Gut microbial diversity is associated with lower arterial stiffness in women

Cristina Menni, Chihung Lin, Marina Cecelja, Massimo Mangino, Maria Luisa Matey-Hernandez, Louise Keehn, Robert P Mohney, Claire J Steves, Tim D Spector, Chang-Fu Kuo, Phil Chowienczyk, Ana M Valdes, Cristina Menni, Chihung Lin, Marina Cecelja, Massimo Mangino, Maria Luisa Matey-Hernandez, Louise Keehn, Robert P Mohney, Claire J Steves, Tim D Spector, Chang-Fu Kuo, Phil Chowienczyk, Ana M Valdes

Abstract

Aims: The gut microbiome influences metabolic syndrome (MetS) and inflammation and is therapeutically modifiable. Arterial stiffness is poorly correlated with most traditional risk factors. Our aim was to examine whether gut microbial composition is associated with arterial stiffness.

Methods and results: We assessed the correlation between carotid-femoral pulse wave velocity (PWV), a measure of arterial stiffness, and gut microbiome composition in 617 middle-aged women from the TwinsUK cohort with concurrent serum metabolomics data. Pulse wave velocity was negatively correlated with gut microbiome alpha diversity (Shannon index, Beta(SE)= -0.25(0.07), P = 1 × 10-4) after adjustment for covariates. We identified seven operational taxonomic units associated with PWV after adjusting for covariates and multiple testing-two belonging to the Ruminococcaceae family. Associations between microbe abundances, microbe diversity, and PWV remained significant after adjustment for levels of gut-derived metabolites (indolepropionate, trimethylamine oxide, and phenylacetylglutamine). We linearly combined the PWV-associated gut microbiome-derived variables and found that microbiome factors explained 8.3% (95% confidence interval 4.3-12.4%) of the variance in PWV. A formal mediation analysis revealed that only a small proportion (5.51%) of the total effect of the gut microbiome on PWV was mediated by insulin resistance and visceral fat, c-reactive protein, and cardiovascular risk factors after adjusting for age, body mass index, and mean arterial pressure.

Conclusions: Gut microbiome diversity is inversely associated with arterial stiffness in women. The effect of gut microbiome composition on PWV is only minimally mediated by MetS. This first human observation linking the gut microbiome to arterial stiffness suggests that targeting the microbiome may be a way to treat arterial ageing.

Figures

Figure 1
Figure 1
Microbes associated between pulse wave velocity and gut bacterial operational taxonomic units (false discovery rate 

Figure 2

Mediation analysis of the association…

Figure 2

Mediation analysis of the association between ( A ) microbiome factors and (…

Figure 2
Mediation analysis of the association between (A) microbiome factors and (B) Shannon diversity and pulse wave velocity using partial least squares structural equation modelling. Path coefficients are denoted beside each path and indirect effect and variance accounted for (variance accounted for) score is denoted below each mediator (*P < 0.05; **P < 0.01; ***P < 0.001).

Take home figure

The gut microbiome is…

Take home figure

The gut microbiome is related to metabolic syndrome and inflammation, is modifiable…

Take home figure
The gut microbiome is related to metabolic syndrome and inflammation, is modifiable via diet, medication and probiotics. Arterial stiffness (measured by pulse wave velocity) is a predictor of major cardiovascular events, which is related to metabolic syndrome and inflammation but poorly correlated with most traditional risk factors other than mean arterial pressure. The hypothesis of this study was that the gut microbiome composition could be related to arterial stiffness. This was measured in 617 women and both specific microbes and gut microbiome diversity, a measure of gut dysbiosis, along with metabolites generated by the gut microbiome were found to be associated with arterial stiffness. In fact, the microbiome related factors explain 8.3% of the variance in pulse wave velocity compared with only 1.8% of insulin resistance combined with visceral fat. These data indicate a strong contribution of the gut microbiome to risk of arterial stiffness and suggest targeting the gut microbiome composition as a therapeutic strategy.
Figure 2
Figure 2
Mediation analysis of the association between (A) microbiome factors and (B) Shannon diversity and pulse wave velocity using partial least squares structural equation modelling. Path coefficients are denoted beside each path and indirect effect and variance accounted for (variance accounted for) score is denoted below each mediator (*P < 0.05; **P < 0.01; ***P < 0.001).
Take home figure
Take home figure
The gut microbiome is related to metabolic syndrome and inflammation, is modifiable via diet, medication and probiotics. Arterial stiffness (measured by pulse wave velocity) is a predictor of major cardiovascular events, which is related to metabolic syndrome and inflammation but poorly correlated with most traditional risk factors other than mean arterial pressure. The hypothesis of this study was that the gut microbiome composition could be related to arterial stiffness. This was measured in 617 women and both specific microbes and gut microbiome diversity, a measure of gut dysbiosis, along with metabolites generated by the gut microbiome were found to be associated with arterial stiffness. In fact, the microbiome related factors explain 8.3% of the variance in pulse wave velocity compared with only 1.8% of insulin resistance combined with visceral fat. These data indicate a strong contribution of the gut microbiome to risk of arterial stiffness and suggest targeting the gut microbiome composition as a therapeutic strategy.
https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6030944/bin/ehy226f3.jpg

References

    1. Weiss GA, Hennet T.. Mechanisms and consequences of intestinal dysbiosis. Cell Mol Life Sci 2017;74:2959–2977.
    1. Li DY, Tang WHW.. Gut microbiota and atherosclerosis. Curr Atheroscler Rep 2017;19:39..
    1. Jia G, Aroor AR, Sowers JR.. Arterial stiffness: a nexus between cardiac and renal disease. Cardiorenal Med 2014;4:60–71.
    1. Jia G, Aroor AR, DeMarco VG, Martinez-Lemus LA, Meininger GA, Sowers JR.. Vascular stiffness in insulin resistance and obesity. Front Physiol 2015;6:231..
    1. Villacorta L, Chang L.. The role of perivascular adipose tissue in vasoconstriction, arterial stiffness, and aneurysm. Horm Mol Biol Clin Investig 2015;21:137–147.
    1. Cecelja M, Chowienczyk P.. Role of arterial stiffness in cardiovascular disease. JRSM Cardiovasc Dis 2012;1:1.
    1. Nakagawa K, Morishima N, Shibata T.. A maturase-like subunit of the sequence-specific endonuclease endo.SceI from yeast mitochondria. J Biol Chem 1991;266:1977–1984.
    1. McEniery CM, Spratt M, Munnery M, Yarnell J, Lowe GD, Rumley A, Gallacher J, Ben-Shlomo Y, Cockcroft JR, Wilkinson IB.. An analysis of prospective risk factors for aortic stiffness in men: 20-year follow-up from the Caerphilly prospective study. Hypertension 2010;56:36–43.
    1. Townsend RR. Arterial stiffness: recommendations and standardization. Pulse (Basel) 2016;4:3–7.
    1. Rizzoni D, Porteri E, Guelfi D, Muiesan ML, Valentini U, Cimino A, Girelli A, Rodella L, Bianchi R, Sleiman I, Rosei EA.. Structural alterations in subcutaneous small arteries of normotensive and hypertensive patients with non-insulin-dependent diabetes mellitus. Circulation 2001;103:1238–1244.
    1. Omelchenko E, Gavish D, Shargorodsky M.. Adiponectin is better predictor of subclinical atherosclerosis than liver function tests in patients with nonalcoholic fatty liver disease. J Am Soc Hypertens 2014;8:376–380.
    1. Jain S, Khera R, Corrales-Medina VF, Townsend RR, Chirinos JA.. Inflammation and arterial stiffness in humans. Atherosclerosis 2014;237:381–390.
    1. Yasmin, McEniery CM, Wallace S, Mackenzie IS, Cockcroft JR, Wilkinson IB.. C-reactive protein is associated with arterial stiffness in apparently healthy individuals. Arterioscler Thromb Vasc Biol 2004;24:969–974.
    1. Mattace-Raso FU, van der Cammen TJ, van der Meer IM, Schalekamp MA, Asmar R, Hofman A, Witteman JC.. C-reactive protein and arterial stiffness in older adults: the Rotterdam Study. Atherosclerosis 2004;176:111–116.
    1. Maki-Petaja KM, Hall FC, Booth AD, Wallace SM, Yasmin, Bearcroft PW, Harish S, Furlong A, McEniery CM, Brown J, Wilkinson IB.. Rheumatoid arthritis is associated with increased aortic pulse-wave velocity, which is reduced by anti-tumor necrosis factor-alpha therapy. Circulation 2006;114:1185–1192.
    1. Shang Q, Tam LS, Li EK, Yip GW, Yu CM.. Increased arterial stiffness correlated with disease activity in systemic lupus erythematosus. Lupus 2008;17:1096–1102.
    1. Everard A, Cani PD.. Diabetes, obesity and gut microbiota. Best Pract Res Clin Gastroenterol 2013;27:73–83.
    1. Pedersen HK, Gudmundsdottir V, Nielsen HB, Hyotylainen T, Nielsen T, Jensen BA, Forslund K, Hildebrand F, Prifti E, Falony G, Le Chatelier E, Levenez F, Dore J, Mattila I, Plichta DR, Poho P, Hellgren LI, Arumugam M, Sunagawa S, Vieira-Silva S, Jorgensen T, Holm JB, Trost K, Kristiansen K, Brix S, Raes J, Wang J, Hansen T, Bork P, Brunak S, Oresic M, Ehrlich SD, Pedersen O.. Human gut microbes impact host serum metabolome and insulin sensitivity. Nature 2016;535:376–381.
    1. Grigg JB, Sonnenberg GF.. Host-microbiota interactions shape local and systemic inflammatory diseases. J Immunol 2017;198:564–571.
    1. Heiman ML, Greenway FL.. A healthy gastrointestinal microbiome is dependent on dietary diversity. Mol Metab 2016;5:317–320.
    1. Wikoff WR, Anfora AT, Liu J, Schultz PG, Lesley SA, Peters EC, Siuzdak G.. Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc Natl Acad Sci USA 2009;106:3698–3703.
    1. de Mello VD, Paananen J, Lindstrom J, Lankinen MA, Shi L, Kuusisto J, Pihlajamaki J, Auriola S, Lehtonen M, Rolandsson O, Bergdahl IA, Nordin E, Ilanne-Parikka P, Keinanen-Kiukaanniemi S, Landberg R, Eriksson JG, Tuomilehto J, Hanhineva K, Uusitupa M.. Indolepropionic acid and novel lipid metabolites are associated with a lower risk of type 2 diabetes in the Finnish Diabetes Prevention Study. Sci Rep 2017;7:46337..
    1. Moayyeri A, Hammond CJ, Valdes AM, Spector TD.. Cohort profile: twins UK and healthy ageing twin study. Int J Epidemiol 2013;42:76–85.
    1. Goodrich JK, Davenport ER, Beaumont M, Jackson MA, Knight R, Ober C, Spector TD, Bell JT, Clark AG, Ley RE.. Genetic determinants of the gut microbiome in UK twins. Cell Host Microbe 2016;19:731–743.
    1. Cecelja M, Jiang B, McNeill K, Kato B, Ritter J, Spector T, Chowienczyk P.. Increased wave reflection rather than central arterial stiffness is the main determinant of raised pulse pressure in women and relates to mismatch in arterial dimensions: a twin study. J Am Coll Cardiol 2009;54:695–703.
    1. Menni C, Migaud M, Glastonbury CA, Beaumont M, Nikolau A, Small K, Brosnan MJ, Mohney R, Spector TD, Valdes AM.. Metabolomic profiling to dissect the role of visceral fat in cardiometabolic health. Obesity (Silver Spring) 2016.
    1. Goff DC Jr, Lloyd-Jones DM, Bennett G, Coady S, D’Agostino RB, Gibbons R, Greenland P, Lackland DT, Levy D, O’Donnell CJ, Robinson JG, Schwartz JS, Shero ST, Smith SC Jr, Sorlie P, Stone NJ, Wilson PW, Jordan HS, Nevo L, Wnek J, Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH, DeMets D, Hochman JS, Kovacs RJ, Ohman EM, Pressler SJ, Sellke FW, Shen WK, Tomaselli GF.. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force. On practice guidelines . Circulation 2014;129:S49–S73.
    1. Redon J. Global cardiovascular risk assessment: strengths and limitations. High Blood Press Cardiovasc Prev 2016;23:87–90.
    1. Bingham SA, Welch AA, McTaggart A, Mulligan AA, Runswick SA, Luben R, Oakes S, Khaw KT, Wareham N, Day NE.. Nutritional methods in the European Prospective Investigation of Cancer in Norfolk. Public Health Nutr 2001;4:847–858.
    1. McCance RA, Widdowson EM, Holland B, Welch A, Buss DH.. McCance and Widdowson’s the Composition of Foods. 5th edition, Cambridge: The Royal Society of Chemistry; 1991.
    1. Englyst HN, Cummings JH.. Improved method for measurement of dietary fiber as non-starch polysaccharides in plant foods. J Assoc Off Anal Chem 1988;71:808–814.
    1. Trichopoulou A, Orfanos P, Norat T, Bueno-de-Mesquita B, Ocke MC, Peeters PH, van der Schouw YT, Boeing H, Hoffmann K, Boffetta P, Nagel G, Masala G, Krogh V, Panico S, Tumino R, Vineis P, Bamia C, Naska A, Benetou V, Ferrari P, Slimani N, Pera G, Martinez-Garcia C, Navarro C, Rodriguez-Barranco M, Dorronsoro M, Spencer EA, Key TJ, Bingham S, Khaw KT, Kesse E, Clavel-Chapelon F, Boutron-Ruault MC, Berglund G, Wirfalt E, Hallmans G, Johansson I, Tjonneland A, Olsen A, Overvad K, Hundborg HH, Riboli E, Trichopoulos D.. Modified Mediterranean diet and survival: ePIC-elderly prospective cohort study. BMJ 2005;330:991..
    1. Long T, Hicks M, Yu HC, Biggs WH, Kirkness EF, Menni C, Zierer J, Small KS, Mangino M, Messier H, Brewerton S, Turpaz Y, Perkins BA, Evans AM, Miller LA, Guo L, Caskey CT, Schork NJ, Garner C, Spector TD, Venter JC, Telenti A.. Whole-genome sequencing identifies common-to-rare variants associated with human blood metabolites. Nat Genet 2017;49:568–578.
    1. WHO Expert Committee on Biological Standardization. WHO Technical Report Series 760. Geneva, Switzerland: World Health Organization; 1987. p. 21–22.
    1. Wilkins J, Gallimore JR, Moore EG, Pepys MB.. Rapid automated high sensitivity enzyme immunoassay of C-reactive protein. Clin Chem 1998;44(6 Pt 1):1358–1361.
    1. Edgar RC, Haas BJ, Clemente JC, Quince C, Knight R.. UCHIME improves sensitivity and speed of chimera detection. Bioinformatics 2011;27:2194–2200.
    1. Jackson MA, Bell JT, Spector T, Steves C.. A heritability-based comparison of methods used to cluster 16S rRNA gene sequences into operational taxonomic units. Peer J Preprints 2016.
    1. Caporaso JG, Kuczynski J, Stombaugh J, Bittinger K, Bushman FD, Costello EK, Fierer N, Pena AG, Goodrich JK, Gordon JI, Huttley GA, Kelley ST, Knights D, Koenig JE, Ley RE, Lozupone CA, McDonald D, Muegge BD, Pirrung M, Reeder J, Sevinsky JR, Turnbaugh PJ, Walters WA, Widmann J, Yatsunenko T, Zaneveld J, Knight R.. QIIME allows analysis of high-throughput community sequencing data. Nat Methods 2010;7:335–336.
    1. Choi HY, Kim SH, Choi AR, Kim SG, Kim H, Lee JE, Kim HJ, Park HC.. Hyperuricemia and risk of increased arterial stiffness in healthy women based on health screening in Korean population. PLoS One 2017;12:e0180406..
    1. Cohen J, Cohen P, West SG, Aiken LS, Applied Multiple Regression/Correlation Analysis for the Behavioral Sciences. Mahwah, NJ: Lawrence Earlbaum Associates; 2003.
    1. Nitzl C, Roldan JL, Cepeda G.. Mediation analysis in partial least squares path modeling helping researchers discuss more sophisticated models. Ind Manag Data Syst 2016;116:1849–1864.
    1. Hair JF, Sarstedt M, Ringle CM, Mena JA.. An assessment of the use of partial least squares structural equation modeling in marketing research. J Acad Mark Sci 2012;40:414–433.
    1. Cohen J. Statistical Power Analysis for the Behavioral Sciences. Hillsdale, NJ: L. Erlbaum Associates; 1988.
    1. Pavlou PA, Fygenson M.. Understanding and predicting electronic commerce adoption: an extension of the theory of planned behavior. Mis Q 2006;30:115–143.
    1. Kassinen A, Krogius-Kurikka L, Makivuokko H, Rinttila T, Paulin L, Corander J, Malinen E, Apajalahti J, Palva A.. The fecal microbiota of irritable bowel syndrome patients differs significantly from that of healthy subjects. Gastroenterology 2007;133:24–33.
    1. Menni C, Zierer J, Pallister T, Jackson MA, Long T, Mohney RP, Steves CJ, Spector TD, Valdes AM.. Omega-3 fatty acids correlate with gut microbiome diversity and production of N-carbamylglutamate in middle aged and elderly women. Sci Rep 2017;7:11079..
    1. Modi SR, Collins JJ, Relman DA.. Antibiotics and the gut microbiota. J Clin Invest 2014;124:4212–4218.
    1. Jackson MA, Goodrich JK, Maxan ME, Freedberg DE, Abrams JA, Poole AC, Sutter JL, Welter D, Ley RE, Bell JT, Spector TD, Steves CJ.. Proton pump inhibitors alter the composition of the gut microbiota. Gut 2016;65:749–756.
    1. Menni C, Jackson MA, Pallister T, Steves C, Spector T, Valdes A.. Gut microbiome diversity and high fibre intake are related to lower long term weight gain. Int J Obes (Lond) 2017.
    1. Tanaka H, Tomoto T, Kosaki K, Sugawara J.. Arterial stiffness of lifelong Japanese female pearl divers. Am J Physiol Regul Integr Comp Physiol 2016;310:R975–R978.
    1. Uemura H, Katsuura-Kamano S, Yamaguchi M, Arisawa K.. Relationships of elevated levels of serum hepatic enzymes and alcohol intake with arterial stiffness in men. Atherosclerosis 2015;238:83–88.
    1. Trudel X, Shipley MJ, McEniery CM, Wilkinson IB, Brunner EJ.. Socioeconomic status, education, and aortic stiffness progression over 5 years: the Whitehall II prospective cohort study. J Hypertens 2016;34:2038–2044.
    1. van de Laar RJ, Stehouwer CD, van Bussel BC, Prins MH, Twisk JW, Ferreira I.. Adherence to a Mediterranean dietary pattern in early life is associated with lower arterial stiffness in adulthood: the Amsterdam Growth and Health Longitudinal Study. J Intern Med 2013;273:79–93.
    1. Pallister T, Jackson MA, Martin TC, Glastonbury CA, Jennings A, Beaumont M, Mohney RP, Small KS, MacGregor A, Steves CJ, Cassidy A, Spector TD, Menni C, Valdes AM.. Untangling the relationship between diet and visceral fat mass through blood metabolomics and gut microbiome profiling. Int J Obes (Lond) 2017;41:1106–1113.
    1. Beaumont M, Goodrich JK, Jackson MA, Yet I, Davenport ER, Vieira-Silva S, Debelius J, Pallister T, Mangino M, Raes J, Knight R, Clark AG, Ley RE, Spector TD, Bell JT.. Heritable components of the human fecal microbiome are associated with visceral fat. Genome Biol 2016;17:189..
    1. Caricilli AM, Saad MJ.. Gut microbiota composition and its effects on obesity and insulin resistance. Curr Opin Clin Nutr Metab Care 2014;17:312–318.
    1. Menni C, Mangino M, Cecelja M, Psatha M, Brosnan MJ, Trimmer J, Mohney RP, Chowienczyk P, Padmanabhan S, Spector TD, Valdes AM.. Metabolomic study of carotid-femoral pulse-wave velocity in women. J Hypertens 2015;33:791–796.
    1. Kang C, Wang B, Kaliannan K, Wang X, Lang H, Hui S, Huang L, Zhang Y, Zhou M, Chen M, Mi M.. Gut microbiota mediates the protective effects of dietary capsaicin against chronic low-grade inflammation and associated obesity induced by high-fat diet. MBio 2017;8:e00900-17..
    1. Boutagy NE, McMillan RP, Frisard MI, Hulver MW.. Metabolic endotoxemia with obesity: is it real and is it relevant? Biochimie 2016;124:11–20.
    1. Dregan A. Arterial stiffness association with chronic inflammatory disorders in the UK Biobank study. Heart 2018; doi:10.1136/heartjnl-2017-312610.
    1. Tehrani DM, Gardin JM, Yanez D, Hirsch CH, Lloyd-Jones DM, Stein PK, Wong ND.. Impact of inflammatory biomarkers on relation of high density lipoprotein-cholesterol with incident coronary heart disease: cardiovascular Health Study. Atherosclerosis 2013;231:246–251.
    1. Kaptoge S, Seshasai SR, Gao P, Freitag DF, Butterworth AS, Borglykke A, Di Angelantonio E, Gudnason V, Rumley A, Lowe GD, Jorgensen T, Danesh J.. Inflammatory cytokines and risk of coronary heart disease: new prospective study and updated meta-analysis. Eur Heart J 2014;35:578–589.
    1. Golia E, Limongelli G, Natale F, Fimiani F, Maddaloni V, Pariggiano I, Bianchi R, Crisci M, D’Acierno L, Giordano R, Di Palma G, Conte M, Golino P, Russo MG, Calabrò R, Calabrò P.. Inflammation and cardiovascular disease: from pathogenesis to therapeutic target. Curr Atheroscler Rep 2014;16:435..
    1. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, Kastelein JJP, Cornel JH, Pais P, Pella D, Genest J, Cifkova R, Lorenzatti A, Forster T, Kobalava Z, Vida-Simiti L, Flather M, Shimokawa H, Ogawa H, Dellborg M, Rossi PRF, Troquay RPT, Libby P, Glynn RJ.. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017;377:1119–1131.
    1. Clemente JC, Manasson J, Scher JU.. The role of the gut microbiome in systemic inflammatory disease. BMJ 2018;360:j5145..
    1. Wu GD, Chen J, Hoffmann C, Bittinger K, Chen YY, Keilbaugh SA, Bewtra M, Knights D, Walters WA, Knight R, Sinha R, Gilroy E, Gupta K, Baldassano R, Nessel L, Li H, Bushman FD, Lewis JD.. Linking long-term dietary patterns with gut microbial enterotypes. Science 2011;334:105–108.
    1. Brunkwall L, Orho-Melander M.. The gut microbiome as a target for prevention and treatment of hyperglycaemia in type 2 diabetes: from current human evidence to future possibilities. Diabetologia 2017;60:943–951.
    1. Robles-Vera I, Toral M, Romero M, Jiménez R, Sánchez M, Pérez-Vizcaíno F, Duarte J.. Antihypertensive effects of probiotics. Curr Hypertens Rep 2017;19:26..
    1. DiGiulio DB, Callahan BJ, McMurdie PJ, Costello EK, Lyell DJ, Robaczewska A, Sun CL, Goltsman DS, Wong RJ, Shaw G, Stevenson DK, Holmes SP, Relman DA.. Temporal and spatial variation of the human microbiota during pregnancy. Proc Natl Acad Sci USA 2015;112:11060–11065.
    1. Relman DA. The human microbiome: ecosystem resilience and health. Nutr Rev 2012;70:S2–S9.
    1. Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, Cooney MT, Corra U, Cosyns B, Deaton C, Graham I, Hall MS, Hobbs FDR, Lochen ML, Lollgen H, Marques-Vidal P, Perk J, Prescott E, Redon J, Richter DJ, Sattar N, Smulders Y, Tiberi M, van der Worp HB, van Dis I, Verschuren WMM, Binno S.. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: the Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts) Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2016;37:2315–2381.

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