Interplay And Causative Relationship Between Frailty And Atherosclerosis

Anastasia V. Poznyak ^1*, Victoria A. Khotina ², Roghayyeh Vakili-Ghartavol ^2,3, Victor Y Glanz ², Vasily N. Sukhorukov ², Alexander N. Orekhov ^2*

Frailty syndrome (FS) and cardiovascular diseases have a significant interaction, which impacts both the patient experience and how they are managed. Knowledge about the intricate associations between the two could provide a meaningful way towards developing targeted interventions.

Abstract

Frailty syndrome is a complex condition with numerous contributing factors. It is characterized by a decline in physiological reserves and increased susceptibility to stress due to multi-system impairments. Commonly associated with aging, frailty can lead to adverse outcomes such as hospitalization, falls, and mortality. Cardiovascular diseases are recognized as a significant risk factor for frailty syndrome and frequently coexist in the elderly population. This review aims to explore the relationship between cardiovascular diseases and frailty syndrome. Research demonstrates that both acute and chronic cardiac conditions are prevalent among the risk factors for frailty. Cardiovascular diseases often manifest against the backdrop of atherosclerosis (AS) and are a leading cause of death in older adults. This review seeks to examine potential pathways through which cardiovascular events contribute to the development of frailty syndrome. Frail individuals often experience impaired physical function, significantly impacting their quality of life. Understanding the link between subclinical cardiovascular events and the pathogenesis of frailty syndrome is crucial for developing effective therapeutic interventions. Investigating how cardiovascular events influence the progression of frailty can provide valuable insights into improving clinical outcomes for frail patients.

Keywords: Frailty, Atherosclerosis, Cardiovascular disease

References

Adabag, S., Vo, T. N., Langsetmo, L., Schousboe, J. T., Cawthon, P. M., Stone, K. L., Shikany, J. M., Taylor, B. C., & Ensrud, K. E. (2018). Frailty as a Risk Factor for Cardiovascular Versus Noncardiovascular Mortality in Older Men: Results From the MrOS Sleep (Outcomes of Sleep Disorders in Older Men) Study. Journal of the American Heart Association, 7(10), e008974. https://doi.org/10.1161/JAHA.118.008974

Adachi, T., Tsunekawa, Y., & Tanimura, D. (2022). Association among mild cognitive impairment, social frailty, and clinical events in elderly patients with cardiovascular disease. Heart & lung : the journal of critical care, 55, 82–88. https://doi.org/10.1016/j.hrtlng.2022.04.011

Afilalo, J., Alexander, K. P., Mack, M. J., Maurer, M. S., Green, P., Allen, L. A., Popma, J. J., Ferrucci, L., & Forman, D. E. (2014). Frailty assessment in the cardiovascular care of older adults. Journal of the American College of Cardiology, 63(8), 747–762. https://doi.org/10.1016/j.jacc.2013.09.070

Anastasia V. Poznyak, Ludmila V Nedosugova, Vasily N. Sukhorukov. (2023a). Hepatitis C and atherosclerosis: inflammatory interplay, Journal of Angiotherpay, 7(1), 1-10, 9361

Anastasia V. Poznyak, Varvara A. Orekhova, Vasily N. Sukhorukov. (2024c). Platelet Implication in Atherosclerosis Pathogenesis, Journal of Angiotherapy, 8(1), 1-8, 9385

Anastasia V. Poznyak, Victoria A. Khotina, Mikhail. Popov, Alexander D. Zhuravlev, Vasily N. Sukhorukov, and Alexander N. Orekhov, (2023b), The way of cholesterol in atherogenesis: from the main enemy to complex biomarkers, Journal of Angiotherpay, 7(1), 1-7

Anastasia V. Poznyak, Victoria A. Khotina, Vasily N. Sukhorukov et al., (2024b). Maternal hypercholesterolemia is a significant risk factor for atherogenesis – A Systematic Review, Journal of Angiotherapy, 8(1), 1-10, 9390

Anastasia V. Poznyak, Victoria A. Khotina, Vasily N. Sukhorukov et al., (2024a). Two Forms of C-Reactive Protein and Their Implication for Atherogenesis: Focus on Monomeric Form, Journal of Angiotherapy, 8(1), 1-12, 9386

Baumeister, D., Akhtar, R., Ciufolini, S., Pariante, C. M., & Mondelli, V. (2016). Childhood trauma and adulthood inflammation: a meta-analysis of peripheral C-reactive protein, interleukin-6 and tumour necrosis factor-α. Molecular psychiatry, 21(5), 642–649. https://doi.org/10.1038/mp.2015.67

Cesari, M., Calvani, R., & Marzetti, E. (2017). Frailty in Older Persons. Clinics in geriatric medicine, 33(3), 293–303. https://doi.org/10.1016/j.cger.2017.02.002

Chen, T. H., Koh, K. Y., Lin, K. M., & Chou, C. K. (2022). Mitochondrial Dysfunction as an Underlying Cause of Skeletal Muscle Disorders. International journal of molecular sciences, 23(21), 12926. https://doi.org/10.3390/ijms232112926

Chen, X., Mao, G., & Leng, S. X. (2014). Frailty syndrome: an overview. Clinical interventions in aging, 9, 433–441. https://doi.org/10.2147/CIA.S45300

Chianca, M., Panichella, G., Fabiani, I., Giannoni, A., L'Abbate, S., Aimo, A., Del Franco, A., Vergaro, G., Grigoratos, C., Castiglione, V., Cipolla, C. M., Fedele, A., Passino, C., Emdin, M., & Cardinale, D. M. (2022). Bidirectional Relationship Between Cancer and Heart Failure: Insights on Circulating Biomarkers. Frontiers in cardiovascular medicine, 9, 936654. https://doi.org/10.3389/fcvm.2022.936654

Clegg, A., & Hassan-Smith, Z. (2018). Frailty and the endocrine system. The lancet. Diabetes & endocrinology, 6(9), 743–752. https://doi.org/10.1016/S2213-8587(18)30110-4

Colin, S., Chinetti-Gbaguidi, G., & Staels, B. (2014). Macrophage phenotypes in atherosclerosis. Immunological reviews, 262(1), 153–166. https://doi.org/10.1111/imr.12218

Custodero, C., Pahor, M., Mazzoccoli, C., Manini, T. M., Anton, S. D., Mazzocca, A., Lozupone, M., Panza, F., Sabbà, C., & Solfrizzi, V. (2023). Effect of change of interleukin-6 over time on gait speed response: Results from the lifestyle interventions and independence for elders study. Mechanisms of ageing and development, 210, 111763. https://doi.org/10.1016/j.mad.2022.111763

Dagli, R. J., & Sharma, A. (2014). Polypharmacy: a global risk factor for elderly people. Journal of international oral health : JIOH, 6(6), i–ii.

Davalli, P., Mitic, T., Caporali, A., Lauriola, A., & D'Arca, D. (2016). ROS, Cell Senescence, and Novel Molecular Mechanisms in Aging and Age-Related Diseases. Oxidative medicine and cellular longevity, 2016, 3565127. https://doi.org/10.1155/2016/3565127

Demer, L. L., & Tintut, Y. (2008). Vascular calcification: pathobiology of a multifaceted disease. Circulation, 117(22), 2938–2948. https://doi.org/10.1161/CIRCULATIONAHA.107.743161

Dugravot, A., Fayosse, A., Dumurgier, J., Bouillon, K., Rayana, T. B., Schnitzler, A., Kivimaki, M., Sabia, S., & Singh-Manoux, A. (2020). Social inequalities in multimorbidity, frailty, disability, and transitions to mortality: a 24-year follow-up of the Whitehall II cohort study. The Lancet. Public health, 5(1), e42–e50. https://doi.org/10.1016/S2468-2667(19)30226-9

Fernandes, J., Gomes, C. D. S., Guerra, R. O., Pirkle, C. M., Vafaei, A., Curcio, C. L., & Dornelas de Andrade, A. (2021). Frailty syndrome and risk of cardiovascular disease: Analysis from the International Mobility in Aging Study. Archives of gerontology and geriatrics, 92, 104279. https://doi.org/10.1016/j.archger.2020.104279

Ferrucci, L., & Fabbri, E. (2018). Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nature reviews. Cardiology, 15(9), 505–522. https://doi.org/10.1038/s41569-018-0064-2

Fried, L. P., Cohen, A. A., Xue, Q. L., Walston, J., Bandeen-Roche, K., & Varadhan, R. (2021). The physical frailty syndrome as a transition from homeostatic symphony to cacophony. Nature aging, 1(1), 36–46. https://doi.org/10.1038/s43587-020-00017-z

Fried, L. P., Tangen, C. M., Walston, J., Newman, A. B., Hirsch, C., Gottdiener, J., Seeman, T., Tracy, R., Kop, W. J., Burke, G., McBurnie, M. A., & Cardiovascular Health Study Collaborative Research Group (2001). Frailty in older adults: evidence for a phenotype. The journals of gerontology. Series A, Biological sciences and medical sciences, 56(3), M146–M156. https://doi.org/10.1093/gerona/56.3.m146

Greenberg, A. S., & Obin, M. S. (2008). Many roads lead to the lipid droplet. Cell metabolism, 7(6), 472–473. https://doi.org/10.1016/j.cmet.2008.05.005

Hardigan, T., Ward, R., & Ergul, A. (2016). Cerebrovascular complications of diabetes: focus on cognitive dysfunction. Clinical science (London, England : 1979), 130(20), 1807–1822. https://doi.org/10.1042/CS20160397

Hepple, R. T., & Rice, C. L. (2016). Innervation and neuromuscular control in ageing skeletal muscle. The Journal of physiology, 594(8), 1965–1978. https://doi.org/10.1113/JP270561

Hubbard, R. E., & Woodhouse, K. W. (2010). Frailty, inflammation and the elderly. Biogerontology, 11(5), 635–641. https://doi.org/10.1007/s10522-010-9292-5

Kim, K. K., Sheppard, D., & Chapman, H. A. (2018). TGF-β1 Signaling and Tissue Fibrosis. Cold Spring Harbor perspectives in biology, 10(4), a022293. https://doi.org/10.1101/cshperspect.a022293

Kita, A., Saito, Y., Miura, N., Miyajima, M., Yamamoto, S., Sato, T., Yotsuyanagi, T., Fujimiya, M., & Chikenji, T. S. (2022). Altered regulation of mesenchymal cell senescence in adipose tissue promotes pathological changes associated with diabetic wound healing. Communications biology, 5(1), 310. https://doi.org/10.1038/s42003-022-03266-3

Lang, P. O., Michel, J. P., & Zekry, D. (2009). Frailty syndrome: a transitional state in a dynamic process. Gerontology, 55(5), 539–549. https://doi.org/10.1159/000211949

Larsson, L., Degens, H., Li, M., Salviati, L., Lee, Y. I., Thompson, W., Kirkland, J. L., & Sandri, M. (2019). Sarcopenia: Aging-Related Loss of Muscle Mass and Function. Physiological reviews, 99(1), 427–511. https://doi.org/10.1152/physrev.00061.2017

Lecordier, S., Manrique-Castano, D., El Moghrabi, Y., & ElAli, A. (2021). Neurovascular Alterations in Vascular Dementia: Emphasis on Risk Factors. Frontiers in aging neuroscience, 13, 727590. https://doi.org/10.3389/fnagi.2021.727590

Lee, S. J., Lee, I. K., & Jeon, J. H. (2020). Vascular Calcification-New Insights Into Its Mechanism. International journal of molecular sciences, 21(8), 2685. https://doi.org/10.3390/ijms21082685

Lee, S. Y., Chao, C. T., Huang, J. W., & Huang, K. C. (2020). Vascular Calcification as an Underrecognized Risk Factor for Frailty in 1783 Community-Dwelling Elderly Individuals. Journal of the American Heart Association, 9(18), e017308. https://doi.org/10.1161/JAHA.120.017308

Li, X., Yang, T., & Sun, Z. (2019). Hormesis in Health and Chronic Diseases. Trends in endocrinology and metabolism: TEM, 30(12), 944–958. https://doi.org/10.1016/j.tem.2019.08.007

Li, X., Zhang, Y., Tian, Y., Cheng, Q., Gao, Y., & Gao, M. (2022). Exercise interventions for older people with cognitive frailty-a scoping review. BMC geriatrics, 22(1), 721. https://doi.org/10.1186/s12877-022-03370-3

Libby, P., Buring, J. E., Badimon, L., Hansson, G. K., Deanfield, J., Bittencourt, M. S., Tokgözoglu, L., & Lewis, E. F. (2019). Atherosclerosis. Nature reviews. Disease primers, 5(1), 56. https://doi.org/10.1038/s41572-019-0106-z

McKechnie, D. G. J., Papacosta, A. O., Lennon, L. T., Ellins, E. A., Halcox, J. P. J., Ramsay, S. E., Whincup, P. H., & Wannamethee, S. G. (2021). Subclinical cardiovascular disease and risk of incident frailty: The British Regional Heart Study. Experimental gerontology, 154, 111522. https://doi.org/10.1016/j.exger.2021.111522

McNallan, S. M., Singh, M., Chamberlain, A. M., Kane, R. L., Dunlay, S. M., Redfield, M. M., Weston, S. A., & Roger, V. L. (2013). Frailty and healthcare utilization among patients with heart failure in the community. JACC. Heart failure, 1(2), 135–141. https://doi.org/10.1016/j.jchf.2013.01.002

Menorca, R. M., Fussell, T. S., & Elfar, J. C. (2013). Nerve physiology: mechanisms of injury and recovery. Hand clinics, 29(3), 317–330. https://doi.org/10.1016/j.hcl.2013.04.002

Nadruz, W., Jr, Kitzman, D., Windham, B. G., Kucharska-Newton, A., Butler, K., Palta, P., Griswold, M. E., Wagenknecht, L. E., Heiss, G., Solomon, S. D., Skali, H., & Shah, A. M. (2017). Cardiovascular Dysfunction and Frailty Among Older Adults in the Community: The ARIC Study. The journals of gerontology. Series A, Biological sciences and medical sciences, 72(7), 958–964. https://doi.org/10.1093/gerona/glw199

Piggott, D. A., & Tuddenham, S. (2020). The gut microbiome and frailty. Translational research : the journal of laboratory and clinical medicine, 221, 23–43. https://doi.org/10.1016/j.trsl.2020.03.012

Polidoro, A., Stefanelli, F., Ciacciarelli, M., Pacelli, A., Di Sanzo, D., & Alessandri, C. (2013). Frailty in patients affected by atrial fibrillation. Archives of gerontology and geriatrics, 57(3), 325–327. https://doi.org/10.1016/j.archger.2013.04.014

Reed, S. C., Dhir, N., & Widmer, R. J. (2022). Optimal cardiovascular medical therapy: current guidelines and new developments. Proceedings (Baylor University. Medical Center), 35(5), 636–642. https://doi.org/10.1080/08998280.2022.2083903

Ruff, C., Gerharz, A., Groll, A., Stoll, F., Wirbka, L., Haefeli, W. E., & Meid, A. D. (2021). Disease-dependent variations in the timing and causes of readmissions in Germany: A claims data analysis for six different conditions. PloS one, 16(4), e0250298. https://doi.org/10.1371/journal.pone.0250298

Schirrmacher V. (2021). Less Can Be More: The Hormesis Theory of Stress Adaptation in the Global Biosphere and Its Implications. Biomedicines, 9(3), 293. https://doi.org/10.3390/biomedicines9030293

Semeraro, G. C., Cipolla, C. M., & Cardinale, D. M. (2021). Role of Cardiac Biomarkers in Cancer Patients. Cancers, 13(21), 5426. https://doi.org/10.3390/cancers13215426

Sergi, G., Veronese, N., Fontana, L., De Rui, M., Bolzetta, F., Zambon, S., Corti, M. C., Baggio, G., Toffanello, E. D., Crepaldi, G., Perissinotto, E., & Manzato, E. (2015). Pre-frailty and risk of cardiovascular disease in elderly men and women: the Pro.V.A. study. Journal of the American College of Cardiology, 65(10), 976–983. https://doi.org/10.1016/j.jacc.2014.12.040

Soeters, P. B., Wolfe, R. R., & Shenkin, A. (2019). Hypoalbuminemia: Pathogenesis and Clinical Significance. JPEN. Journal of parenteral and enteral nutrition, 43(2), 181–193. https://doi.org/10.1002/jpen.1451

Soysal, P., Stubbs, B., Lucato, P., Luchini, C., Solmi, M., Peluso, R., Sergi, G., Isik, A. T., Manzato, E., Maggi, S., Maggio, M., Prina, A. M., Cosco, T. D., Wu, Y. T., & Veronese, N. (2016). Inflammation and frailty in the elderly: A systematic review and meta-analysis. Ageing research reviews, 31, 1–8. https://doi.org/10.1016/j.arr.2016.08.006

Soysal, P., Veronese, N., Thompson, T., Kahl, K. G., Fernandes, B. S., Prina, A. M., Solmi, M., Schofield, P., Koyanagi, A., Tseng, P. T., Lin, P. Y., Chu, C. S., Cosco, T. D., Cesari, M., Carvalho, A. F., & Stubbs, B. (2017). Relationship between depression and frailty in older adults: A systematic review and meta-analysis. Ageing research reviews, 36, 78–87. https://doi.org/10.1016/j.arr.2017.03.005

Stewart R. (2019). Cardiovascular Disease and Frailty: What Are the Mechanistic Links?. Clinical chemistry, 65(1), 80–86. https://doi.org/10.1373/clinchem.2018.287318

Stewart R. (2019). Cardiovascular Disease and Frailty: What Are the Mechanistic Links?. Clinical chemistry, 65(1), 80–86. https://doi.org/10.1373/clinchem.2018.287318

Tran, N., Garcia, T., Aniqa, M., Ali, S., Ally, A., & Nauli, S. M. (2022). Endothelial Nitric Oxide Synthase (eNOS) and the Cardiovascular System: in Physiology and in Disease States. American journal of biomedical science & research, 15(2), 153–177.

Uchmanowicz, I., Mlynarska, A., Lisiak, M., Kaluzna-Oleksy, M., Wleklik, M., Chudiak, A., Dudek, M., Migaj, J., Hinterbuchner, L., & Gobbens, R. (2019). Heart Failure and Problems with Frailty Syndrome: Why it is Time to Care About Frailty Syndrome in Heart Failure. Cardiac failure review, 5(1), 37–43. https://doi.org/10.15420/cfr.2018.37.1

Valsdóttir, V., Magnúsdóttir, B. B., Chang, M., Sigurdsson, S., Gudnason, V., Launer, L. J., & Jónsdóttir, M. K. (2022). Cognition and brain health among older adults in Iceland: the AGES-Reykjavik study. GeroScience, 44(6), 2785–2800. https://doi.org/10.1007/s11357-022-00642-z

Veronese N. (2020). Frailty as Cardiovascular Risk Factor (and Vice Versa). Advances in experimental medicine and biology, 1216, 51–54. https://doi.org/10.1007/978-3-030-33330-0_6

Veronese, N., Custodero, C., Demurtas, J., Smith, L., Barbagallo, M., Maggi, S., Cella, A., Vanacore, N., Aprile, P. L., Ferrucci, L., Pilotto, A., Special Interest Group in Systematic Reviews of the European Geriatric Medicine Society (EuGMS), & Special Interest Group in Meta-analyses and Comprehensive Geriatric Assessment of the European Geriatric Medicine Society (EuGMS) (2022). Comprehensive geriatric assessment in older people: an umbrella review of health outcomes. Age and ageing, 51(5), afac104. https://doi.org/10.1093/ageing/afac104

Volpato, S., Ferrucci, L., Secchiero, P., Corallini, F., Zuliani, G., Fellin, R., Guralnik, J. M., Bandinelli, S., & Zauli, G. (2011). Association of tumor necrosis factor-related apoptosis-inducing ligand with total and cardiovascular mortality in older adults. Atherosclerosis, 215(2), 452–458. https://doi.org/10.1016/j.atherosclerosis.2010.11.004

Waritu, N. C., Nair, S. K. P., Birhan, B., Adugna, T., Awgichew, G. B., & Jemal, M. (2024). Serum Lipid Profiles, Blood Glucose, and High-Sensitivity C-Reactive Protein Levels Among People Living with HIV Taking Dolutegravir and Ritonavir-Boosted Atazanavir-Based Antiretroviral Therapy at Jimma University Medical Center, Southwest Ethiopia, 2021. HIV/AIDS (Auckland, N.Z.), 16, 17–32. https://doi.org/10.2147/HIV.S430310

Wleklik, M., Denfeld, Q., Lisiak, M., Czapla, M., Kaluzna-Oleksy, M., & Uchmanowicz, I. (2022). Frailty Syndrome in Older Adults with Cardiovascular Diseases-What Do We Know and What Requires Further Research?. International journal of environmental research and public health, 19(4), 2234. https://doi.org/10.3390/ijerph19042234

Wong, T. Y., Massa, M. S., O'Halloran, A. M., Kenny, R. A., & Clarke, R. (2018). Cardiovascular risk factors and frailty in a cross-sectional study of older people: implications for prevention. Age and ageing, 47(5), 714–720. https://doi.org/10.1093/ageing/afy080

Yan, Y., Li, M., Lin, J., Ji, Y., Wang, K., Yan, D., Shen, Y., Wang, W., Huang, Z., Jiang, H., Sun, H., & Qi, L. (2022). Adenosine monophosphate activated protein kinase contributes to skeletal muscle health through the control of mitochondrial function. Frontiers in pharmacology, 13, 947387. https://doi.org/10.3389/fphar.2022.947387

Yao, S., Guo, J., Shi, G., Zhu, Y., Wang, Y., Chu, X., Jiang, X., Jin, L., Wang, Z., & Wang, X. (2019). Association of BNP with Frailty in Elderly Population: Rugao Longevity and Ageing Study. The journal of nutrition, health & aging, 23(1), 73–78. https://doi.org/10.1007/s12603-018-1112-7

Zha, Y., Zhuang, W., Yang, Y., Zhou, Y., Li, H., & Liang, J. (2022). Senescence in Vascular Smooth Muscle Cells and Atherosclerosis. Frontiers in cardiovascular medicine, 9, 910580. https://doi.org/10.3389/fcvm.2022.910580