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Age-Related Vascular Dysfunction: What Registered Dietitian Nutritionists Need to Know

      Cardiovascular disease (CVD) is an age-related chronic disease, where advancing age is the primary risk factor largely due to age-related vascular dysfunction.
      • Benjamin E.J.
      • Blaha M.J.
      • Chiuve S.E.
      • et al.
      Heart Disease and Stroke Statistics-2017 update: A report from the American Heart Association.
      • LaRocca T.J.
      • Martens C.R.
      • Seals D.R.
      Nutrition and other lifestyle influences on arterial aging.
      • Lakatta E.G.
      • Levy D.
      Arterial and cardiac aging: Major shareholders in cardiovascular disease enterprises: Part I: Aging arteries: A “set up” for vascular disease.
      During aging, several adverse structural and functional changes occur throughout the entire vascular system (ie, heart, coronary arteries, peripheral arteries, and microvasculature); however, two prominent changes to the arteries are emerging as the most clinically important due to their striking effect on age-related CVD risk: stiffening of the large elastic arteries (carotid and aorta) and vascular endothelial dysfunction (Figure 1).
      • LaRocca T.J.
      • Martens C.R.
      • Seals D.R.
      Nutrition and other lifestyle influences on arterial aging.
      • Seals D.R.
      • Brunt V.E.
      • Rossman M.J.
      Keynote lecture: strategies for optimal cardiovascular aging.
      • Rossman M.J.
      • LaRocca T.J.
      • Martens C.R.
      • Seals D.R.
      Healthy lifestyle-based approaches for successful vascular aging.
      These arterial changes, referred to together as vascular dysfunction, vascular aging, arterial dysfunction, and/or arterial aging (referred to herein as vascular dysfunction), contribute to the development of atherosclerosis and hypertension (isolated systolic hypertension in particular), and can lead to stroke, myocardial infarction, and other adverse events including death. Mechanisms underlying vascular dysfunction with aging are complex and multifactorial, but excessive oxidative stress and chronic inflammation are believed to be the major central contributors.
      • Seals D.R.
      • Brunt V.E.
      • Rossman M.J.
      Keynote lecture: strategies for optimal cardiovascular aging.
      • Rossman M.J.
      • LaRocca T.J.
      • Martens C.R.
      • Seals D.R.
      Healthy lifestyle-based approaches for successful vascular aging.
      Numerous factors can accelerate these processes and therefore vascular dysfunction in aging individuals, or cause premature development in others.
      • Gimbrone Jr., M.A.
      • Garcia-Cardena G.
      Endothelial cell dysfunction and the pathobiology of atherosclerosis.
      For instance, menopause is associated with accelerated vascular dysfunction in women,
      • Moreau K.L.
      • Hildreth K.L.
      Vascular aging across the menopause transition in healthy women.
      whereas obesity and related metabolic disorders can also induce and accelerate vascular dysfunction with aging.
      • Lakatta E.G.
      • Levy D.
      Arterial and cardiac aging: Major shareholders in cardiovascular disease enterprises: Part I: Aging arteries: A “set up” for vascular disease.
      Certain lifestyle behaviors such as regular physical activity, healthy dietary patterns, and phytochemical-rich food consumption can help attenuate and in some cases reverse these processes and reduce age-related CVD risk.
      • Seals D.R.
      • Brunt V.E.
      • Rossman M.J.
      Keynote lecture: strategies for optimal cardiovascular aging.
      • Rossman M.J.
      • LaRocca T.J.
      • Martens C.R.
      • Seals D.R.
      Healthy lifestyle-based approaches for successful vascular aging.
      Figure thumbnail gr1
      Figure 1Aging leads to vascular dysfunction (endothelial dysfunction and arterial stiffness) largely through excessive oxidative stress and inflammation. Vascular dysfunction is antecedent to the development of atherosclerosis and hypertension, and therefore the development of cardiovascular disease. Cardiovascular risk factors such as hypertension and obesity can accelerate this process. Diet, food, and nutrition-related intervention strategies can reduce cardiovascular disease risk by attenuating age-related vascular dysfunction, in large part, through reducing oxidative stress and inflammation. These strategies can play a role in primary prevention of cardiovascular disease by mitigating risk factors, and secondary prevention through improvements in vascular function, blood pressure, and other atherogenic processes. NFκB=nuclear factor κB. ROS=reactive oxygen species. TNF-α=tumor necrosis factor-α. VCAM-1=vascular cell adhesion molecule-1.
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      References

        • Benjamin E.J.
        • Blaha M.J.
        • Chiuve S.E.
        • et al.
        Heart Disease and Stroke Statistics-2017 update: A report from the American Heart Association.
        Circulation. 2017; 135: e146-e603
        • LaRocca T.J.
        • Martens C.R.
        • Seals D.R.
        Nutrition and other lifestyle influences on arterial aging.
        Ageing Res Rev. 2017; 39: 106-119
        • Lakatta E.G.
        • Levy D.
        Arterial and cardiac aging: Major shareholders in cardiovascular disease enterprises: Part I: Aging arteries: A “set up” for vascular disease.
        Circulation. 2003; 107: 139-146
        • Seals D.R.
        • Brunt V.E.
        • Rossman M.J.
        Keynote lecture: strategies for optimal cardiovascular aging.
        Am J Physiol Heart Circ Physiol. 2018; 315: H183-H188
        • Rossman M.J.
        • LaRocca T.J.
        • Martens C.R.
        • Seals D.R.
        Healthy lifestyle-based approaches for successful vascular aging.
        J Appl Physiol (1985). 2018; 125: 1888-1900
        • Gimbrone Jr., M.A.
        • Garcia-Cardena G.
        Endothelial cell dysfunction and the pathobiology of atherosclerosis.
        Circ Res. 2016; 118: 620-636
        • Moreau K.L.
        • Hildreth K.L.
        Vascular aging across the menopause transition in healthy women.
        Adv Vasc Med. 2014; 2014
        • Bruno R.M.
        • Bianchini E.
        • Faita F.
        • Taddei S.
        • Ghiadoni L.
        Intima media thickness, pulse wave velocity, and flow mediated dilation.
        Cardiovasc Ultrasound. 2014; 12: 34
        • Wang T.J.
        Assessing the role of circulating, genetic, and imaging biomarkers in cardiovascular risk prediction.
        Circulation. 2011; 123: 551-565
        • Luscher TF BM
        Biology of the endothelium.
        Clin Cardiol. 1997; 20: 3-10
        • Flammer A.J.
        • Lüscher T.F.
        Human endothelial dysfunction: EDRFs.
        Pflügers Arch. 2010; 459: 1005-1013
        • Virdis A.
        • Ghiadoni L.
        • Taddei S.
        Human endothelial dysfunction: EDCFs.
        Pflügers Arch. 2010; 459: 1015-1023
        • Seals DR JK
        • Donato A.J.
        Aging and vascular endothelial function in humans.
        Clin Sci (Lond). 2011; 120: 357-375
        • Donato A.J.
        • Morgan R.G.
        • Walker A.E.
        • Lesniewski L.A.
        Cellular and molecular biology of aging endothelial cells.
        J Mol Cell Cardiol. 2015; 89: 122-135
        • Seals D.R.
        • Jablonski K.L.
        • Donato A.J.
        Aging and vascular endothelial function in humans.
        Clin Sci (Lond). 2011; 120: 357-375
      1. Assar ME AJ, Vallejo S, Peiro C, Sachez-Ferrer CF, Rodriguez-Manas L. Mechanims involved in the aging-induced vascular dysfunction Frontier Physiol. 2012;3:132.

        • Taddei S.
        • Virdis A.
        • Ghiadoni L.
        • et al.
        Age-related reduction of NO Availability and oxidative stress in humans.
        Hypertension. 2001; 38: 274-279
        • Taddei S.
        • Virdis A.
        • Ghiadoni L.
        • et al.
        Menopause is associated with endothelial dysfunction in women.
        Hypertension. 1996; 28: 576-582
        • Heitzer T.
        • Ylä-Herttuala S.
        • Luoma J.
        • et al.
        Cigarette smoking potentiates endothelial dysfunction of forearm resistance vessels in patients with hypercholesterolemia. Role of oxidized LDL.
        Circulation. 1996; 93: 1346-1353
        • Brunner H.
        • Cockcroft J.R.
        • Deanfield J.
        • et al.
        Endothelial function and dysfunction. Part II: Association with cardiovascular risk factors and diseases. A statement by the Working Group on Endothelins and Endothelial Factors of the European Society of Hypertension.
        J Hypertens. 2005; 23: 233-246
        • Moreau K.L.
        • Hildreth K.L.
        • Meditz A.L.
        • Deane K.D.
        • Kohrt W.M.
        Endothelial function is impaired across the stages of the menopause transition in healthy women.
        J Clin Endocrinol Metab. 2012; 97: 4692-4700
        • Celermajer D.S.
        • Sorensen K.E.
        • Spiegelhalter D.J.
        • Georgakopoulos D.
        • Robinson J.
        • Deanfield J.E.
        Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women.
        J Am Coll Cardiol. 1994; 24: 471-476
        • Wassmann S.
        • Baumer A.T.
        • Strehlow K.
        • et al.
        Endothelial dysfunction and oxidative stress during estrogen deficiency in spontaneously hypertensive rats.
        Circulation. 2001; 103: 435-441
        • Gavin K.M.
        • Seals D.R.
        • Silver A.E.
        • Moreau K.L.
        Vascular endothelial estrogen receptor alpha is modulated by estrogen status and related to endothelial function and endothelial nitric oxide synthase in healthy women.
        J Clin Endocrinol Metab. 2009; 94: 3513-3520
        • Bleakley C.
        • Hamilton P.K.
        • Pumb R.
        • Harbinson M.
        • McVeigh G.E.
        Endothelial function in hypertension: Victim or culprit?.
        J Clin Hypertens (Greenwich). 2015; 17: 651-654
        • Reho J.J.
        • Rahmouni K.
        Oxidative and inflammatory signals in obesity-associated vascular abnormalities.
        Clin Sci (Lond). 2017; 131: 1689-1700
        • Cersosimo E.
        • DeFronzo R.A.
        Insulin resistance and endothelial dysfunction: The road map to cardiovascular diseases.
        Diabetes Metab Res Rev. 2006; 22: 423-436
        • Santos-Parker J.R.
        • LaRocca T.J.
        • Seals D.R.
        Aerobic exercise and other healthy lifestyle factors that influence vascular aging.
        Adv Physiol Educ. 2014; 38: 296-307
        • Stout M.
        Flow-mediated dilatation: A review of techniques and applications.
        Echocardiography. 2009; 26: 832-841
        • Inaba Y.
        • Chen J.A.
        • Bergmann S.R.
        Prediction of future cardiovascular outcomes by flow-mediated vasodilatation of brachial artery: A meta-analysis.
        Intl J Cardiovasc Imaging. 2010; 26: 631-640
        • Hamburg N.M.
        • Palmisano J.
        • Larson M.G.
        • et al.
        Relation of brachial and digital measures of vascular function in the community: The Framingham Heart Study.
        Hypertension. 2011; 57: 390-396
        • Bruno R.M.
        • Gori T.
        • Ghiadoni L.
        Endothelial function testing and cardiovascular disease: Focus on peripheral arterial tonometry.
        Vasc Health Risk Manag. 2014; 10: 577-584
        • Raitakari O.T.
        • Celermajer D.S.
        Flow-mediated dilatation.
        Br J Clin Pharmacol. 2000; 50: 397-404
        • Ras R.T.
        • Streppel M.T.
        • Draijer R.
        • Zock P.L.
        Flow-mediated dilation and cardiovascular risk prediction: A systematic review with meta-analysis.
        Intl J Cardiol. 2013; 168: 344-351
        • Flammer A.J.
        • Anderson T.
        • Celermajer D.S.
        • et al.
        The assessment of endothelial function: From research into clinical practice.
        Circulation. 2012; 126: 753-767
        • Nohria A.
        • Gerhard-Herman M.
        • Creager M.A.
        • Hurley S.
        • Mitra D.
        • Ganz P.
        Role of nitric oxide in the regulation of digital pulse volume amplitude in humans.
        J Appl Physiol (1985). 2006; 101: 545-548
        • Benjamin N.
        • Calver A.
        • Collier J.
        • Robinson B.
        • Vallance P.
        • Webb D.
        Measuring forearm blood flow and interpreting the responses to drugs and mediators.
        Hypertension. 1995; 25: 918-923
        • Barac A.
        • Campia U.
        • Panza J.A.
        Methods for evaluating endothelial function in humans.
        Hypertension. 2007; 49: 748-760
        • Deanfield J.
        • Donald A.
        • Ferri C.
        • et al.
        Endothelial function and dysfunction. Part I: Methodological issues for assessment in the different vascular beds: A statement by the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension.
        J Hypertens. 2005; 23: 7-17
        • Deanfield J.E.
        • Halcox J.P.
        • Rabelink T.J.
        Endothelial function and dysfunction: Testing and clinical relevance.
        Circulation. 2007; 115: 1285-1295
        • Bouras G.
        • Deftereos S.
        • Tousoulis D.
        • et al.
        Asymmetric dimethylarginine (ADMA): A promising biomarker for cardiovascular disease?.
        Curr Top Med Chem. 2013; 13: 180-200
        • Xuan C.
        • Tian Q.W.
        • Li H.
        • Zhang B.B.
        • He G.W.
        • Lun L.M.
        Levels of asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, and risk of coronary artery disease: A meta-analysis based on 4713 participants.
        Eur J Prev Cardiol. 2016; 23: 502-510
        • Hill J.M.
        • Zalos G.
        • Halcox J.P.
        • et al.
        Circulating endothelial progenitor cells, vascular function, and cardiovascular risk.
        N Engl J Med. 2003; 348: 593-600
        • Cohn J.N.
        • Quyyumi A.A.
        • Hollenberg N.K.
        • Jamerson K.A.
        Surrogate markers for cardiovascular disease: Functional markers.
        Circulation. 2004; 109 (IV-31-IV-46)
        • Fleenor B.S.
        Large elastic artery stiffness with aging: Novel translational mechanisms and interventions.
        Aging Dis. 2013; 4: 76-83
        • Zieman S.J.
        • Melenovsky V.
        • Kass D.A.
        Mechanisms, pathophysiology, and therapy of arterial stiffness.
        Arterioscler Thromb Vasc Biol. 2005; 25: 932-943
        • Wang M.
        • Jiang L.
        • Monticone R.E.
        • Lakatta E.G.
        Proinflammation: The key to arterial aging.
        Trends Endocrinol Metab. 2014; 25: 72-79
        • Quinn U.
        • Tomlinson L.A.
        • Cockcroft J.R.
        Arterial stiffness.
        JRSM Cardiovasc Dis. 2012; 1
        • Wallace S.M.L.
        • Yasmin
        • McEniery C.M.
        • et al.
        Isolated systolic hypertension is characterized by increased aortic stiffness and endothelial dysfunction.
        Hypertension. 2007; 50: 228-233
        • O’Rourke M.F.
        • Safar M.E.
        Relationship between aortic stiffening and microvascular disease in brain and kidney.
        Cause Logic Therapy. 2005; 46: 200-204
        • Oliver J.J.
        • Webb D.J.
        Noninvasive assessment of arterial stiffness and risk of atherosclerotic events.
        Arterioscler Thromb Vasc Biol. 2003; 23: 554-566
        • Mattace-Raso F.U.S.
        • van der Cammen T.J.M.
        • Hofman A.
        • et al.
        Arterial stiffness and risk of coronary heart disease and stroke: The Rotterdam Study.
        Circulation. 2006; 113: 657-663
        • Chiha J.
        • Mitchell P.
        • Gopinath B.
        • et al.
        Prediction of coronary artery disease extent and severity using pulse wave velocity.
        PLoS ONE. 2016; 11e0168598
        • Lim H.E.
        • Park C.G.
        • Shin S.H.
        • Ahn J.C.
        • Seo H.S.
        • Oh D.J.
        Aortic pulse wave velocity as an independent marker of coronary artery disease.
        Blood Pressure. 2004; 13: 369-375
        • Guerin A.P.
        • Blacher J.
        • Pannier B.
        • Marchais S.J.
        • Safar M.E.
        • London G.M.
        Impact of aortic stiffness attenuation on survival of patients in end-stage renal failure.
        Circulation. 2001; 103: 987-992
        • Boutouyrie P.
        • Tropeano A.I.
        • Asmar R.
        • et al.
        Aortic stiffness is an independent predictor of primary coronary events in hypertensive patients: A longitudinal study.
        Hypertension. 2002; 39: 10-15
        • Laurent S.
        • Cockcroft J.
        • Van Bortel L.
        • et al.
        Expert consensus document on arterial stiffness: Methodological issues and clinical applications.
        Eur Heart J. 2006; 27: 2588-2605
        • Vlachopoulos C.
        • Aznaouridis K.
        • Stefanadis C.
        Prediction of cardiovascular events and all-cause mortality with arterial stiffness: A systematic review and meta-analysis.
        J Am Coll Cardiol. 2010; 55: 1318-1327
        • Najjar S.S.
        • Scuteri A.
        • Shetty V.
        • et al.
        Pulse wave velocity is an independent predictor of the longitudinal increase in systolic blood pressure and of incident hypertension in the Baltimore Longitudinal Study of Aging.
        J Am Coll Cardiol. 2008; 51: 1377-1383
        • Meaume S.
        • Rudnichi A.
        • Lynch A.
        • et al.
        Aortic pulse wave velocity as a marker of cardiovascular disease in subjects over 70 years old.
        J Hypertens. 2001; 19: 871-877
        • Pereira T.
        • Correia C.
        • Cardoso J.
        Novel methods for pulse wave velocity measurement.
        J Med Biol Engineer. 2015; 35: 555-565
        • Wentland A.L.
        • Grist T.M.
        • Wieben O.
        Review of MRI-based measurements of pulse wave velocity: A biomarker of arterial stiffness.
        Cardiovasc Diagn Ther. 2014; 4: 193-206
        • Mackenzie I.S.
        • Wilkinson I.B.
        • Cockcroft J.R.
        Assessment of arterial stiffness in clinical practice.
        QJM. 2002; 95: 67-74
        • Calabia J.
        • Torguet P.
        • Garcia M.
        • et al.
        Doppler ultrasound in the measurement of pulse wave velocity: Agreement with the Complior method.
        Cardiovasc Ultrasound. 2011; 9: 13
        • Hamilton P.K.
        • Lockhart C.J.
        • Quinn C.E.
        • McVeigh G.E.
        Arterial stiffness: Clinical relevance, measurement and treatment.
        Clin Sci (Lond). 2007; 113: 157-170
        • Vlachopoulos C.
        • Aznaouridis K.
        • O'Rourke M.F.
        • Safar M.E.
        • Baou K.
        • Stefanadis C.
        Prediction of cardiovascular events and all-cause mortality with central haemodynamics: A systematic review and meta-analysis.
        Eur Heart J. 2010; 31: 1865-1871
        • Anderson T.J.
        Arterial stiffness or endothelial dysfunction as a surrogate marker of vascular risk.
        Can J Cardiol. 2006; 22: 72B-80B
        • Davies J.I.
        • Struthers A.D.
        Beyond blood pressure: Pulse wave analysis—a better way of assessing cardiovascular risk?.
        Future Cardiol. 2005; 1: 69-78
        • Butlin M.
        • Qasem A.
        Large artery stiffness assessment using SphygmoCor technology.
        Pulse (Basel). 2017; 4: 180-192
        • Tapsell L.C.
        • Neale E.P.
        • Satija A.
        • Hu F.B.
        Foods, nutrients, and dietary patterns: Interconnections and implications for dietary guidelines.
        Adv Nutr. 2016; 7: 445-454
        • Lin P.H.
        • Allen J.D.
        • Li Y.J.
        • Yu M.
        • Lien L.F.
        • Svetkey L.P.
        Blood pressure-lowering mechanisms of the DASH dietary pattern.
        J Nutr Metab. 2012; 2012: 472396
        • Schwingshackl L.
        • Hoffmann G.
        Mediterranean dietary pattern, inflammation and endothelial function: A systematic review and meta-analysis of intervention trials.
        Nutr Metab Cardiovasc Dis. 2014; 24: 929-939
        • Esposito K.
        • Marfella R.
        • Ciotola M.
        • et al.
        Effect of a mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: A randomized trial.
        JAMA. 2004; 292: 1440-1446
        • Rallidis L.S.
        • Lekakis J.
        • Kolomvotsou A.
        • et al.
        Close adherence to a Mediterranean diet improves endothelial function in subjects with abdominal obesity.
        Am J Clin Nutr. 2009; 90: 263-268
        • Al-Solaiman Y.
        • Jesri A.
        • Zhao Y.
        • Morrow J.D.
        • Egan B.M.
        Low-sodium DASH reduces oxidative stress and improves vascular function in salt-sensitive humans.
        J Hum Hypertens. 2009; 23: 826-835
        • Mozaffarian D.
        Dietary and policy priorities for cardiovascular disease, diabetes, and obesity: A comprehensive review.
        Circulation. 2016; 133: 187-225
        • Chrysohoou C.
        • Panagiotakos D.B.
        • Pitsavos C.
        • Das U.N.
        • Stefanadis C.
        Adherence to the Mediterranean diet attenuates inflammation and coagulation process in healthy adults: The ATTICA Study.
        J Am Coll Cardiol. 2004; 44: 152-158
        • Estruch R.
        • Martinez-Gonzalez M.A.
        • Corella D.
        • et al.
        Effects of a Mediterranean-style diet on cardiovascular risk factors: a randomized trial.
        Ann Intern Med. 2006; 145: 1-11
        • Sacks F.M.
        • Svetkey L.P.
        • Vollmer W.M.
        • et al.
        Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group.
        N Engl J Med. 2001; 344: 3-10
        • Siervo M.
        • Lara J.
        • Chowdhury S.
        • Ashor A.
        • Oggioni C.
        • Mathers J.C.
        Effects of the Dietary Approach to Stop Hypertension (DASH) diet on cardiovascular risk factors: A systematic review and meta-analysis.
        Br J Nutr. 2015; 113: 1-15
        • Soltani S.
        • Shirani F.
        • Chitsazi M.J.
        • Salehi-Abargouei A.
        The effect of dietary approaches to stop hypertension (DASH) diet on weight and body composition in adults: A systematic review and meta-analysis of randomized controlled clinical trials.
        Obes Rev. 2016; 17: 442-454
        • Jablonski K.L.
        • Fedorova O.V.
        • Racine M.L.
        • et al.
        Dietary sodium restriction and association with urinary marinobufagenin, blood pressure, and aortic stiffness.
        Clin J Am Soc Nephrol. 2013; 8: 1952-1959
        • Jablonski K.L.
        • Racine M.L.
        • Geolfos C.J.
        • et al.
        Dietary sodium restriction reverses vascular endothelial dysfunction in middle-aged/older adults with moderately elevated systolic blood pressure.
        J Am Coll Cardiol. 2013; 61: 335-343
        • Cicero A.F.G.
        • Fogacci F.
        • Colletti A.
        Food and plant bioactives for reducing cardiometabolic disease risk: An evidence based approach.
        Food Funct. 2017; 8: 2076-2088
        • Hall W.L.
        Dietary saturated and unsaturated fats as determinants of blood pressure and vascular function.
        Nutr Res Rev. 2009; 22: 18-38
        • Thota R.N.
        • Ferguson J.J.A.
        • Abbott K.A.
        • Dias C.B.
        • Garg M.L.
        Science behind the cardio-metabolic benefits of omega-3 polyunsaturated fatty acids: biochemical effects vs. clinical outcomes.
        Food Funct. 2018; 9: 3576-3596
        • Weaver C.M.
        Bioactive foods and ingredients for health.
        Adv Nutr. 2014; 5: 306S-311S
      2. Functional foods: Opportunities and challenges.
      3. Functional foods.
        • Milner J.A.
        Functional foods: The US perspective.
        Am J Clin Nutr. 2000; 71: 1654S-1659S
        • Crowe K.M.
        • Francis C.
        Position of the Academy of Nutrition and Dietetics: Functional foods.
        J Acad Nutr Diet. 2013; 113: 1096-1103
        • Liu R.H.
        Health-promoting components of fruits and vegetables in the diet.
        Adv Nutr. 2013; 4: 384S-392S
        • Litwin N.
        • Clifford J.
        • Johnson S.
        Defining functional foods.
        • Del Rio D.
        • Rodriguez-Mateos A.
        • Spencer J.P.
        • Tognolini M.
        • Borges G.
        • Crozier A.
        Dietary (poly)phenolics in human health: structures, bioavailability, and evidence of protective effects against chronic diseases.
        Antioxid Redox Signal. 2013; 18: 1818-1892
        • Sansone R.
        • Ottaviani J.I.
        • Rodriguez-Mateos A.
        • et al.
        Methylxanthines enhance the effects of cocoa flavanols on cardiovascular function: randomized, double-masked controlled studies.
        Am J Clin Nutr. 2017; 105: 352-360
        • Ludovici V.
        • Barthelmes J.
        • Nagele M.P.
        • et al.
        Cocoa, blood pressure, and vascular function.
        Front Nutr. 2017; 4: 36
        • West S.G.
        • McIntyre M.D.
        • Piotrowski M.J.
        • et al.
        Effects of dark chocolate and cocoa consumption on endothelial function and arterial stiffness in overweight adults.
        Br J Nutr. 2014; 111: 653-661
        • Babar A.
        • Bujold E.
        • Leblanc V.
        • et al.
        Changes in endothelial function, arterial stiffness and blood pressure in pregnant women after consumption of high-flavanol and high-theobromine chocolate: A double blind randomized clinical trial.
        Hypertens Pregnancy. 2018; 37: 68-80
        • Smolders L.
        • Mensink R.P.
        • van den Driessche J.J.
        • Joris P.J.
        • Plat J.
        Theobromine consumption does not improve fasting and postprandial vascular function in overweight and obese subjects.
        Eur J Nutr. 2019; 58: 981-987
        • Stull A.J.
        • Cash K.C.
        • Champagne C.M.
        • et al.
        Blueberries improve endothelial function, but not blood pressure, in adults with metabolic syndrome: A randomized, double-blind, placebo-controlled clinical trial.
        Nutrients. 2015; 7: 4107-4123
        • Rodriguez-Mateos A.
        • Rendeiro C.
        • Bergillos-Meca T.
        • et al.
        Intake and time dependence of blueberry flavonoid-induced improvements in vascular function: A randomized, controlled, double-blind, crossover intervention study with mechanistic insights into biological activity.
        Am J Clin Nutr. 2013; 98: 1179-1191
        • Johnson S.A.
        • Figueroa A.
        • Navaei N.
        • et al.
        Daily blueberry consumption improves blood pressure and arterial stiffness in postmenopausal women with pre- and stage 1-hypertension: A randomized, double-blind, placebo-controlled clinical trial.
        J Acad Nutr Diet. 2015; 115: 369-377
        • Del Bo C.
        • Porrini M.
        • Fracassetti D.
        • Campolo J.
        • Klimis-Zacas D.
        • Riso P.
        A single serving of blueberry (V. corymbosum) modulates peripheral arterial dysfunction induced by acute cigarette smoking in young volunteers: A randomized-controlled trial.
        Food Funct. 2014; 5: 3107-3116
        • Garcia-Conesa M.T.
        • Chambers K.
        • Combet E.
        • et al.
        Meta-analysis of the effects of foods and derived products containing ellagitannins and anthocyanins on cardiometabolic biomarkers: Analysis of factors influencing variability of the individual responses.
        Int J Mol Sci. 2018; 19
        • Grassi D.
        • Desideri G.
        • Di Giosia P.
        • et al.
        Tea, flavonoids, and cardiovascular health: Endothelial protection.
        Am J Clin Nutr. 2013; 98: 1660S-1666S
        • Wightman J.D.
        • Heuberger R.A.
        Effect of grape and other berries on cardiovascular health.
        J Sci Food Agric. 2015; 95: 1584-1597
        • Barbour J.A.
        • Howe P.R.
        • Buckley J.D.
        • Bryan J.
        • Coates A.M.
        Nut consumption for vascular health and cognitive function.
        Nutr Res Rev. 2014; 27: 131-158
        • Catry E.
        • Bindels L.B.
        • Tailleux A.
        • et al.
        Targeting the gut microbiota with inulin-type fructans: Preclinical demonstration of a novel approach in the management of endothelial dysfunction.
        Gut. 2018; 67: 271-283
        • Battson M.L.
        • Lee D.M.
        • Weir T.L.
        • Gentile C.L.
        The gut microbiota as a novel regulator of cardiovascular function and disease.
        J Nutr Biochem. 2018; 56: 1-15
        • Lau K.
        • Srivatsav V.
        • Rizwan A.
        • et al.
        Bridging the gap between gut microbial dysbiosis and cardiovascular diseases.
        Nutrients. 2017; 9: E859
        • Bondonno C.P.
        • Blekkenhorst L.C.
        • Liu A.H.
        • et al.
        Vegetable-derived bioactive nitrate and cardiovascular health.
        Mol Aspects Med. 2018; 61: 83-91
        • Lundberg J.O.
        • Gladwin M.T.
        • Weitzberg E.
        Strategies to increase nitric oxide signalling in cardiovascular disease.
        Nat Rev Drug Discov. 2015; 14: 623-641
        • Wang Q.
        • Liang X.
        • Wang L.
        • et al.
        Effect of omega-3 fatty acids supplementation on endothelial function: A meta-analysis of randomized controlled trials.
        Atherosclerosis. 2012; 221: 536-543
        • Chakrabarti S.
        • Wu J.
        Bioactive peptides on endothelial function.
        Food Sci Hum Wellness. 2016; 5: 1-7
        • Gleeson J.P.
        • Ryan S.M.
        • Brayden D.J.
        Oral delivery strategies for nutraceuticals: Delivery vehicles and absorption enhancers.
        Trends Food Sci Technol. 2016; 53: 90-101
        • Andrew R.
        • Izzo A.A.
        Principles of pharmacological research of nutraceuticals.
        Br J Pharmacol. 2017; 174: 1177-1194
      4. Chapter 1: Dietary Supplement Health And Education Act of 1994.
        http://health.gov/dietsupp/ch1.htm
        Date accessed: March 12, 2019
        • Kris-Etherton P.M.
        • Lichtenstein A.H.
        • Howard B.V.
        • et al.
        Antioxidant vitamin supplements and cardiovascular disease.
        Circulation. 2004; 110: 637-641
        • Pase M.P.
        • Grima N.A.
        • Sarris J.
        The effects of dietary and nutrient interventions on arterial stiffness: A systematic review.
        Am J Clin Nutr. 2011; 93: 446-454
        • Campbell M.S.
        • Fleenor B.S.
        The emerging role of curcumin for improving vascular dysfunction: A review.
        Crit Rev Food Sci Nutr. 2017; : 1-10
        • Santos-Parker J.R.
        • Strahler T.R.
        • Bassett C.J.
        • Bispham N.Z.
        • Chonchol M.B.
        • Seals D.R.
        Curcumin supplementation improves vascular endothelial function in healthy middle-aged and older adults by increasing nitric oxide bioavailability and reducing oxidative stress.
        Aging (Albany, NY). 2017; 9: 187-208
        • Akazawa N.
        • Choi Y.
        • Miyaki A.
        • et al.
        Curcumin ingestion and exercise training improve vascular endothelial function in postmenopausal women.
        Nutr Res. 2012; 32: 795-799
        • Sugawara J.
        • Akazawa N.
        • Miyaki A.
        • et al.
        Effect of endurance exercise training and curcumin intake on central arterial hemodynamics in postmenopausal women: Pilot study.
        Am J Hypertens. 2012; 25: 651-656
        • Xia N.
        • Forstermann U.
        • Li H.
        Resveratrol and endothelial nitric oxide.
        Molecules. 2014; 19: 16102-16121