeding Risk; ATT, antithrombotic therapy; BP, blood pressure; CCS, chronic coronary syndrome; DAPT, dual antiplatelet therapy; EMA, European Medicines Agency; Hb, haemoglobin; LAAC, left atrial appendage closure; MI, myocardial infarction; NOAC, non-vitamin K antagonist oral anticoagulant; NSTE, non-ST-elevation; NSAID, non-steroidal anti-inflammatory drugs; PAD, peripheral artery disease; PPI, proton pump inhibitor; TAT, triple antithrombotic therapy; TAVI, transcatheter aortic valve implantation; TNK, tenecteplase.

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Factor XI inhibitors: cardiovascular perspectives

De Caterina, Raffaele; Prisco, Domenico; Eikelboom, John W

2022 European Heart Journal

doi: 10.1093/eurheartj/ehac464pmid: 36263776

Graphical AbstractGraphical AbstractPossible forthcoming therapeutic indications for FXI/XIa inhibitors.

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Growth differentiation factor 15 and cardiovascular risk: individual patient meta-analysis

Kato, Eri Toda; Morrow, David A; Guo, Jianping; Berg, David D; Blazing, Michael A; Bohula, Erin A; Bonaca, Marc P; Cannon, Christopher P; de Lemos, James A; Giugliano, Robert P; Jarolim, Petr; Kempf, Tibor; Kristin Newby, L; O’Donoghue, Michelle L; Pfeffer, Marc A; Rifai, Nader; Wiviott, Stephen D; Wollert, Kai C; Braunwald, Eugene; Sabatine, Marc S

2022 European Heart Journal

doi: 10.1093/eurheartj/ehac577pmid: 36303404

AimsLevels of growth differentiation factor 15 (GDF-15), a cytokine secreted in response to cellular stress and inflammation, have been associated with multiple types of cardiovascular (CV) events. However, its comparative prognostic performance across different presentations of atherosclerotic cardiovascular disease (ASCVD) remains unknown.Methods and resultsAn individual patient meta-analysis was performed using data pooled from eight trials including 53 486 patients. Baseline GDF-15 concentration was analyzed as a continuous variable and using established cutpoints (<1200 ng/L, 1200–1800 ng/L, > 1800 ng/L) to evaluate its prognostic performance for CV death/hospitalization for heart failure (HHF), major adverse cardiovascular events (MACE), and their components using Cox models adjusted for clinical variables and established CV biomarkers. Analyses were further stratified on ASCVD status: acute coronary syndrome (ACS), stabilized after recent ACS, and stable ASCVD. Overall, higher GDF-15 concentration was significantly and independently associated with an increased rate of CV death/HHF and MACE (P < 0.001 for each). However, while GDF-15 showed a robust and consistent independent association with CV death and HHF across all presentations of ASCVD, its prognostic association with future myocardial infarction (MI) and stroke only remained significant in patients stabilized after recent ACS or with stable ASCVD [hazard ratio (HR): 1.24, 95% confidence interval (CI): 1.17–1.31 and HR: 1.16, 95% CI: 1.05–1.28 for MI and stroke, respectively] and not in ACS (HR: 0.98, 95% CI: 0.90–1.06 and HR: 0.87, 95% CI: 0.39–1.92, respectively).ConclusionGrowth differentiation factor 15 consistently adds prognostic information for CV death and HHF across the spectrum of ASCVD. GDF-15 also adds prognostic information for MI and stroke beyond clinical risk factors and cardiac biomarkers but not in the setting of ACS.

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Growth differentiation factor 15: a biomarker searching for an indication

Mueller, Christian; Muench-Gerber, Tamar S; de Boer, Rudolf A

2022 European Heart Journal

doi: 10.1093/eurheartj/ehac681pmid: 36459111

Graphical AbstractGraphical AbstractLimitations for a possible clinical use of GDF-15 as a biomarker in cardiovascular disease (CVD), elements to be evaluated as part of a reality check for suggested novel plasma biomarkers, and clinical settings still in urgent need for help by a biomarker. ACS = acute coronary syndrome; AMI = acute myocardial infarction; cTnT = cardiac troponin T; CTnI = cardiac troponin I, BNP = brain natriuretic peptide; NT-proBNP = N-terminal pro B-type natriuretic peptide; GDF-15 = growth differentiation factor 15.

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Vinculin phosphorylation impairs vascular endothelial junctions promoting atherosclerosis

Shih, Yu-Tsung; Wei, Shu-Yi; Chen, Jin-Hua; Wang, Wei-Li; Wu, Hsin-Yi; Wang, Mei-Cun; Lin, Chia-Yu; Lee, Pei-Lin; Lin, Chih-Yuan; Chiang, Hung-Che; Chen, Yu-Ju; Chien, Shu; Chiu, Jeng-Jiann

2022 European Heart Journal

doi: 10.1093/eurheartj/ehac647pmid: 36380599

Background and aimsAtherosclerosis preferentially develops in arterial branches and curvatures where vascular endothelium is exposed to disturbed flow. In this study, the effects of disturbed flow on the regulation of vascular endothelial phosphoproteins and their contribution to therapeutic application in atherogenesis were elucidated.MethodsPorcine models, large-scale phosphoproteomics, transgenic mice, and clinical specimens were used to discover novel site-specific phosphorylation alterations induced by disturbed flow in endothelial cells (ECs).ResultsA large-scale phosphoproteomics analysis of native endothelium from disturbed (athero-susceptible) vs. pulsatile flow (athero-resistant) regions of porcine aortas led to the identification of a novel atherosclerosis-related phosphoprotein vinculin (VCL) with disturbed flow-induced phosphorylation at serine 721 (VCLS721p). The induction of VCLS721p was mediated by G-protein-coupled receptor kinase 2 (GRK2)S29p and resulted in an inactive form of VCL with a closed conformation, leading to the VE-cadherin/catenin complex disruption to enhance endothelial permeability and atherogenesis. The generation of novel apolipoprotein E-deficient (ApoE−/−) mice overexpressing S721-non-phosphorylatable VCL mutant in ECs confirmed the critical role of VCLS721p in promoting atherosclerosis. The administration of a GRK2 inhibitor to ApoE−/− mice suppressed plaque formation by inhibiting endothelial VCLS721p. Studies on clinical specimens from patients with coronary artery disease (CAD) revealed that endothelial VCLS721p is a critical clinicopathological biomarker for atherosclerosis progression and that serum VCLS721p level is a promising biomarker for CAD diagnosis.ConclusionsThe findings of this study indicate that endothelial VCLS721p is a valuable hemodynamic-based target for clinical assessment and treatment of vascular disorders resulting from atherosclerosis.

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Vinculin phosphorylation modulates endothelial cell permeability: a new target for cardiovascular disease?

Bonacina, Fabrizia; Danilo Norata, Giuseppe

2022 European Heart Journal

doi: 10.1093/eurheartj/ehac704pmid: 36514951

Graphical AbstractGraphical AbstractIn athero-resistant vessels, the pulsatile, laminar shear stress restrains vinculin (VCL) in an active open conformation that allows the interaction of its head and tail with adaptor ligands preserving vascular endothelial (VE) junctions and in turn endothelial barrier integrity. In athero-susceptible regions, the turbulent and vicious blood flow induces post-translational modification of VCL which becomes highly phosphorylated at Ser721, resulting in the modification of the protein conformation towards the closed form with a poor interaction with VE-cadherin, thus influencing endothelial barrier integration and favouring progression of atherosclerosis. Phosphorylated (i.e. active) GRK2 promotes VCL phosphorylation, and its inhibition could be a potential approach to limit VCLS721 phosphorylation, improve endothelial function, and limit atherogenesis.

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