International Journal of Heart Failure

The Korean Society of Heart Failure (대한심부전학회)
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Heart Failure With Preserved Ejection Fraction and Frailty: From Young to Superaged Coexisting HFpEF and Frailty

  • Amina Rakisheva (City Cardiology Center) ;
  • Anzhela Soloveva (Department of Cardiology, Almazov Almazov National Medical Research Centre) ;
  • Anastasia Shchendrygina (I.M. Sechenov First Moscow State Medical University) ;
  • Ilya Giverts (Maimonides Medical Center)
  • Received : 2023.12.14
  • Accepted : 2024.06.14
  • Published : 2024.07.30
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Abstract

Being commonly diagnosed in elderly women and associated with comorbidities as well as ageing-related cardio-vascular changes, heart failure with preserved ejection fraction (HFpEF) has been recently considered as a distinct cardiogeriatric syndrome. Frailty is another frequent geriatric syndrome. HFpEF and frailty share common underlying mechanisms, often co-exist, and represent each other's risk factors. A threshold of 65 years old is usually used to screen patients for both frailty and HFpEF in research and clinical settings. However, both HFpEF and frailty are very heterogenous conditions that may develop at younger ages. In this review we aim to provide a broader overview on the coexistence of HFpEF and frailty throughout the lifetime. We hypothesize that HFpEF and frailty patients' profiles (young, elderly, superaged) represent a continuum of the common ageing process modified by cumulative exposure to risk factors resulting to a presentation of HFpEF and frailty at different ages. We believe, that suggested approach might stimulate assessment of frailty in HFpEF assessment and vice versa regardless of age and early implementation of targeted interventions. Future studies of pathophysiology, clinical features, and outcomes of frailty in HFpEF by age are needed.

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References

  1. Ferrucci L, Giallauria F, Guralnik JM. Epidemiology of aging. Radiol Clin North Am 2008;46:643-52.
  2. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 2001;56:M146-56.
  3. Sanders NA, Supiano MA, Lewis EF, et al. The frailty syndrome and outcomes in the TOPCAT trial. Eur J Heart Fail 2018;20:1570-7.
  4. Goyal P, Yum B, Navid P, et al. Frailty and post-hospitalization outcomes in patients with heart failure with preserved ejection fraction. Am J Cardiol 2021;148:84-93.
  5. Sun J, Qiao Y, Zhao M, Magnussen CG, Xi B. Global, regional, and national burden of cardiovascular diseases in youths and young adults aged 15-39 years in 204 countries/territories, 1990-2019: a systematic analysis of Global Burden of Disease Study 2019. BMC Med 2023;21:222.
  6. Loecker C, Schmaderer M, Zimmerman L. Frailty in young and middle-aged adults: an integrative review. J Frailty Aging 2021;10:327-33.
  7. Blodgett JM, Rockwood K, Theou O. Changes in the severity and lethality of age-related health deficit accumulation in the USA between 1999 and 2018: a population-based cohort study. Lancet Healthy Longev 2021;2:e96-104.
  8. Bai G, Wang Y, Mak JK, Ericsson M, Hagg S, Jylhava J. Is frailty different in younger adults compared to old? Prevalence, characteristics and risk factors of early-life and late-life frailty in samples from Sweden and UK. Gerontology 2023;69:1385-93.
  9. Aggarwal R, Yeh RW, Joynt Maddox KE, Wadhera RK. Cardiovascular risk factor prevalence, treatment, and control in US adults aged 20 to 44 years, 2009 to March 2020. JAMA 2023;329:899-909.
  10. Sinclair DR, Maharani A, Chandola T, et al. Frailty among older adults and its distribution in England. J Frailty Aging 2022;11:163-8.
  11. Villani ER, Tummolo AM, Palmer K, et al. Frailty and atrial fibrillation: a systematic review. Eur J Intern Med 2018;56:33-8.
  12. Bellumkonda L, Tyrrell D, Hummel SL, Goldstein DR. Pathophysiology of heart failure and frailty: a common inflammatory origin? Aging Cell 2017;16:444-50.
  13. Pandey A, Kitzman D, Reeves G. Frailty is intertwined with heart failure: mechanisms, prevalence, prognosis, assessment, and management. JACC Heart Fail 2019;7:1001-11.
  14. Vitale C, Jankowska E, Hill L, et al. Heart Failure Association/European Society of Cardiology position paper on frailty in patients with heart failure. Eur J Heart Fail 2019;21:1299-305.
  15. Uchmanowicz I, Nessler J, Gobbens R, et al. Coexisting frailty with heart failure. Front Physiol 2019;10:791.
  16. Zhang L, Zeng X, He F, Huang X. Inflammatory biomarkers of frailty: a review. Exp Gerontol 2023;179:112253.
  17. Povar-Echeverria M, Auquilla-Clavijo PE, Andres E, et al. Interleukin-6 could be a potential prognostic factor in ambulatory elderly patients with stable heart failure: results from a pilot study. J Clin Med 2021;10:1-11.
  18. Butt JH, Dewan P, Jhund PS, et al. Sacubitril/valsartan and frailty in patients with heart failure and preserved ejection fraction. J Am Coll Cardiol 2022;80:1130-43.
  19. Butts B, Gary RA, Dunbar SB, Butler J. The importance of NLRP3 inflammasome in heart failure. J Card Fail 2015;21:586-93.
  20. Sato R, Vatic M, da Fonseca GW, von Haehling S. Sarcopenia and frailty in heart failure: is there a biomarker signature? Curr Heart Fail Rep 2022;19:400-11.
  21. Lau ES, Roshandelpoor A, Zarbafian S, et al. Eicosanoid and eicosanoid-related inflammatory mediators and exercise intolerance in heart failure with preserved ejection fraction. Nat Commun 2023;14:7557.
  22. Talha KM, Pandey A, Fudim M, Butler J, Anker SD, Khan MS. Frailty and heart failure: state-of-the-art review. J Cachexia Sarcopenia Muscle 2023;14:1959-72.
  23. Vitale C, Uchmanowicz I. Frailty in patients with heart failure. Eur Heart J Suppl 2019;21:L12-6.
  24. Anderson M, Parrott CF, Haykowsky MJ, Brubaker PH, Ye F, Upadhya B. Skeletal muscle abnormalities in heart failure with preserved ejection fraction. Heart Fail Rev 2023;28:157-68.
  25. Farmakis D, Thodi M, Elpidoforou M, Filippatos G. Assessing frailty in heart failure. Eur J Heart Fail 2020;22:2134-7.
  26. Tanaka S, Yamashita M, Saito H, et al. Multidomain frailty in heart failure: current status and future perspectives. Curr Heart Fail Rep 2021;18:107-20.
  27. Spiers GF, Kunonga TP, Hall A, et al. Measuring frailty in younger populations: a rapid review of evidence. BMJ Open 2021;11:e047051.
  28. Panchangam C, White DA, Goudar S, et al. Translation of the frailty paradigm from older adults to children with cardiac disease. Pediatr Cardiol 2020;41:1031-41.
  29. Studyvin S, Birnbaum BF, Staggs VS, et al. Development and initial validation of a frailty score for pediatric patients with congenital and acquired heart disease. Pediatr Cardiol 2024;45:888-900.
  30. Moons P, Marelli A. Born to age: when adult congenital heart disease converges with geroscience. JACC Adv 2022;1:100012.
  31. Naessen T, Einarsson G, Henrohn D, Wikstrom G. Peripheral vascular ageing in pulmonary arterial hypertension as assessed by common carotid artery intima thickness and intima/media thickness ratio: an investigation using non-invasive high-resolution ultrasound. Heart Lung Circ 2023;32:338-47.
  32. Culley MK, Chan SY. Endothelial senescence: a new age in pulmonary hypertension. Circ Res 2022;130:928-41.
  33. Tromp J, Paniagua SM, Lau ES, et al. Age dependent associations of risk factors with heart failure: pooled population based cohort study. BMJ 2021;372:n461.
  34. Wong CM, Hawkins NM, Petrie MC, et al. Heart failure in younger patients: the Meta-analysis Global Group in Chronic Heart Failure (MAGGIC). Eur Heart J 2014;35:2714-21.
  35. Tromp J, MacDonald MR, Tay WT, et al. Heart failure with preserved ejection fraction in the young. Circulation 2018;138:2763-73.
  36. Dent E, Morley JE, Cruz-Jentoft AJ, et al. Physical frailty: ICFSR international clinical practice guidelines for identification and management. J Nutr Health Aging 2019;23:771-87.
  37. Leong DP, Joseph P, McMurray JJ, et al. Frailty and outcomes in heart failure patients from high-, middle-, and low-income countries. Eur Heart J 2023;44:4435-44.
  38. Butt JH, Jhund PS, Belohlavek J, et al. Efficacy and safety of dapagliflozin according to frailty in patients with heart failure: a prespecified analysis of the DELIVER trial. Circulation 2022;146:1210-24.
  39. Kaul P, Rathwell S, Lam CSP, et al. Patient-reported frailty and functional status in heart failure with preserved ejection fraction: insights from VITALITY-HFpEF. JACC Heart Fail 2023;11:392-403.
  40. Kehler DS, Ferguson T, Stammers AN, et al. Prevalence of frailty in Canadians 18-79 years old in the Canadian Health Measures Survey. BMC Geriatr 2017;17:28.
  41. Rockwood K, Song X, Mitnitski A. Changes in relative fitness and frailty across the adult lifespan: evidence from the Canadian National Population Health Survey. CMAJ 2011;183:E487-94.
  42. Fan J, Yu C, Guo Y, et al. Frailty index and all-cause and cause-specific mortality in Chinese adults: a prospective cohort study. Lancet Public Health 2020;5:e650-60.
  43. Hou Y, Xu C, Lu Q, et al. Associations of frailty with cardiovascular disease and life expectancy: a prospective cohort study. Arch Gerontol Geriatr 2022;99:104598.
  44. Zhao L, Zierath R, John JE, et al. Subclinical risk factors for heart failure with preserved and reduced ejection fraction among black adults. JAMA Netw Open 2022;5:e2231878.
  45. Cai A, Chen C, Wang J, Ou Y, Nie Z, Feng Y. Social determinants of health, cardiovascular health, and outcomes in community-dwelling adults without cardiovascular disease. JACC Asia 2023;4:44-54.
  46. Teshale AB, Htun HL, Owen A, et al. The role of social determinants of health in cardiovascular diseases: an umbrella review. J Am Heart Assoc 2023;12:e029765.
  47. White-Williams C, Rossi LP, Bittner VA, et al. Addressing social determinants of health in the care of patients with heart failure: a scientific statement from the American Heart Association. Circulation 2020;141:e841-63.
  48. Woolley RJ, Ceelen D, Ouwerkerk W, et al. Machine learning based on biomarker profiles identifies distinct subgroups of heart failure with preserved ejection fraction. Eur J Heart Fail 2021;23:983-91.
  49. Tromp J, Shen L, Jhund PS, et al. Age-related characteristics and outcomes of patients with heart failure with preserved ejection fraction. J Am Coll Cardiol 2019;74:601-12.
  50. Buch A, Keinan-Boker L, Kis O, et al. Severe central obesity or diabetes can replace weight loss in the detection of frailty in obese younger elderly - a preliminary study. Clin Interv Aging 2018;13:1907-18.
  51. Donini LM, Busetto L, Bischoff SC, et al. Definition and diagnostic criteria for sarcopenic obesity: ESPEN and EASO consensus statement. Obes Facts 2022;15:321-35.
  52. Zembura M, Matusik P. Sarcopenic obesity in children and adolescents: a systematic review. Front Endocrinol (Lausanne) 2022;13:914740.
  53. Hanlon P, Nicholl BI, Jani BD, Lee D, McQueenie R, Mair FS. Frailty and pre-frailty in middle-aged and older adults and its association with multimorbidity and mortality: a prospective analysis of 493 737 UK Biobank participants. Lancet Public Health 2018;3:e323-32.
  54. Packer M, Synovial LB, Inflammation M. Conceptual framework to explain the pathogenesis of heart failure with preserved ejection fraction in patients with systemic rheumatic diseases. Cardiac Failure Review 2020;6:e10. CROSSREF
  55. Freiberg MS, Chang CH, Skanderson M, et al. Association between HIV infection and the risk of heart failure with reduced ejection fraction and preserved ejection fraction in the antiretroviral therapy era: results from the Veterans Aging Cohort Study. JAMA Cardiol 2017;2:536-46.
  56. Conrad N, Misra S, Verbakel JY, et al. Incidence, prevalence, and co-occurrence of autoimmune disorders over time and by age, sex, and socioeconomic status: a population-based cohort study of 22 million individuals in the UK. Lancet 2023;401:1878-90.
  57. Wang M, Mei K, Chao C, et al. Rheumatoid arthritis increases the risk of heart failure-current evidence from genome-wide association studies. Front Endocrinol (Lausanne) 2023;14:1154271.
  58. Sierra-Galan LM, Bhatia M, Alberto-Delgado AL, et al. Cardiac magnetic resonance in rheumatology to detect cardiac involvement since early and pre-clinical stages of the autoimmune diseases: a narrative review. Front Cardiovasc Med 2022;9:870200.
  59. Kobayashi H, Kobayashi Y, Yokoe I, Akashi Y, Takei M, Giles JT. Magnetic resonance imaging-detected myocardial inflammation and fibrosis in rheumatoid arthritis: associations with disease characteristics and N-terminal pro-brain natriuretic peptide levels. Arthritis Care Res (Hoboken) 2017;69:1304-11.
  60. Huang S, Cai T, Weber BN, et al. Association between inflammation, incident heart failure, and heart failure subtypes in patients with rheumatoid arthritis. Arthritis Care Res (Hoboken) 2023;75:1036-45.
  61. Gunther F, Ehrenstein B, Hartung W, Boschiero D, Fleck M, Straub RH. Increased extracellular water measured by bioimpedance analysis and increased serum levels of atrial natriuretic peptide in polymyalgia rheumatica patients : signs of volume overload. Z Rheumatol 2021;80:140-8.
  62. Straub RH, Ehrenstein B, Gunther F, et al. Increased extracellular water measured by bioimpedance and by increased serum levels of atrial natriuretic peptide in RA patients-signs of volume overload. Clin Rheumatol 2017;36:1041-51.
  63. Mantel A, Holmqvist M, Andersson DC, Lund LH, Askling J. Association between rheumatoid arthritis and risk of ischemic and nonischemic heart failure. J Am Coll Cardiol 2017;69:1275-85.
  64. Gao RC, Wu ZG, Wu ZZ, Hao M, Wu GC. Frailty in rheumatoid arthritis: a systematic review and meta-analysis. Joint Bone Spine 2022;89:105343.
  65. Sinha A, Feinstein M. Epidemiology, pathophysiology, and prevention of heart failure in people with HIV. Prog Cardiovasc Dis 2020;63:134-41.
  66. Erqou S, Lodebo BT, Masri A, et al. Cardiac dysfunction among people living with HIV: a systematic review and meta-analysis. JACC Heart Fail 2019;7:98-108.
  67. de Leuw P, Arendt CT, Haberl AE, et al. Myocardial fibrosis and inflammation by CMR predict cardiovascular outcome in people living with HIV. JACC Cardiovasc Imaging 2021;14:1548-57.
  68. Piggott DA, Muzaale AD, Mehta SH, et al. Frailty, HIV infection, and mortality in an aging cohort of injection drug users. PLoS One 2013;8:e54910.
  69. Rockwood K, Blodgett JM, Theou O, et al. A frailty index based on deficit accumulation quantifies mortality risk in humans and in mice. Sci Rep 2017;7:43068.
  70. Rockwood K, Howlett SE. Fifteen years of progress in understanding frailty and health in aging. BMC Med 2018;16:220.
  71. Santos-Eggimann B, Cuenoud P, Spagnoli J, Junod J. Prevalence of frailty in middle-aged and older community-dwelling Europeans living in 10 countries. J Gerontol A Biol Sci Med Sci 2009;64:675-81.
  72. Junius-Walker U, Onder G, Soleymani D, et al. The essence of frailty: a systematic review and qualitative synthesis on frailty concepts and definitions. Eur J Intern Med 2018;56:3-10.
  73. Camafort M, Park SM, Kang SM. Lifestyle modification in heart failure management: are we using evidence-based recommendations in real world practice? Int J Heart Fail 2023;5:21-33.
  74. Kim SR, Cho DH, Kim MN, Park SM. Rationale and study design of differences in cardiopulmonary exercise capacity according to coronary microvascular dysfunction and body composition in patients with suspected heart failure with preserved ejection fraction. Int J Heart Fail 2021;3:237-43.
  75. Saeedi P, Petersohn I, Salpea P, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res Clin Pract 2019;157:107843.
  76. Abudureyimu M, Luo X, Wang X, et al. Heart failure with preserved ejection fraction (HFpEF) in type 2 diabetes mellitus: from pathophysiology to therapeutics. J Mol Cell Biol 2022;14:mjac028.
  77. Hanlon P, Faure I, Corcoran N, et al. Frailty measurement, prevalence, incidence, and clinical implications in people with diabetes: a systematic review and study-level meta-analysis. Lancet Healthy Longev 2020;1:e106-16.
  78. Bouillon K, Kivimaki M, Hamer M, et al. Diabetes risk factors, diabetes risk algorithms, and the prediction of future frailty: the Whitehall II prospective cohort study. J Am Med Dir Assoc 2013;14:851.e1-6.
  79. Aguayo GA, Hulman A, Vaillant MT, et al. Prospective association among diabetes diagnosis, HbA1c, glycemia, and frailty trajectories in an elderly population. Diabetes Care 2019;42:1903-11.
  80. Sinclair AJ, Abdelhafiz AH, Rodriguez-Manas L. Frailty and sarcopenia - newly emerging and high impact complications of diabetes. J Diabetes Complications 2017;31:1465-73.
  81. Travers J, Romero-Ortuno R, Bailey J, Cooney MT. Delaying and reversing frailty: a systematic review of primary care interventions. Br J Gen Pract 2019;69:e61-9.
  82. Seferovic PM, Petrie MC, Filippatos GS, et al. Type 2 diabetes mellitus and heart failure: a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2018;20:853-72.
  83. Mentz RJ, Kelly JP, von Lueder TG, et al. Noncardiac comorbidities in heart failure with reduced versus preserved ejection fraction. J Am Coll Cardiol 2014;64:2281-93.
  84. Schiattarella GG, Rodolico D, Hill JA. Metabolic inflammation in heart failure with preserved ejection fraction. Cardiovasc Res 2021;117:423-34.
  85. Yap J, Tay WT, Teng TK, et al. Association of diabetes mellitus on cardiac remodeling, quality of life, and clinical outcomes in heart failure with reduced and preserved ejection fraction. J Am Heart Assoc 2019;8:e013114.
  86. Writing Committee MembersACC/AHA Joint Committee Members. 2022 AHA/ACC/HFSA guideline for the management of heart failure. J Card Fail 2022;28:e1-167.
  87. Marx N, Federici M, Schutt K, et al. 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. Eur Heart J 2023;44:4043-140.
  88. McDonagh TA, Metra M, Adamo M, et al. 2023 Focused update of the 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2023;44:3627-39.
  89. Kovesdy CP. Epidemiology of chronic kidney disease: an update 2022. Kidney Int Suppl (2011) 2022;12:7-11.
  90. Hill NR, Fatoba ST, Oke JL, et al. Global prevalence of chronic kidney disease -a systematic review and meta-analysis. PLoS One 2016;11:e0158765.
  91. Lofman I, Szummer K, Dahlstrom U, Jernberg T, Lund LH. Associations with and prognostic impact of chronic kidney disease in heart failure with preserved, mid-range, and reduced ejection fraction. Eur J Heart Fail 2017;19:1606-14.
  92. Smith DH, Thorp ML, Gurwitz JH, et al. Chronic kidney disease and outcomes in heart failure with preserved versus reduced ejection fraction: the Cardiovascular Research Network PRESERVE Study. Circ Cardiovasc Qual Outcomes 2013;6:333-42.
  93. Zelnick LR, Shlipak MG, Soliman EZ, et al. Prediction of incident heart failure in CKD: the CRIC study. Kidney Int Rep 2022;7:708-19.
  94. Chowdhury R, Peel NM, Krosch M, Hubbard RE. Frailty and chronic kidney disease: a systematic review. Arch Gerontol Geriatr 2017;68:135-42.
  95. Wilhelm-Leen ER, Hall YN, K Tamura M, Chertow GM. Frailty and chronic kidney disease: the Third National Health and Nutrition Evaluation Survey. Am J Med 2009;122:664-71.e2.
  96. Tarazona-Santabalbina FJ, Gomez-Cabrera MC, Perez-Ros P, et al. A multicomponent exercise intervention that reverses frailty and improves cognition, emotion, and social networking in the community-dwelling frail elderly: a randomized clinical trial. J Am Med Dir Assoc 2016;17:426-33.
  97. Hosseini K, Mortazavi SH, Sadeghian S, et al. Prevalence and trends of coronary artery disease risk factors and their effect on age of diagnosis in patients with established coronary artery disease: Tehran Heart Center (2005-2015). BMC Cardiovasc Disord 2021;21:477.
  98. Liperoti R, Vetrano DL, Palmer K, et al. Association between frailty and ischemic heart disease: a systematic review and meta-analysis. BMC Geriatr 2021;21:357.
  99. Damluji AA, Huang J, Bandeen-Roche K, et al. Frailty among older adults with acute myocardial infarction and outcomes from percutaneous coronary interventions. J Am Heart Assoc 2019;8:e013686.
  100. Reichart D, Rosato S, Nammas W, et al. Clinical frailty scale and outcome after coronary artery bypass grafting. Eur J Cardiothorac Surg 2018;54:1102-9.
  101. Udell JA, Lu D, Bagai A, et al. Preexisting frailty and outcomes in older patients with acute myocardial infarction. Am Heart J 2022;249:34-44.
  102. Gharacholou SM, Slusser JP, Lennon RJ, et al. Factors associated with change in frailty scores and long-term outcomes in older adults with coronary artery disease. J Geriatr Cardiol 2021;18:196-203.
  103. Uchmanowicz I. Oxidative stress, frailty and cardiovascular diseases: current evidence. Adv Exp Med Biol 2020;1216:65-77.
  104. John JE, Claggett B, Skali H, et al. Coronary artery disease and heart failure with preserved ejection fraction: the ARIC study. J Am Heart Assoc 2022;11:e021660.
  105. Rush CJ, Berry C, Oldroyd KG, et al. Prevalence of coronary artery disease and coronary microvascular dysfunction in patients with heart failure with preserved ejection fraction. JAMA Cardiol 2021;6:1130-43.
  106. Hanlon P, Lewsey J, Quint JK, et al. Frailty in COPD: an analysis of prevalence and clinical impact using UK Biobank. BMJ Open Respir Res 2022;9:e001314.
  107. Marengoni A, Vetrano DL, Manes-Gravina E, Bernabei R, Onder G, Palmer K. The relationship between COPD and frailty: a systematic review and meta-analysis of observational studies. Chest 2018;154:21-40.
  108. Romme EA, Smeenk FW, Rutten EP, Wouters EF. Osteoporosis in chronic obstructive pulmonary disease. Expert Rev Respir Med 2013;7:397-410.
  109. Inoue D, Watanabe R, Okazaki R. COPD and osteoporosis: links, risks, and treatment challenges. Int J Chron Obstruct Pulmon Dis 2016;11:637-48.
  110. Bernard S, LeBlanc P, Whittom F, et al. Peripheral muscle weakness in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998;158:629-34.
  111. Shah SJ, Heitner JF, Sweitzer NK, et al. Baseline characteristics of patients in the treatment of preserved cardiac function heart failure with an aldosterone antagonist trial. Circ Heart Fail 2013;6:184-92.
  112. Solomon SD, Rizkala AR, Lefkowitz MP, et al. Baseline characteristics of patients with heart failure and preserved ejection fraction in the PARAGON-HF trial. Circ Heart Fail 2018;11:e004962.
  113. McMurray JJ, Carson PE, Komajda M, et al. Heart failure with preserved ejection fraction: clinical characteristics of 4133 patients enrolled in the I-PRESERVE trial. Eur J Heart Fail 2008;10:149-56.
  114. Streng KW, Nauta JF, Hillege HL, et al. Non-cardiac comorbidities in heart failure with reduced, mid-range and preserved ejection fraction. Int J Cardiol 2018;271:132-9.
  115. Mooney L, Hawkins NM, Jhund PS, et al. Impact of chronic obstructive pulmonary disease in patients with heart failure with preserved ejection fraction: insights from PARAGON-HF. J Am Heart Assoc 2021;10:e021494.
  116. Cuthbert JJ, Kearsley JW, Kazmi S, et al. The impact of heart failure and chronic obstructive pulmonary disease on mortality in patients presenting with breathlessness. Clin Res Cardiol 2019;108:185-93.
  117. Trinkmann F, Saur J, Borggrefe M, Akin I. Cardiovascular comorbidities in chronic obstructive pulmonary disease (COPD)-current considerations for clinical practice. J Clin Med 2019;8:69.
  118. Groenewegen A, Zwartkruis VW, Rienstra M, et al. Improving early diagnosis of cardiovascular disease in patients with type 2 diabetes and COPD: protocol of the RED-CVD cluster randomised diagnostic trial. BMJ Open 2021;11:e046330.
  119. Maddocks M, Kon SS, Canavan JL, et al. Physical frailty and pulmonary rehabilitation in COPD: a prospective cohort study. Thorax 2016;71:988-95.
  120. Rosa VE, Lopes AS, Accorsi TA, et al. EuroSCORE II and STS as mortality predictors in patients undergoing TAVI. Rev Assoc Med Bras 2016;62:32-7.
  121. Rockwood K, Stadnyk K, MacKnight C, McDowell I, Hebert R, Hogan DB. A brief clinical instrument to classify frailty in elderly people. Lancet 1999;353:205-6.
  122. Speechley M, Tinetti M. Falls and injuries in frail and vigorous community elderly persons. J Am Geriatr Soc 1991;39:46-52.
  123. Winograd CH. Targeting strategies: an overview of criteria and outcomes. J Am Geriatr Soc 1991;39:25S-35S.
  124. Li H, Hastings MH, Rhee J, Trager LE, Roh JD, Rosenzweig A. Targeting age-related pathways in heart failure. Circ Res 2020;126:533-51.
  125. Lakatta EG, Levy D. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part I: aging arteries: a "set up" for vascular disease. Circulation 2003;107:139-46.
  126. Pfeffer MA, Shah AM, Borlaug BA. Heart failure with preserved ejection fraction in perspective. Circ Res 2019;124:1598-617.
  127. Camafort M, Kario K. Hypertension, heart failure, and frailty in older people: a common but unclear situation. J Clin Hypertens (Greenwich) 2020;22:1763-8.
  128. Aprahamian I, Sassaki E, Dos Santos MF, et al. Hypertension and frailty in older adults. J Clin Hypertens (Greenwich) 2018;20:186-92.
  129. Kang MG, Kim SW, Yoon SJ, Choi JY, Kim KI, Kim CH. Association between frailty and hypertension prevalence, treatment, and control in the elderly Korean population. Sci Rep 2017;7:7542.
  130. Vetrano DL, Palmer KM, Galluzzo L, et al. Hypertension and frailty: a systematic review and meta-analysis. BMJ Open 2018;8:e024406.
  131. Williamson JD, Supiano MA, Applegate WB, et al. Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged ≥75 years: a randomized clinical trial. JAMA 2016;315:2673-82.
  132. Benetos A, Labat C, Rossignol P, et al. Treatment with multiple blood pressure medications, achieved blood pressure, and mortality in older nursing home residents: the PARTAGE study. JAMA Intern Med 2015;175:989-95.
  133. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study. JAMA 2001;285:2370-5.
  134. Chung SC, Sofat R, Acosta-Mena D, et al. Atrial fibrillation epidemiology, disparity and healthcare contacts: a population-wide study of 5.6 million individuals. Lancet Reg Health Eur 2021;7:100157.
  135. Kannel WB, Abbott RD, Savage DD, McNamara PM. Epidemiologic features of chronic atrial fibrillation: the Framingham study. N Engl J Med 1982;306:1018-22.
  136. Uchikado Y, Ikeda Y, Ohishi M. Current understanding of the role of frailty in cardiovascular disease. Circ J 2020;84:1903-8.
  137. Maisel WH, Stevenson LW. Atrial fibrillation in heart failure: epidemiology, pathophysiology, and rationale for therapy. Am J Cardiol 2003;91:2D-8D.
  138. Mamas MA, Caldwell JC, Chacko S, Garratt CJ, Fath-Ordoubadi F, Neyses L. A meta-analysis of the prognostic significance of atrial fibrillation in chronic heart failure. Eur J Heart Fail 2009;11:676-83.
  139. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest 2010;137:263-72.
  140. Santangeli P, Di Biase L, Bai R, et al. Atrial fibrillation and the risk of incident dementia: a meta-analysis. Heart Rhythm 2012;9:1761-8.
  141. Crocker TF, Brown L, Clegg A, et al. Quality of life is substantially worse for community-dwelling older people living with frailty: systematic review and meta-analysis. Qual Life Res 2019;28:2041-56.
  142. de Terwangne C, Sorgente A, Macovei S, et al. Association between atrial fibrillation, frailty, and geriatric syndromes in the late elderly in a south Belgian outpatient and inpatient setting. Am Heart J Plus 2022;13:100106.
  143. Meng C, Chai K, Li YY, Luo Y, Wang H, Yang JF. Prevalence and prognosis of frailty in older patients with stage B heart failure with preserved ejection fraction. ESC Heart Fail 2023;10:1133-43.
  144. Joosten LP, van Doorn S, van de Ven PM, et al. Safety of switching from a vitamin K antagonist to a non-vitamin K antagonist oral anticoagulant in frail older patients with atrial fibrillation: results of the FRAIL-AF randomized controlled trial. Circulation 2024;149:279-89.
  145. Osnabrugge RL, Mylotte D, Head SJ, et al. Aortic stenosis in the elderly: disease prevalence and number of candidates for transcatheter aortic valve replacement: a meta-analysis and modeling study. J Am Coll Cardiol 2013;62:1002-12.
  146. De Biase N, Mazzola M, Del Punta L, et al. Haemodynamic and metabolic phenotyping of patients with aortic stenosis and preserved ejection fraction: a specific phenotype of heart failure with preserved ejection fraction? Eur J Heart Fail 2023;25:1947-58.
  147. Anker SD, Usman MS, Anker MS, et al. Patient phenotype profiling in heart failure with preserved ejection fraction to guide therapeutic decision making. A scientific statement of the Heart Failure Association, the European Heart Rhythm Association of the European Society of Cardiology, and the European Society of Hypertension. Eur J Heart Fail 2023;25:936-55.
  148. Fukui S, Kawakami M, Otaka Y, et al. Physical frailty in older people with severe aortic stenosis. Aging Clin Exp Res 2016;28:1081-7.
  149. Ramos M, Quezada M, Ayala R, et al. Asymptomatic aortic stenosis in a geriatric population. The role of frailty and comorbidity in mortality. Rev Esp Cardiol (Engl Ed) 2021;74:167-74.
  150. Rodriguez-Pascual C, Paredes-Galan E, Ferrero-Martinez AI, et al. The frailty syndrome and mortality among very old patients with symptomatic severe aortic stenosis under different treatments. Int J Cardiol 2016;224:125-31.
  151. Vasques F, Lucenteforte E, Paone R, Mugelli A, Biancari F. Outcome of patients aged ≥80 years undergoing combined aortic valve replacement and coronary artery bypass grafting: a systematic review and meta-analysis of 40 studies. Am Heart J 2012;164:410-418.e1.