hemodialysis. Kidney International. 1994;**46(3)**:830-837

Investigation. 2005;**115(2):**451-458

Metabolism. 2003;**284(3)**:E488-E498

Investigation. 2006;**36(10)**:713-719

2002;**39(7)**:1175-1181

aging muscle health. Endocrine 2012;**42:**29-38

[89] Bean JF, Kiely DK, Herman S, Leveille SG, Mizer K, Frontera WR, Fielding RA. The relationship between leg power and physical performance in mobility-limited older people. Journal of the American Geriatrics Society. 2002;**50(3)**:461-467

[76] Sullivan DH, Walls RC, Bopp MM. Protein energy undernutrition and the risk of mortality within one years of hospital discharge: A follow-up study. Journal of the American

[77] Fanelli MT, Kuczmarski RJ. Ultrasound as an approach to assessing body composition.

[78] Kuczmarski RJ, Fanelli MT, Koch GG. Ultrasonic assessment of body composition in obese adults: Overcoming the limitations of the skinfold caliper.  Evaluation of a portable ultrasonoscope in assessing the body composition of college-age women. Medicine & Science in Sports & Exercise.

[81] Abe T, Kondo M, Kawakami Y, Fukunaga T. Prediction equations for body composition of Japanese adults by B-mode ultrasound. American Journal of Human Biology.

[82] Saito K, Nakaji S, Umeda T, Shimoyama T, Sugawara K, Yamamoto Y. Development of predictive equations for body density of sumo wrestlers using B-mode ultrasound for the determination of subcutaneous fat thickness. British Journal of Sports Medicine.

[83] Eston R, Evans R, Fu F. Estimation of body composition in Chinese and British men by ultrasonographic assessment of segmental adipose tissue volume. British Journal of

[84] Silva L. An Introduction to Ultrasound and the BodyMetrixSystem. Livermore,

[85] Watanabe Y, Yamada Y, Fukumoto Y, Ishihara T, Yokoyama K, Yoshida T et al. Echo intensity obtained from ultrasonography images reflecting muscle strength in elderly

[86] Lauretani F, Russo CR, Bandinelli S, Bartali B, Cavazzini C, Di Iorio A,. Age-associated changes in skeletal muscles and their effect on mobility: An operational diagnosis of

[87] Roberts HC, Denison HJ, Martin HJ, Patel HP, Syddall H, Cooper C, Sayer AA. A review of the measurement of grip strength in clinical and epidemiological studies: Towards a

[88] Magasi SR, Bubela DJ, Wang Y-C, Gershon RC. Grip and knee extension muscle strength reflect a common construct among adults. Muscle and Nerve 2012; **46**:555-558.

of young adults. Ultrasound in Medicine and Biology. 2012;**38(1)**:28-34

Geriatrics Society 1995b;**43**:507-512

192 Frailty and Sarcopenia - Onset, Development and Clinical Challenges

Clinical Nutrition. 1987;**45(4)**:717-724

1984;**16(1):**97-102

1994;**6(2)**:161-170.

2003;**37(2)**:144-148.

Sports Medicine. 1994;28(1):9-13.

California, USA: IntelaMetrix; 2010.

men. Clinical Interventions in Aging 2013;**8:**993-998

sarcopenia. Journal of Applied Physiology. 2003;**95(5)**:1851-1860

standardised approach. Age and Ageing. 2011;**40(4)**:423

American Journal of Clinical Nutrition1984;**39(5)**:703-709

[117] Coto-Montes A, Boga JA, Reite RJ. Melatonin as a potential agent in the treatment of sarcopenia. International Journal of Molecular Sciences 2016;**17(10)**:177. DOI: 10.3390/ ijms17101771

[104] Pennings B, Boirie Y, Senden J, Gijsen AP, Kuipers H, van Loon LJ. Whey protein stimulates postprandial muscle protein accretion more effectively than do casein and casein hydrolysate in older men. The American Journal of Clinical Nutrition 2011;**93**:997-1005.

[105] Burd NA, Yang Y, Moore DR, Tang JE, Tarnopolsky MA, Phillips SM. Greater stimulation of myofibrillar protein synthesis with ingestion of whey protein isolate v. micellar casein at rest and after resistance exercise in elderly men. British Journal of Nutrition.

[106] Mitchell CJ, Della Gatta PA, Petersen AC, Cameron-Smith D. Soy protein ingestion results in less prolonged p70S6 kinase phosphorylation compared to whey protein after resistance exercise in older men. Journal of the International Society of Sports Nutrition

[107] Di Girolamo FG, Situlin R, Mazzucco S. Omega-3 fatty acids and protein metabolism: Enhancement of anabolic interventions for sarcopenia. Nutrition in Clinical Practice.

[108] Stehle J, Reuss S, Riemann R, Seidel A, Vollrath L. The role of arginine-vasopressin for pineal melatonin synthesis in the rat: Involvement of vasopressinergic receptors.

[109] Dawson D, Encel N. Melatonin and sleep in humans. Journal of Pineal Research

[110] Pechanova O, Paulis L, Simko F. Peripheral and central effects of melatonin on blood pressure regulation. International Journal of Molecular Sciences 2014, 15, 17920-17937.

[111] Erkanl N K, Kayalar N, Ercan F, Sener G, KNrali K. Melatonin protects against ischemia/reperfusion injury in skeletal muscle. Journal of Pineal Research. 2005;**39**:238-242

[112] Lee JY, Kim JH, Lee DC. Urine melatonin levels are inversely associated with sarcopenia in postmenopausal women. Menopause. 2014; **21(1)**:39-44. DOI: 10.1097/

[113] Ramis MR, Esteban S, Miralles A, Tan DX, Reiter R. Protective effects of melatonin and mitochondria-targeted antioxidants against oxidative stress: A review. Current

[114] Kim CH, Kim KH, Yoo YM. Melatonin-induced autophagy is associated with degradation of MyoD protein in C2C12 myoblast cells. Journal of Pineal Research 2012;53:289-297

[115] Borges LS, Dermargos A, da Silva J EP, Weimann E, Lambertucci RH, Hatanaka E. Melatonin decreases muscular oxidative stress and inflammation induced by strenuous exercise and stimulates growth factor synthesis. Journal of Pineal Research.

[116] Ochoa JJ, Díaz-Castro J, Kajarabille N, García C, Guisado IM, de Teresa C, Guisado R. Melatonin supplementation ameliorates oxidative stress and inflammatory signaling induced by strenuous exercise in adult human males. Journal of Pineal Research

2012;**108**:958-962.

1993;**15**:1-12.

GME.0b013e318291f6c8.

2015;**58**:166-172.

2011;**51**:373-380.

2015; **12**:6. DOI: 10.1186/s12970-015-0070-2.

194 Frailty and Sarcopenia - Onset, Development and Clinical Challenges

Neuroscience Letters 1991;**123**:131-134.

Medicinal Chemistry 2015;**22**:2690-2711

2013;**28(6)**:684-690. DOI: 10.1177/0884533613507607.

### **Frailty and Cardiovascular Disease**

Vinod Chainani, Russell Riehl, Geeta Chainani, Abir Abdo, Mauricio G. Cohen, Carlos Alfonso, Pedro Martinez‐Clark, Carl J. Lavie, John P. Reilly and Nidal Abi‐Rafeh

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.69877

#### **Abstract**

[131] Binder E, Schechtman K, Ehsani A, Steger-May KMA, Brown M, Sinacore DR, et al. Effects of exercise training on frailty in community-dwelling elderly adults: Results of a randomized, controlled trial. Journal of the American Geriatrics Society.

[132] Schulte JN, Yarasheski KE. Effects of resistance training on the rate of muscle protein synthesis in frail elderly people. International Journal of Sport Nutrition and Exercise

[133] Candow DG, Chilibeck PD, Abeysekara S, Zello GA J. Short-term heavy resistance training eliminates age-related deficits in muscle mass and strength in healthy older

[134] Liu CJ, Latham NK. Progressive resistance strength training for improving physical function in older adults. Cochrane Database of Systematic Reviews. 2009;**8(3)**:CD002759.

[135] Reid KF, Callahan DM, Carabello RJ, Phillips EM, Frontera WR, Fielding RA. Lower extremity power training in elderly subjects with mobility limitations: A randomized

controlled trial. Aging Clinical and Experimental Research. 2008;**20(4)**:337-343. [136] American Geriatrics Society, British Geriatrics Society, and American Academy of Orthopaedic Surgeons Panel on Falls Prevention. Guideline for the prevention of falls

in older persons. Journal of the American Geriatrics Society. 2001;**49(5)**:664-672 [137] Bellomo RG, Iodice P, Maffulli N, Maghradze T, Coco V, Saggini R. Muscle strength and balance training in sarcopenic elderly: A pilot study with randomized controlled

[138] Bellomo RG, Khodor H, Barassi G, Carmignano SM, Di Stefano A, Di Pancrazio L, Saggini R. Global bioprogressive rehabilitation program and postural instability in

[139] Saggini R, Di Pancrazio L, Pisciella V, Iodice P, Marri A, Bellomo RG. Postural antigravitational reprogramming in the elderly with flexed posture. European Journal of

Physical and Rehabilitation Medicine. 2010;**46** - suppl.1 - No.2. ISSN: 1973-9087. [140] Saggini R, Di Stefano A, Capogrosso F, Carmignano SM, D'Ettole S, Iodice P et al.Taskoriented physical exercise using postural re-alignment with body weight support in

[141] Bellomo RG, Pisciella V, Di Pancrazio L, Saggini R. The virtual images into physical rehabilitation. In: book abstract SIMFER the Italian Society of Physical and Rehabilitation Medicine 37th National Congress. Campobasso, Italy; 20-23 September 2009; 189. [142] Devereux K, Robertson D, Briffa NK. Effects of a water-based training on women 65 years and over: A randomised controlled trial. The Australian Journal of Physiotherapy

[143] Montero-Fernández N, Serra-Rexach JA. Role of exercise on sarcopenia in the elderly. European Journal of Physical and Rehabilitation Medicine. 2013;**49(1)**:131-143 [144] Phu S, Boersma D, Duque G. Exercise and sarcopenia. Journal of Clinical Densitometry.

trial. European Journal of Inflammation. 2013;**11**:193-201

Parkinson's disease. European Scientific Journal. 2014;**2**:310-321

chronic stroke. European Journal of Inflammation. 2013;**11(3)**:739-749

males. Journal of Strength and Conditioning Research. 2011;**25(2)**:326-333.

2002;**50(12)**:1921-1928

2005;**51**:102-108

2015;**18(4)**:488-492

Metabolism 2001;**11**:S111-S118.

196 Frailty and Sarcopenia - Onset, Development and Clinical Challenges

Cardiovascular disease (CVD) comprises a vast spectrum of disease states ranging from hypertension (HTN) to valvular heart disease (VHD). CVD is known to be the lead‐ ing cause of morbidity, mortality, and health‐care expenditure throughout the world. According to the World Health Organization, coronary artery disease (CAD) and stroke, both subsets of CVD, are the world's biggest killers, accounting for a combined 15 mil‐ lion deaths in 2015. These diseases have remained the leading causes of death globally in the last 15 years. In 2010, CAD alone was projected to cost the U.S. \$108.9 billion includ‐ ing the cost of health‐care services, medications, and lost productivity. The presence of frailty significantly worsens outcomes for patients suffering from CAD. With just this one example of how frailty affects CVD, it is clear that understanding the impact of frailty upon patients afflicted with the spectrum of cardiovascular disease is integral for the care of this very significant patient population.

**Keywords:** frailty, cardiovascular disease, valvular heart disease, outcomes in cardiovascular disease, hypertension, coronary artery disease, peripheral vascular disease, lipid dysregulation

#### **1. Introduction**

Cardiovascular disease (CVD) comprises a vast spectrum of disease states ranging from hyper‐ tension (HTN) to valvular heart disease (VHD) and is known to be the leading cause of mor‐ bidity, mortality, and health‐care expenditure throughout the world. According to the World Health Organization, coronary heart disease (CHD) and stroke, both subsets of CVD, are the world's most impactful causes of mortality, accounting for a combined 15 million deaths in

© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

2015. These diseases have remained the leading causes of death globally in the last 15 years. In 2010, CHD alone was projected to cost the United States (US) \$108.9 billion including the cost of health‐care services, medications, and lost productivity. The presence of frailty significantly worsens outcomes for patients suffering from CHD [1]. With just this one example of how frailty affects CVD, it is clear that understanding the impact of frailty upon patients afflicted with the spectrum of CVD is integral for the care of this very significant patient population.

While frailty as an entity is manifested by the interplay of multiple factors, there are some that are pertinent to the relationship between CVD and frailty. Endocrine dysregulation and higher levels of inflammatory markers have been found in frail compared with non‐frail per‐ sons, and these derangements have been appreciated in patients with CHD. Elevations in some markers of frailty are also risk factors for the development of progressive vascular and CHD [2]. So while it can be inferred that CVD and frailty share common links, the effect of frailty upon the outcomes of CVD is still an area of interest and continued study [3].

We now know that CVD can worsen sarcopenia and lead to frailty, while frailty worsens morbidity and mortality in CVD [4, 5]. Maximal aerobic power (MAP), a measure of frailty, decreases with age due to a decrease in cardiac output. And though CVD is not the primary cause of decline of MAP, CVD clearly exacerbates the said decline [5]. Recently, in a meta‐ analysis of 54,250 elderly individuals with a mean follow‐up of 6.2 years, the presence of ath‐ erosclerotic CVD was associated with the coexistence of frailty syndrome (FS) with an odds ratio (OR) of 2.7–4.1 [6]. Also, in patients who did not begin the study with FS, CVD was asso‐ ciated with the onset of FS during follow‐up of these patients. There have been several studies that highlight the relationship between CVD and frailty, as described in **Tables 1** and **2**.

**Table 1.** Effect of cardiovascular disease on frailty.

**Table 2.** Effect of frailty on cardiovascular disease.

2015. These diseases have remained the leading causes of death globally in the last 15 years. In 2010, CHD alone was projected to cost the United States (US) \$108.9 billion including the cost of health‐care services, medications, and lost productivity. The presence of frailty significantly worsens outcomes for patients suffering from CHD [1]. With just this one example of how frailty affects CVD, it is clear that understanding the impact of frailty upon patients afflicted with the spectrum of CVD is integral for the care of this very significant patient population.

While frailty as an entity is manifested by the interplay of multiple factors, there are some that are pertinent to the relationship between CVD and frailty. Endocrine dysregulation and higher levels of inflammatory markers have been found in frail compared with non‐frail per‐ sons, and these derangements have been appreciated in patients with CHD. Elevations in some markers of frailty are also risk factors for the development of progressive vascular and CHD [2]. So while it can be inferred that CVD and frailty share common links, the effect of

We now know that CVD can worsen sarcopenia and lead to frailty, while frailty worsens morbidity and mortality in CVD [4, 5]. Maximal aerobic power (MAP), a measure of frailty, decreases with age due to a decrease in cardiac output. And though CVD is not the primary cause of decline of MAP, CVD clearly exacerbates the said decline [5]. Recently, in a meta‐ analysis of 54,250 elderly individuals with a mean follow‐up of 6.2 years, the presence of ath‐ erosclerotic CVD was associated with the coexistence of frailty syndrome (FS) with an odds ratio (OR) of 2.7–4.1 [6]. Also, in patients who did not begin the study with FS, CVD was asso‐ ciated with the onset of FS during follow‐up of these patients. There have been several studies that highlight the relationship between CVD and frailty, as described in **Tables 1** and **2**.

> Assess association between classic cardiovascular risk factors and subsequent functional disability and mental well‐being

> Assess the relationship between subclinical cardiovascular disease and frailty.

Examined the cross‐sectional relationship between hemoglobin (Hb) and a recently‐validated measure of frailty in community‐dwelling older women, and whether this relationship was modified by cardiovascular disease (CVD) status.

Identified risk factors for frailty as targets for prevention. Investigated the predictive validity of this frailty classification for death, hospitalization, hip fracture, and activity of daily living (ADL) disability.

in elderly men.

**Objective Outcome**

Combined classic cardiovascular risk factors are predictive of functional

Cardiovascular disease was associated with an increased likelihood of frail health.

Mildly low and low‐normal Hb levels were independently associated with increased frailty risk. This risk was synergistically modified by the presence of CVD.

Community‐dwelling older women with CVD and cardiovascular risk factors were at higher risk of developing incident frailty.

disability.

frailty upon the outcomes of CVD is still an area of interest and continued study [3].

**Study Study type/number of patients**

patients

women

Population‐based cohort study/545 men

198 Frailty and Sarcopenia - Onset, Development and Clinical Challenges

Observational cohort/4375

Prospective population based cohort/670 patients

Prospective study, the Women's Health Initiative Observational Study/40.657

**Table 1.** Effect of cardiovascular disease on frailty.

Chin et al. [7]

Newman et al. [8]

Chaves et al. [9]

Woods et al. [10] A scoring system easily used on an inpatient basis highlights the interplay of CVD and frailty [16]. Sanchis et al. described seven independent predictors of frailty: age ≥75 years, female sex, prior CHD, admission for heart failure (HF), hemoglobin ≤12.5 g/dL, vitamin D ≤9 ng/mL, and cystatin‐C ≥1.2 mg, which could be measured on an inpatient basis. Defining frailty as positive when there were ≥3 had a good correlation with the Fried score of frailty.

In this chapter, we delve into a basic understanding of the underlying pathophysiology of CVD in relation to frailty and how it is worsened by the latter, inflammatory markers that have proven significant in CVD and frailty, and how frailty affects a vast spectrum of CVD, ranging from lipid dysregulation to outcomes in VHD.

#### **2. Pathophysiology**

The pathophysiology of CVD and frailty relates to a baseline chronic inflammatory state [17–20]. This phenomenon is caused by a metabolic imbalance in the body, hereby systemic demand is not met by metabolic supply, and consequently the body becomes primarily catabolic, oxidative stress increases, and ultimately a low‐level inflammatory phenotype is established [18, 21–28].

Multiple diseases place systemic stress demands on the body [1] that in turn leads to the inability of the body to keep pace with the demands of daily living, such as thermoregulation, aerobic respiration, glycolysis, and oxidative phosphorylation [17, 22, 29]. As a consequence of this baseline mismatch between the body's demand and its ability to supply, the body enters a pro‐catabolic state and begins to metabolize itself for nutrient utilization [17, 25]. During this state, more inefficient systems are used to produce energy, and weakness and weight loss occur [30]. A pro‐catabolic state is frequently seen in both CHD and frailty and leads to, as we already know exists in frailty, a pro‐inflammatory state [18, 24].

The aforementioned pro‐inflammatory state is highlighted by the presence of elevated inflam‐ matory markers. There are markers specific to frailty and others that are common between CVD and frailty. Interleukin (IL)‐6 is the most consistently seen inflammatory marker in patients with frailty, and is thought to be central to the pathogenesis of the phenotype [18, 21, 24, 26–28]. Studies have reported seeing elevated plasma uric acid, D‐dimer, white blood cells (WBCs), erythrocyte sedimentation rate (ESR), triglycerides, homocysteine, glucose, hemoglobin A1C (HbA1c), cre‐ atinine, cystatin C, insulin‐like growth factor (IGF)‐1, fibrinogen, von Willebrand factor, factors VIII and IX, oxidized proteins, protein carbonylation, as well as decreased vitamin D and testos‐ terone in patients with frailty [31]. In order to highlight the common role inflammation plays in both CVD and frailty, we can appreciate that elevations of C‐reactive protein (CRP), factor VIII, and D‐dimer are commonly seen even after correction of CVD [32]. Particularly, D‐dimer, CRP, IL‐6, and tumor necrosis factor (TNF)‐alpha will be discussed where pertinent.

#### **3. Frailty and hypertension (HTN)**

Though not all frail patients are hypertensive, there is some evidence to suggest that HTN is independently associated with frailty [33]. The mechanism behind this finding is further elu‐ cidated by the fact that frail patients have a decreased ability to use adenosine triphosphate (ATP) [23, 29, 34]. This leads to a decreased ability of smooth muscle to use ATP to pump calcium back into the sarcoplasmic reticulum, which is marked by a slower rate of decay of the calcium transit. In practical terms, this means the blood vessels of frail patients have decreased compliance and difficulty relaxing, which leads to HTN.

The renin‐angiotensin‐aldosterone system (RAAS) is one of the primary systems used by the body to regulate blood pressure (BP) (**Figure 1**) [35, 36]. Chronic inflammation directly stimulates RAAS, which causes HTN [37]. Since frail patients have persistently increased inflammation, stimulating RAAS, they are more likely to develop HTN. Thus, there is a direct link between the chronic inflammation phenotype and HTN in frail patients.

**2. Pathophysiology**

200 Frailty and Sarcopenia - Onset, Development and Clinical Challenges

The pathophysiology of CVD and frailty relates to a baseline chronic inflammatory state [17–20]. This phenomenon is caused by a metabolic imbalance in the body, hereby systemic demand is not met by metabolic supply, and consequently the body becomes primarily catabolic, oxidative stress increases, and ultimately a low‐level inflammatory phenotype is established [18, 21–28]. Multiple diseases place systemic stress demands on the body [1] that in turn leads to the inability of the body to keep pace with the demands of daily living, such as thermoregulation, aerobic respiration, glycolysis, and oxidative phosphorylation [17, 22, 29]. As a consequence of this baseline mismatch between the body's demand and its ability to supply, the body enters a pro‐catabolic state and begins to metabolize itself for nutrient utilization [17, 25]. During this state, more inefficient systems are used to produce energy, and weakness and weight loss occur [30]. A pro‐catabolic state is frequently seen in both CHD and frailty and

leads to, as we already know exists in frailty, a pro‐inflammatory state [18, 24].

IL‐6, and tumor necrosis factor (TNF)‐alpha will be discussed where pertinent.

decreased compliance and difficulty relaxing, which leads to HTN.

chronic inflammation phenotype and HTN in frail patients.

**3. Frailty and hypertension (HTN)**

The aforementioned pro‐inflammatory state is highlighted by the presence of elevated inflam‐ matory markers. There are markers specific to frailty and others that are common between CVD and frailty. Interleukin (IL)‐6 is the most consistently seen inflammatory marker in patients with frailty, and is thought to be central to the pathogenesis of the phenotype [18, 21, 24, 26–28]. Studies have reported seeing elevated plasma uric acid, D‐dimer, white blood cells (WBCs), erythrocyte sedimentation rate (ESR), triglycerides, homocysteine, glucose, hemoglobin A1C (HbA1c), cre‐ atinine, cystatin C, insulin‐like growth factor (IGF)‐1, fibrinogen, von Willebrand factor, factors VIII and IX, oxidized proteins, protein carbonylation, as well as decreased vitamin D and testos‐ terone in patients with frailty [31]. In order to highlight the common role inflammation plays in both CVD and frailty, we can appreciate that elevations of C‐reactive protein (CRP), factor VIII, and D‐dimer are commonly seen even after correction of CVD [32]. Particularly, D‐dimer, CRP,

Though not all frail patients are hypertensive, there is some evidence to suggest that HTN is independently associated with frailty [33]. The mechanism behind this finding is further elu‐ cidated by the fact that frail patients have a decreased ability to use adenosine triphosphate (ATP) [23, 29, 34]. This leads to a decreased ability of smooth muscle to use ATP to pump calcium back into the sarcoplasmic reticulum, which is marked by a slower rate of decay of the calcium transit. In practical terms, this means the blood vessels of frail patients have

The renin‐angiotensin‐aldosterone system (RAAS) is one of the primary systems used by the body to regulate blood pressure (BP) (**Figure 1**) [35, 36]. Chronic inflammation directly stimulates RAAS, which causes HTN [37]. Since frail patients have persistently increased inflammation, stimulating RAAS, they are more likely to develop HTN. Thus, there is a direct link between the

**Figure 1.** Renin‐angiotensin‐aldosterone system. ACE I, angiotensin‐converting enzyme inhibitor; ACE‐2, angiotensin‐ converting enzyme‐2; Ang, angiotensin; BK, bradykinin; BP, blood pressure; HFpEF, heart failure with preserved ejection fraction; JG, juxtaglomerular; LV, left ventricle; LVEDV, left ventricular end diastolic volume; LVH, left ventricular hypertrophy; NO, nitric oxide; PAI‐1, plasminogen activator inhibitor‐1; SNS, sympathetic nervous system.

Evidence from randomized controlled trials over the past decade indicates there is benefit to treating hypertension in older patients [38, 39]. This is inconsistent with earlier observa‐ tional and subgroup analyses of previous randomized control trials which were inconclusive [40, 41]. The HYVET trial in 2008 specifically focused the treatment of hypertension in elderly patients and found that antihypertensive treatment in patients older than 80 was benefi‐ cial [39]. In 2015, the Systolic Blood Pressure Intervention Trial (SPRINT) was undertaken. This trial should not be confused with the Sarcopenia and Physical Frailty in Older People: Multicomponent Treatment Strategies (SPRINTT) trial, which aims to provide a clear opera‐ tional definition of physical frailty and assess the impact a multi‐component intervention has on its progression [42]. The SPRINT trial showed that among patients >50 years old, lowering BP to <120 mmHg, particularly in the elderly, was associated with a significant decrease in mortality compared to a target of less than 140 mmHg at 5 years (5.2% vs. 6.8%; hazard ratio (HR): 0.75; 95% confidence interval (CI): 0.64–0.89, *p* < 0.001) [38]. Of note, patients who were >75 years old tended to fare better than younger patients. Taken together, this suggests that all elderly patients benefit from antihypertensive treatments, but there is an important caveat to both of these studies: enrolled patients tended to be relatively healthy patients and specifi‐ cally excluded patients with heart failure, stroke, and end‐stage renal disease [35, 38].

The exclusion criteria for HYVET and SPRINT raise concern that their findings may not be generalizable to frail patients [43]. A subgroup analysis of patients enrolled in HYVET addressed this concern [44]. Participants in both the control and treatment groups were given a frailty index according to 60 different variables. The impact of the frailty index on subse‐ quent risk of stroke, mortality, and cardiac events was found to be non‐significant, suggesting that benefits associated with BP lowering were conserved in frail patients. A frailty index was calculated for SPRINT participants using a similar set of 36 variables [45]. The frailty index distribution among the participants was comparable to general population cohorts. This sug‐ gests the heterogeneity of frailty among participants is similar to the general population.

Another 2015 report as a part of the Zwolle Outpatient Diabetes Project Integrating Available Care‐34 (ZODIAC‐34) cohort study, this time including all‐comers, confirmed what observa‐ tional studies had shown: for all‐cause mortality (especially frail patients), there was an inverse relationship between blood pressure and all‐cause mortality with a hazard ratio for systolic blood pressure of 0.92 (95% CI: 0.87–0.98) and 0.83 for diastolic blood pressure (95% CI: 0.73– 0.93) [46]. This suggested that among all patients >75 years of age, this time including those with less than 1 year life expectancy and DM, lower BP was associated with an increase in mortality. Contiguously, intensive lowering of BP in patients with low gate speed (a commonly used proxy for frailty) did not reduce mortality and the rate of CVD events (*p* = 0.05, 0.28, respectively) [47].

#### **4. Frailty and lipids**

The metabolism of lipids has been shown to affect aging, such that having a high‐density lipo‐ protein (HDL) level above 70 mg/dL is referred to as longevity syndrome. The Invecchiamento e Longevità nel Sirente (ilSERENTE) study showed that the HDL levels of the patients in their study who died during follow‐up were significantly lower than the levels of the survivors. This finding contributed to the understanding of the effect of HDL on lifespan, highlighting the role of lipid metabolism in decreasing mortality in the frail, elderly patient [48]. Another study of the same group of patients showed that, among frail patients, those with the high‐ est HDL levels had the best functional states [49]. To further support this idea, another study done in 2015 supported frailty as an independent risk factor for various diseases along the CVD spectrum. A low HDL level was one of the parameters [50]. As a part of the Longitudinal Aging Study Amsterdam, it was described that a lower total cholesterol was related to a higher rate of decline on information‐processing speed indicating, ultimately, that lower total choles‐ terol may be considered to be a marker of frailty and predictive of lower cognitive function in the elderly [51]. As described earlier, there has been significant study regarding the relation‐ ship between frailty, HDL status, and its effect on mortality. Conversely, the relation between low‐density lipoprotein (LDL) levels and frailty has yet to be established. Also, whereas the effect of lipids in the frail patient has been studied, the effect of frailty on the patient with a lipid disorder has yet to be established.

There has been speculation upon the metabolism of lipids in the frail patient. As there is a pro‐inflammatory milieu in the frail patient, this inflammation may affect lipid metabolism and, hence, lipid profiles in those who are frail. There may also be some correlation between dysfunctional lipid metabolism due to endocrine dysregulation evidenced by lower IGF‐1 and growth hormone levels in frail patients, lower HDL levels, and resultant poorer outcomes in CHD [52, 53]. A study on metabolic syndrome and disability showed a correlation between high triglycerides and a limitation in mobility and activities of daily living [54]. Overall, the effect of frailty, its pro‐inflammatory state, and the collective effect on lipids seems to be con‐ tiguous with an elevation in triglycerides (TGs) and a decrease in HDL likely contributing to the elevated CVD risk in the frail population.

#### **5. Frailty and atrial fibrillation (AF)**

The exclusion criteria for HYVET and SPRINT raise concern that their findings may not be generalizable to frail patients [43]. A subgroup analysis of patients enrolled in HYVET addressed this concern [44]. Participants in both the control and treatment groups were given a frailty index according to 60 different variables. The impact of the frailty index on subse‐ quent risk of stroke, mortality, and cardiac events was found to be non‐significant, suggesting that benefits associated with BP lowering were conserved in frail patients. A frailty index was calculated for SPRINT participants using a similar set of 36 variables [45]. The frailty index distribution among the participants was comparable to general population cohorts. This sug‐ gests the heterogeneity of frailty among participants is similar to the general population.

202 Frailty and Sarcopenia - Onset, Development and Clinical Challenges

Another 2015 report as a part of the Zwolle Outpatient Diabetes Project Integrating Available Care‐34 (ZODIAC‐34) cohort study, this time including all‐comers, confirmed what observa‐ tional studies had shown: for all‐cause mortality (especially frail patients), there was an inverse relationship between blood pressure and all‐cause mortality with a hazard ratio for systolic blood pressure of 0.92 (95% CI: 0.87–0.98) and 0.83 for diastolic blood pressure (95% CI: 0.73– 0.93) [46]. This suggested that among all patients >75 years of age, this time including those with less than 1 year life expectancy and DM, lower BP was associated with an increase in mortality. Contiguously, intensive lowering of BP in patients with low gate speed (a commonly used proxy for frailty) did not reduce mortality and the rate of CVD events (*p* = 0.05, 0.28, respectively) [47].

The metabolism of lipids has been shown to affect aging, such that having a high‐density lipo‐ protein (HDL) level above 70 mg/dL is referred to as longevity syndrome. The Invecchiamento e Longevità nel Sirente (ilSERENTE) study showed that the HDL levels of the patients in their study who died during follow‐up were significantly lower than the levels of the survivors. This finding contributed to the understanding of the effect of HDL on lifespan, highlighting the role of lipid metabolism in decreasing mortality in the frail, elderly patient [48]. Another study of the same group of patients showed that, among frail patients, those with the high‐ est HDL levels had the best functional states [49]. To further support this idea, another study done in 2015 supported frailty as an independent risk factor for various diseases along the CVD spectrum. A low HDL level was one of the parameters [50]. As a part of the Longitudinal Aging Study Amsterdam, it was described that a lower total cholesterol was related to a higher rate of decline on information‐processing speed indicating, ultimately, that lower total choles‐ terol may be considered to be a marker of frailty and predictive of lower cognitive function in the elderly [51]. As described earlier, there has been significant study regarding the relation‐ ship between frailty, HDL status, and its effect on mortality. Conversely, the relation between low‐density lipoprotein (LDL) levels and frailty has yet to be established. Also, whereas the effect of lipids in the frail patient has been studied, the effect of frailty on the patient with a

There has been speculation upon the metabolism of lipids in the frail patient. As there is a pro‐inflammatory milieu in the frail patient, this inflammation may affect lipid metabolism and, hence, lipid profiles in those who are frail. There may also be some correlation between

**4. Frailty and lipids**

lipid disorder has yet to be established.

The up‐regulation of the RAAS system in frail patients, as mentioned earlier, mediates an up‐regulation of endothelin‐1, which in turn mediates an increase in cardiac fibrosis [55]. Cardiac fibrosis, in turn, increases the likelihood of AF by disrupting the cardiac neurocon‐ duction pathways [23]. Additionally, frailty may be an independent risk factor for AF [46] due to a decreased ability to modulate heart rate, resulting in an increased likelihood of a patient developing AF [56, 57]. Additionally, an increased calcium influx, as discussed earlier, causes changes in the trans‐cellular membrane potential, which in turn makes a patient more likely to develop AF [23].

Frail patients have a 4.4 times higher chance (95% CI: 2.104–9.080, *p* < 0.001) of having AF com‐ pared to the general population [57]. Additionally, Polidoro et al. found that even after adjust‐ ing for age, sex, CVD, and CVD risk factors, AF was associated with a fourfold increase in frailtyhighlighting the relation between frailty and AF [58]. Additional evidence supporting the link between frailty and AF is the impairment of autonomic control vis‐à‐vis decreased heart rate variability which often precedes episodes of paroxysmal AF [57]. Similarly, there is decreased heart rate variability in frail patients.

AF has a significant impact on outcomes, including mortality, in frail patients [59]. Nguyen et al. found that in patients with AF, there was a 2.69 times higher risk of death in frail patients over a 6‐month period after hospitalization (HR: 2.69, 95% CI: 1.53–4.74). This relationship held even after correction for potential co‐founders (HR: 2.33; 95% CI: 1.31–4.14). It may be plausible to infer that AF also causes significant risk for cognitive decline to these patients see‐ ing as they are already at an increased risk for microbleeds as discussed subsequently in the section on cerebrovascular disease. Furthermore, the strong risk of stroke and TIA outlined in the subsequent text is indubitably linked with AF [60].

Despite the increased risk of death with AF, frail patients have an eightfold less likelihood of being discharged home on an oral anticoagulant after hospitalization [57]. In fact, frailty is the third most cited reason for not prescribing an oral anticoagulant. This makes the report by Granzera et al. more pertinent as the population ages [61]. In this study, he provides an approach to deciding if oral anticoagulation is appropriate in elderly frail patients (**Figure 2**).

Granziera et al. also discussed what factors should go into making the decision of whether to use warfarin or novel oral anticoagulants (NOACs) in frail patients [61]. Severe renal impair‐ ment, severe liver impairment, and poor adherence favored the use of warfarin. The exceptions

**Figure 2.** Decision algorithm for use of oral anticoagulants in elderly frail patients (<75 vs. ≥75 years). Adapted from Granziera et al. [61].

to favoring warfarin in renal impairment are apixaban and edoxaban, both of which may be prescribed in patients with compromised renal function. Decreased renal and hepatic clear‐ ances have minimal effect on warfarin. In patients at risk for poor compliance, their risk for stroke will not revert to baseline if a dose is missed. For patients with decreased mobility, they are less likely to comply with nutritional changes for warfarin and have polypharmacy; NOACs are the better choice for improved compliance.

Frail patients may have less of a benefit from device therapy than healthy patients [57]. In a combined analysis of four clinical trials, the benefits of implantable cardioverter defibrillators were inversely proportional to the number of comorbidities. This line of thought was further supported by a retrospective study of 83,792 undergoing ICD implantation in which frail patients had a 22% risk of mortality at 1 year compared to 12% overall.

#### **6. Frailty and cerebrovascular disease**

**Figure 2.** Decision algorithm for use of oral anticoagulants in elderly frail patients (<75 vs. ≥75 years). Adapted from

Granziera et al. [61].

204 Frailty and Sarcopenia - Onset, Development and Clinical Challenges

Several studies have indicated that frailty is associated with low cognitive performance. This is attributed to multiple causes including increased rates of Alzheimer's disease (AD), mild cognitive impairment, and a distinct subtype of frailty—cognitive frailty [62, 63]. Cognitive frailty is a clinical syndrome found in elderly patients without AD or other dementias, and occurs concurrently with physical frailty [63]. The key feature differentiating this syndrome from AD and other dementias is its potential for reversibility. The proposed mechanism for cognitive frailty is similar to physical frailty—a decrease in physiological reserves for responding to systemic stressors that manifests as an erosion of homeostatic mechanisms. The erosion of homeostatic mechanisms seen in cognitive frailty is manifested as β‐amyloid accumulation. These changes are independent other causes of dementia such as vascular and Alzheimer's dementia.

Frail patients were also more likely to have any form of dementia (HR 1.85; 95% CI: 1.01–3.40) and vascular dementia in particular (HF 2.68; 95% CI: 1.16–7.17) [62]. Frail patients are 3.38 times (95% CI: 2.37–4.81, *p* < 0.001) more likely to have a stroke or TIA than non‐frail patients [60]. This association with cerebrovascular disease extends to include pre‐frail patients, who have a 1.98 times greater risk of having a stroke versus non‐frail patients (95% CI: 1.53–2.57, *p* < 0.001). Another manifestation of cerebrovascular disease, cerebromicrobleeds, is one of the primary lesions responsible for vascular dementia. When the number of lesions is low (only one or two), there is usually no clinical evidence of microbleed, but when there is a larger lesion burden, patients present with stroke or dementia [64]. Even when adjusted for age, sex, and presence of vascular risk factors (CHD, chronic kidney disease, and global cognitive impairment), the lesion number was positively correlated with the severity of physical frailty. Chung et al. also found that the severity of physical frailty was positively correlated with proportion of cerebromicro‐ bleeds present in the deep and infratentorial regions of the brain.

Furthermore, a study performed on patients undergoing carotid endarterectomy (CEA) using the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database from 2005 to 2011 showed that frailty is a predictor of increased stroke, mortality, myocardial infarction, and length of stay after CEA, further supporting the idea that CVD and frailty are strongly interlinked with frail patients suffering poorer outcomes postintervention [65].

#### **6.1. Inflammatory markers in CHD**

The relationship between frailty and CHD is one that has been extensively studied as well. Chronic inflammation is a shared mechanism between atherosclerosis and frailty [18, 66, 67]. In Libby et al.'s strong and well‐cited review article, they show that, in addition to plaque characteristics, acute coronary syndromes are also caused by a chronic inflammatory state [59]. This link is most strongly seen by four markers of inflammation shared by both frailty and coronary vascular disease: IL‐6, CRP, fibrinogen, and D‐dimer [26, 27].

Hunter et al. made the strong case that IL‐6 is a keystone mediator of systemic inflammation in multiple disease processes, especially CVD [28]. There have been numerous other stud‐ ies linking IL‐6 and CHD [18, 66, 67]. This suggests that IL‐6 is central to the immunogenic dysregulation that accounts for the disease burden suffered by patients with both CVD and frailty [28]. Another significant marker of chronic inflammation shared between both CHD and frailty is CRP [26, 27]. Like IL‐6, this marker is elevated in frailty even when CHD is accounted for [32].

Fibrinogen is an acute‐phase reactant shown to be elevated with chronic inflammation and is strongly correlated with both frailty and atherosclerosis [26, 66]. Elevated fibrinogen is an independent risk factor for CVD events [66]. The mechanism is thought to be caused by fibrin‐ ogen affecting the plaque phenotype, causing it to be more permeable, able to accumulate oxi‐ dized LDL, increase platelet reactivity, and aggregation. A direct association between frailty and fibrinogen has been observed independent of chronic disease states [26].

Similar to fibrinogen, D‐dimer fragments are an independent risk factor for CHD to the point where they are considered a biomarker for atherothrombosis [66]. Moreover, elevated D‐dimers are also independently associated with frailty [32].

#### **7. Frailty and CHD**

A meta‐analysis of 54,250 elderly individuals with a mean follow‐up of 6.2 years showed that the presence of atherosclerotic CVD was associated with the coexistence of frailty syndrome with an odds ratio of 2.7–4.1 [6]. The relationship between CVD and frailty is significantly bidirectional [6, 60]. This is highlighted by the twofold increase in mortality among frail CHD patients compared to non‐frail patients even when adjusted for age and comorbidities [68]. In the Women's Health Initiative Study, women with CHD were more likely to become frail over the subsequent 6 years; likewise, the Health, Aging, and Body Composition Study showed that older adults with frailty were more likely to develop CHD. This same study showed that the presence of frailty, assessed by gait speed, was associated with an increased risk of inci‐ dent CVD. After adjustment for potential confounding factors, a slower gait was associated with an increased incidence of CVD events and all‐cause mortality compared with individuals having higher walking speed [69]. Furthering the complexity of this disease interplay is the fact that patients with both frailty and CHD have a higher frequency of multivessel disease and left main disease (74%) than non‐frail patients (60%) and moderately frail (68%) patients (*p* = 0.019) [70]. These differences persisted even after correcting for age and gender (*p* = 0.005). The wealth of evidence clearly defines the effect of frailty upon CHD.

mortality, myocardial infarction, and length of stay after CEA, further supporting the idea that CVD and frailty are strongly interlinked with frail patients suffering poorer outcomes

The relationship between frailty and CHD is one that has been extensively studied as well. Chronic inflammation is a shared mechanism between atherosclerosis and frailty [18, 66, 67]. In Libby et al.'s strong and well‐cited review article, they show that, in addition to plaque characteristics, acute coronary syndromes are also caused by a chronic inflammatory state [59]. This link is most strongly seen by four markers of inflammation shared by both frailty

Hunter et al. made the strong case that IL‐6 is a keystone mediator of systemic inflammation in multiple disease processes, especially CVD [28]. There have been numerous other stud‐ ies linking IL‐6 and CHD [18, 66, 67]. This suggests that IL‐6 is central to the immunogenic dysregulation that accounts for the disease burden suffered by patients with both CVD and frailty [28]. Another significant marker of chronic inflammation shared between both CHD and frailty is CRP [26, 27]. Like IL‐6, this marker is elevated in frailty even when CHD is

Fibrinogen is an acute‐phase reactant shown to be elevated with chronic inflammation and is strongly correlated with both frailty and atherosclerosis [26, 66]. Elevated fibrinogen is an independent risk factor for CVD events [66]. The mechanism is thought to be caused by fibrin‐ ogen affecting the plaque phenotype, causing it to be more permeable, able to accumulate oxi‐ dized LDL, increase platelet reactivity, and aggregation. A direct association between frailty

Similar to fibrinogen, D‐dimer fragments are an independent risk factor for CHD to the point where they are considered a biomarker for atherothrombosis [66]. Moreover, elevated

A meta‐analysis of 54,250 elderly individuals with a mean follow‐up of 6.2 years showed that the presence of atherosclerotic CVD was associated with the coexistence of frailty syndrome with an odds ratio of 2.7–4.1 [6]. The relationship between CVD and frailty is significantly bidirectional [6, 60]. This is highlighted by the twofold increase in mortality among frail CHD patients compared to non‐frail patients even when adjusted for age and comorbidities [68]. In the Women's Health Initiative Study, women with CHD were more likely to become frail over the subsequent 6 years; likewise, the Health, Aging, and Body Composition Study showed that older adults with frailty were more likely to develop CHD. This same study showed that the presence of frailty, assessed by gait speed, was associated with an increased risk of inci‐ dent CVD. After adjustment for potential confounding factors, a slower gait was associated with an increased incidence of CVD events and all‐cause mortality compared with individuals

and coronary vascular disease: IL‐6, CRP, fibrinogen, and D‐dimer [26, 27].

and fibrinogen has been observed independent of chronic disease states [26].

D‐dimers are also independently associated with frailty [32].

postintervention [65].

accounted for [32].

**7. Frailty and CHD**

**6.1. Inflammatory markers in CHD**

206 Frailty and Sarcopenia - Onset, Development and Clinical Challenges

Interestingly, atherogenesis is also affected by sarcopenia. This effect is partially due to the replacement of muscle with adipose tissue, and partially to the neurohumoral dysregula‐ tion and decreased mobility brought on by sarcopenia [71–73]. Atherogenesis is worsened by the presence of sarcopenia and frailty in humans as evidenced by the association between carotid atherosclerosis, arterial stiffness, and sarcopenia [6]. It, therefore, seems natural that frail patients fare worse after an acute CHD event compared to non‐frail patients. This notion was validated by Dodson et al., who found that at 1 year after an acute CHD event, older adults with slow gait speed (<0.8 m/s measured 1 month after the event) were more likely to die or be re‐admitted to the hospital than those with faster speeds (35.4% vs. 18.5%; *p* = 0.006) [74]. However, it is important to note that the majority of these events were re‐admissions not death.

Regarding interventions, there has been an extensive amount of investigation into whether coronary artery bypass grafting (CABG) is better than percutaneous coronary intervention (PCI) in frail patients. Fifty‐six percent of frail patients who underwent CABG had postop‐ erative complications compared to seventeen percent of those who were non‐frail (*p* < 0.001) [75]. Frailty was also an independent predictor of in‐hospital mortality after CABG (OR 1.8; 92% CI: 1.1–3.0). Similarly, PCI also carried significant risks. Frailty was associated with a longer hospital stay (HR 4.8, 95% CI: 1.4–16.3; *p* = 0.013), higher 30‐day mortality (HR 4.8, 95% CI: 1.4–16.3; *p* = 0.01), and higher 1‐year mortality (HR 5.9, 95% CI: 2.5–13.8; *p* < 0.001) [76, 77]. Importantly, there is evidence that there is no significant difference in change in frailty at 30 months between CABG and PCI (*p* = 0.090) [78]. In patients ≥75 years old treated with either PCI or CABG, there was a significantly different trajectory in their frailty score at 30 months (0.188 vs. 247, respectively) and at baseline (0.164 vs. 0.189, respectively; *p* = 0.041). Including frailty as part of the three‐tiered criterion in the assessment of a patient under‐ going PCI improved the discriminatory ability of the Mayo Clinic risk score [79]. Of great importance is the decision as to which modality of intervention is most effective in the frail population with obstructive coronary artery disease (CAD). Although we suspect that being less invasive in frail patients may be preferable, a prospective, randomized trial in the frail population addressing this quandary, as well as whether revascularization impacts frailty, would be beneficial.

#### **8. Frailty and peripheral arterial disease (PAD)**

Clearly, PAD is a pandemic condition that could potentially lead to the literal loss of life and limb. It manifests as tissue hypoperfusion caused by acute insult upon a limb with preexist‐ ing underlying atherosclerosis. This disease process is a significant cause of morbidity and mortality in both the frail and non‐frail populations [80, 81].

Frailty has been shown to be associated with and worsen outcomes in patients with PAD. A study of the participants >50 years of age in the National Health and Nutritional Examination Survey (NHANES) showed that, in multivariable multinomial logistic regression models, ankle brachial index (ABI) <0.9 predicted frailty and pre‐frailty. A higher prevalence of frailty was seen in participants with ABI ≥1.4. Frailty predicted general and CVD mortality in par‐ ticipants with ABI <0.9. Hence, this study suggested that frailty mediates increased morbidity and mortality in PAD [82]. A cross‐sectional study was carried out in a geriatric population of ≥65‐year‐old residents of Taichung, Taiwan, in June 2009 to assess the association between frailty and subclinical PAD. It reported findings suggesting that frail individuals had a signifi‐ cantly increased risk for subclinical PAD with an odds ratio of 3.168 [83]. In a study assessing gait in patients with PAD versus non‐PAD both with and without frailty, the pre‐frail group defined by the Fried Frailty Index had a diminished difference between study groups. This indicated that pre‐frail patients have a poor functional status overall, which may overshadow the level of dysfunction imposed upon them by PAD alone [84].

Another study assessing the effect of frailty on outcomes after vascular surgery showed that frailty, assessed by the modified Frailty Index (mFI), predicted mortality in patients under‐ going open procedures and Clavien‐Dindo class IV (life‐threatening) complications for both open and endovascular abdominal aortic aneurysm repairs [85]. Affecting disposition and, hence, patient wellness and health‐care expenditure, frailty also increases the propensity of home‐dwelling patients classified as frail to be discharged to a facility other than their home after elective vascular interventions [86]. There is also evidence to support the idea that frail females are potentially at the highest risk of death after vascular surgery, suggesting that female gender may be an additive risk factor [87].

#### **9. Frailty and heart failure**

The pathogenesis of HF has significant overlap with the processes leading to the frailty phe‐ notype [17, 88]. With HF, much like frailty, the metabolic demands of the body outstrip physi‐ ologic reserves. The findings of Lavie et al. likewise show that a loss of fat (reserves) signals a worsening prognosis in HF [30].

Frail patients and patients with HF consistently have a similar biochemical profile of ele‐ vated CRP and interleukin‐6, which in turn promote mitochondrial dysfunction [18, 22, 31]. Mitochondrial dysfunction produces excessive reactive oxygen species producing a pro‐ apoptotic intracellular environment. In the case of HF, apoptosis of cardiomyocytes fosters a local pro‐inflammatory atmosphere, leading to cardiac fibrosis and ultimately decreased contractility. Likewise, when applied to skeletal muscle, this process causes sarcopenia, one of the hallmarks and precursors of frailty.

The likelihood of a frail patient to manifest HF is 8.76 times higher than that of a non‐frail patient and, compared to any other element of CVD, HF is the most strongly linked with frailty [60, 89]. However, it should be noted that frailty is not limited to geriatric heart failure patient, and been observed in up to one‐third of younger patients with HF [68]. The prevalence of frailty among heart failure patients is important because frailty is an even stronger predictor of mortality than is HF per se [88]. Cacciatore et al. assessed the role frailty had on mortality in HF patients (*n* = 1139) over a 12‐year period compared to patients without CHF (*n* = 120) and found that frailty was independently associated with mortality in HF (HR 1.48, 95% CI: 1.04–2.11; *p* = 0.0032) and control group patients (HR 1.36, 95% CI: 1.17–1.57; *p* < 0.001), prov‐ ing that it indeed was a more important predictor of mortality than HF itself [12]. Lupon et al. found that among 622 outpatient HF patients, frailty was an independent predictor of mortal‐ ity even after adjustment for HF (HR 2.09, 95% CI: 1.11–3.92; *p* = 0.022) [90].

Frailty has been shown to be associated with and worsen outcomes in patients with PAD. A study of the participants >50 years of age in the National Health and Nutritional Examination Survey (NHANES) showed that, in multivariable multinomial logistic regression models, ankle brachial index (ABI) <0.9 predicted frailty and pre‐frailty. A higher prevalence of frailty was seen in participants with ABI ≥1.4. Frailty predicted general and CVD mortality in par‐ ticipants with ABI <0.9. Hence, this study suggested that frailty mediates increased morbidity and mortality in PAD [82]. A cross‐sectional study was carried out in a geriatric population of ≥65‐year‐old residents of Taichung, Taiwan, in June 2009 to assess the association between frailty and subclinical PAD. It reported findings suggesting that frail individuals had a signifi‐ cantly increased risk for subclinical PAD with an odds ratio of 3.168 [83]. In a study assessing gait in patients with PAD versus non‐PAD both with and without frailty, the pre‐frail group defined by the Fried Frailty Index had a diminished difference between study groups. This indicated that pre‐frail patients have a poor functional status overall, which may overshadow

Another study assessing the effect of frailty on outcomes after vascular surgery showed that frailty, assessed by the modified Frailty Index (mFI), predicted mortality in patients under‐ going open procedures and Clavien‐Dindo class IV (life‐threatening) complications for both open and endovascular abdominal aortic aneurysm repairs [85]. Affecting disposition and, hence, patient wellness and health‐care expenditure, frailty also increases the propensity of home‐dwelling patients classified as frail to be discharged to a facility other than their home after elective vascular interventions [86]. There is also evidence to support the idea that frail females are potentially at the highest risk of death after vascular surgery, suggesting that

The pathogenesis of HF has significant overlap with the processes leading to the frailty phe‐ notype [17, 88]. With HF, much like frailty, the metabolic demands of the body outstrip physi‐ ologic reserves. The findings of Lavie et al. likewise show that a loss of fat (reserves) signals a

Frail patients and patients with HF consistently have a similar biochemical profile of ele‐ vated CRP and interleukin‐6, which in turn promote mitochondrial dysfunction [18, 22, 31]. Mitochondrial dysfunction produces excessive reactive oxygen species producing a pro‐ apoptotic intracellular environment. In the case of HF, apoptosis of cardiomyocytes fosters a local pro‐inflammatory atmosphere, leading to cardiac fibrosis and ultimately decreased contractility. Likewise, when applied to skeletal muscle, this process causes sarcopenia, one

The likelihood of a frail patient to manifest HF is 8.76 times higher than that of a non‐frail patient and, compared to any other element of CVD, HF is the most strongly linked with frailty [60, 89]. However, it should be noted that frailty is not limited to geriatric heart failure patient, and been observed in up to one‐third of younger patients with HF [68]. The prevalence

the level of dysfunction imposed upon them by PAD alone [84].

female gender may be an additive risk factor [87].

208 Frailty and Sarcopenia - Onset, Development and Clinical Challenges

**9. Frailty and heart failure**

worsening prognosis in HF [30].

of the hallmarks and precursors of frailty.

Discerning which patients are frail versus non‐frail also has an impact on clinic resources. Frail patients versus non‐frail patients in one study had a 92% increase in Emergency Department (ED) visits (HR 1.92, 1.60; 95% CI: 1.30–2.83) and 65% increased risk for hospitalizations (HR 1.65; 95% CI: 1.17–2.35) [91]. Of note, there was no significant association between outpatient visits in HF patients and frailty. This raises the question as to whether or not more intensive outpatient management of frail HF patients would decrease ED and hospital utilization.

One possible intervention to decrease the amount of hospital utilization in frail patients and, moreover, improve their morbidity and mortality is specifically resistance exercise [92]. As noted by Lavie et al., there is compelling evidence that muscle mass and muscle strength are protective in HF patients [93]. Moreover, a lack of muscular fitness overall is a strong determi‐ nant of cardiac cachexia which, as mentioned earlier, may be seen as a classification of frailty. There is evidence to suggest that maximal aerobic power, a measure of frailty, decreases with age, due to a decrease in cardiac output, and is exacerbated by CVD. Importantly, this is a measure of frailty which could be addressed with an increase in muscle mass and anaerobic exercise [94]. It is important to note that resistance training is the most well‐validated coun‐ termeasure to slow the decline of muscle mass and muscle strength, even in frail patients [92]. By slowing the decline in muscle strength, the decline into frailty is consequently retarded. Taken together, this evidence points to muscle bulk, or the lack thereof, as being a significant marker of disease progression in HF and element of CVD.

The choice of pursuing advanced therapeutic options in the frail population with HF is a difficult one. As Joyce points out, HF itself and its ensuing sequelae can simulate the frailty phenotype [95]. Discerning between frailty caused specifically by HF and frailty attributable to non‐CVD causes has significant implications in this selection of patients for destination therapy with left ventricular assist devices (LVADs). In patients with HF as the primary driver of his or her frailty, implantation of an LVAD led to restoration of aberrant cardiac output and metabolism. Flint et al. sorted out frail patients receiving an LVAD into three groups: LVAD‐ responsive, LVAD‐independent, and LVAD‐intermediate. In the LVAD‐responsive group, whose frailty was primarily due to HF, implantation of LVAD caused a significant decrease in post‐LVAD frailty as measured by hand‐grip strength compared to both the LVAD‐intermedi‐ ate and LVAD‐independent patients. These LVAD‐responsive patients may be more accurate representatives of cardiac cachexia versus frailty.

Frailty in the heart‐transplant (HT) population has more significant and far‐reaching impor‐ tance. Frail patients who underwent HT in one study had a 1‐year survival rate of 52 ± 23% versus 100% in the non‐frail control arm. This has significant implications in the way HT therapy is allocated. This is a realm that requires more study, though studies will be sparse given the requirements for HT approval, including appropriate performance on pre‐HT cardiopulmonary testing, in which frail and pre‐frail patient would likely have suboptimal results.

#### **10. Frailty and valvular heart disease (VHD)**

In industrialized countries, the prevalence of VHD is estimated at 2.5%. Degenerative calcifi‐ cation seems to augment the prevalence of VHD markedly after the age of 65 years, particu‐ larly regarding aortic stenosis (AS) and mitral regurgitation (MR). These two disease entities account for three in four cases of VHD. Also contributing to the incidence of VHD is infec‐ tive endocarditis, the incidence of which is approximately 30 cases per million individuals per year worldwide. Finally, rheumatic heart disease (RHD) is another very significant con‐ tributor to the incidence of VHD and still represents a significant health burden with over 15 million cases of RHD worldwide, 282,000 new cases, and 233,000 deaths annually [96]. Health‐care expenditure for these disease entities is substantial. In fact, US expenditure esti‐ mates close to \$2 billion annually for symptomatic and asymptomatic aortic VHD, and \$2.6 billion for symptomatic and asymptomatic mitral VHD [97, 98].

Patients who meet indications for VHD surgery are frequently not offered surgery due to prohibitive risk features. As an example in the mitral VHD population, among patients who meet the current indications for surgical treatment of MR, almost 50% are not offered therapy due to several factors, including high surgical risk from comorbidities and frailty associated with advanced age [99, 100]. Importantly, though some patients may tolerate a surgical pro‐ cedure, meaningful functional recovery is not achieved if they demonstrate marked frailty prior to the intervention [101]. Unfortunately, such patients are left with few clinical options, resulting in frequent referrals to palliative care and hospice programs. Fortunately, as we now know, patients earlier deemed inoperable or high risk for conventional VHD surgery have minimally invasive options to address their comorbid state. These include transcatheter aortic valve replacement (TAVR), transcatheter mitral valve replacement (TMVR), and Mitraclip. These procedures may be the ones most suitable for the frail population as they are part of the aforementioned patient populations that would otherwise be left without options. Currently, of the interventions for VHD that are performed, the three mentioned earlier are the ones that have the most impact on the frail population.

In a study aimed at studying inflammatory markers in patients undergoing TAVR in an attempt to estimate preoperative risk, two inflammatory markers were studied. Neopterin, a pteridine synthesized by activated macrophages, and immune activation‐mediated trypto‐ phan and its subsequent degradation had both been shown prior to be associated with frailty and chronic disease. Ultimately, increased immune activation and associated tryptophan deg‐ radation underscored the prognostic role of baseline inflammation for outcome in patients with severe AS undergoing TAVR [102]. The aforementioned inflammatory markers like IL‐6, TNF‐alpha, D‐dimer, and CRP have not yet been studied in the frail population in regard to outcomes in VHD but may prove to be valuable area of further research.

Frailty is well known in the VHD population to be associated with poorer outcomes when compared to non‐frail patients. Patients with a moderate to severe degree of frailty (defined as requiring assistance to ambulate or attend to their own bodily needs, or a modified Rankin score 4) are generally considered high risk for valvular surgery [103]. In a study conducted by Sepeheri et al., frailty had a strong positive relationship with the risk of major adverse cardio‐ vascular and cerebrovascular events (MACCE) (odds ratio, 4.89; 95% confidence interval, 1.64– 14.60) [104]. Relationships were stronger in older patients undergoing TAVR than younger patients undergoing CABG and VHD surgery (hazard ratio for frailty in TAVR, 3.31–4.89 vs. hazard ratio for non‐TAVR, 1.10–3.16). One single‐center experience of all cardiac operations demonstrated frailty to be an independent predictor of in‐hospital mortality, institutional dis‐ charge, and reduced midterm survival [105]. In a study assessing the effect of frailty on mor‐ tality, length of stay (LOS), and discharge destination in patients post‐TAVR, Chauhan et al. showed that frailty portended an increase in LOS and mortality [106]. Additionally, a study assessing preoperative computed tomography (CT) scans that are done as part of the workup for transcatheter therapeutic interventions for VHD shows that these CTs have proven useful in measuring the patient's skeletal mass index (SMI) and, thus, preoperative sarcopenia. This correlated directly to length of stay more strongly than the frailty index [107].

Many of the frail patients afflicted with MR, however, tolerate MitraClip and are able to recover from the femoral venotomy and general anesthesia required for this procedure. In one study assessing effectiveness of transcutaneous mitral valve repair with Mitraclip in 564 patients, frailty was noted in 57% of patients. The procedural success rate, nonetheless, was 91% defined as MR less than or equal to grade 2 and surviving the hospital stay. A majority of patients were discharged home with moderate or less MR than prior [108]. Patients with severe frailty who are bedridden and/or require constant nursing care may be too disabled to achieve meaningful benefit from MitraClip and may also be considered prohibitive for TAVR [101]. This, though, has yet to be assessed prospectively.

The interesting aspect of frailty in VHD is that the novel interventions in this field are gener‐ ally aimed to treat non‐operable or high, prohibitive risk individuals. Frail patients comprise a significant portion of this population indicating that understanding how best to treat these patients is of significant import for the field in its gestalt. As this field continues to develop more prolifically, addressing the frail patient will prove to be an area of in‐depth study. Many practitioners share the belief that current interventions prove to reverse certain aspects of frailty but this has yet to be studied in a prospective trial.

#### **11. Conclusions**

therapy is allocated. This is a realm that requires more study, though studies will be sparse given the requirements for HT approval, including appropriate performance on pre‐HT cardiopulmonary testing, in which frail and pre‐frail patient would likely have suboptimal

In industrialized countries, the prevalence of VHD is estimated at 2.5%. Degenerative calcifi‐ cation seems to augment the prevalence of VHD markedly after the age of 65 years, particu‐ larly regarding aortic stenosis (AS) and mitral regurgitation (MR). These two disease entities account for three in four cases of VHD. Also contributing to the incidence of VHD is infec‐ tive endocarditis, the incidence of which is approximately 30 cases per million individuals per year worldwide. Finally, rheumatic heart disease (RHD) is another very significant con‐ tributor to the incidence of VHD and still represents a significant health burden with over 15 million cases of RHD worldwide, 282,000 new cases, and 233,000 deaths annually [96]. Health‐care expenditure for these disease entities is substantial. In fact, US expenditure esti‐ mates close to \$2 billion annually for symptomatic and asymptomatic aortic VHD, and \$2.6

Patients who meet indications for VHD surgery are frequently not offered surgery due to prohibitive risk features. As an example in the mitral VHD population, among patients who meet the current indications for surgical treatment of MR, almost 50% are not offered therapy due to several factors, including high surgical risk from comorbidities and frailty associated with advanced age [99, 100]. Importantly, though some patients may tolerate a surgical pro‐ cedure, meaningful functional recovery is not achieved if they demonstrate marked frailty prior to the intervention [101]. Unfortunately, such patients are left with few clinical options, resulting in frequent referrals to palliative care and hospice programs. Fortunately, as we now know, patients earlier deemed inoperable or high risk for conventional VHD surgery have minimally invasive options to address their comorbid state. These include transcatheter aortic valve replacement (TAVR), transcatheter mitral valve replacement (TMVR), and Mitraclip. These procedures may be the ones most suitable for the frail population as they are part of the aforementioned patient populations that would otherwise be left without options. Currently, of the interventions for VHD that are performed, the three mentioned earlier are the ones that

In a study aimed at studying inflammatory markers in patients undergoing TAVR in an attempt to estimate preoperative risk, two inflammatory markers were studied. Neopterin, a pteridine synthesized by activated macrophages, and immune activation‐mediated trypto‐ phan and its subsequent degradation had both been shown prior to be associated with frailty and chronic disease. Ultimately, increased immune activation and associated tryptophan deg‐ radation underscored the prognostic role of baseline inflammation for outcome in patients with severe AS undergoing TAVR [102]. The aforementioned inflammatory markers like IL‐6, TNF‐alpha, D‐dimer, and CRP have not yet been studied in the frail population in regard to

outcomes in VHD but may prove to be valuable area of further research.

**10. Frailty and valvular heart disease (VHD)**

210 Frailty and Sarcopenia - Onset, Development and Clinical Challenges

billion for symptomatic and asymptomatic mitral VHD [97, 98].

have the most impact on the frail population.

results.

Frailty is a significant disease entity affecting a myriad of clinical situations. How it affects the spectrum of CVD has been an area of interest and study for a number of years. With the advent of novel procedures in the realm of VHD and the expansion of patient populations now being considered as candidates for interventions, the topic of frailty, its interplay with CVD, and how it affects outcomes in patients with CVD are of the utmost import. As discussed earlier, current risk scores for patients undergoing cardiovascular surgery (STS and euroSCORE) have yet to include frailty as official criteria in their scoring systems, yet many practitioners still note frailty to be a condition predisposing patients to unfavorable outcomes and, thus, precluding them from interventions.

That frail patient suffers poorer outcomes is significant. From postintervention mortality to disposition postdischarge, frail patients perform suboptimally when compared to their non‐ frail counterparts. The generalized debility to which frail patients are predisposed may make them less tolerant of therapeutic postintervention treatments that would otherwise improve their outcomes, such as physical therapy and progressive exercise training. Their subclinical inflammatory state may further prevent wound healing and resolution. Also, their comorbid conditions may prevent complete healing and recovery as well. These hypotheses have not yet been studied and warrant further investigation for the purpose of elucidating ways to counteract the aforementioned poorer outcomes experienced by frail patients.

Frailty can be treated, potentially, with specific modalities, such as exercise, protein‐calorie supplementation, vitamin D, and reduction of polypharmacy [109]. This shows that, although frailty is incredibly significant and has undeniable impacts on morbidity and mortality, it is something that is potentially reversible. With further study and therapeutic interventions tai‐ lored specifically to the frail patient, we may be able to expand our indications and improve the quality of life for a patient population known to suffer with a disease process different from any other.

#### **Author details**

Vinod Chainani1 \*, Russell Riehl1 , Geeta Chainani5 , Abir Abdo2 , Mauricio G. Cohen3 , Carlos Alfonso3 , Pedro Martinez‐Clark3 , Carl J. Lavie1 , John P. Reilly1 and Nidal Abi‐Rafeh4

#### **References**

[3] Singh M, Alexander K, Roger VL, et al. Frailty and its potential relevance to cardiovas‐ cular care. Mayo Clinic Proceedings. 2008;**83**(10):1146‐1153

yet to include frailty as official criteria in their scoring systems, yet many practitioners still note frailty to be a condition predisposing patients to unfavorable outcomes and, thus, precluding

That frail patient suffers poorer outcomes is significant. From postintervention mortality to disposition postdischarge, frail patients perform suboptimally when compared to their non‐ frail counterparts. The generalized debility to which frail patients are predisposed may make them less tolerant of therapeutic postintervention treatments that would otherwise improve their outcomes, such as physical therapy and progressive exercise training. Their subclinical inflammatory state may further prevent wound healing and resolution. Also, their comorbid conditions may prevent complete healing and recovery as well. These hypotheses have not yet been studied and warrant further investigation for the purpose of elucidating ways to

Frailty can be treated, potentially, with specific modalities, such as exercise, protein‐calorie supplementation, vitamin D, and reduction of polypharmacy [109]. This shows that, although frailty is incredibly significant and has undeniable impacts on morbidity and mortality, it is something that is potentially reversible. With further study and therapeutic interventions tai‐ lored specifically to the frail patient, we may be able to expand our indications and improve the quality of life for a patient population known to suffer with a disease process different

counteract the aforementioned poorer outcomes experienced by frail patients.

, Geeta Chainani5

2 Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA

1 Ochsner Health System, John Ochsner Heart and Vascular Institute, Jefferson, Louisiana, USA

[1] Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics—2013 update: A report from the American Heart Association. Circulation. 2013;**127**(1):e6‐e245

[2] Tracy RP. Emerging relationships of inflammation, cardiovascular disease and chronic diseases of aging. International Journal of Obesity and Related Metabolic Disorders.

, Carl J. Lavie1

3 University of Miami Miller School of Medicine, Miami, Florida, USA 4 Tulane University School of Medicine, New Orleans, Louisiana, USA

5 Windsor University School of Medicine, Saint kitts, Carribean

, Abir Abdo2

, John P. Reilly1

, Mauricio G. Cohen3

and Nidal Abi‐Rafeh4

, Carlos

them from interventions.

212 Frailty and Sarcopenia - Onset, Development and Clinical Challenges

from any other.

**Author details**

Vinod Chainani1

**References**

Alfonso3

\*, Russell Riehl1

\*Address all correspondence to<EMAIL_ADDRESS>
, Pedro Martinez‐Clark3

2003;**27**(Suppl 3):S29‐S34

[34] Feridooni HA, Dibb KM, Howlett SE. How cardiomyocyte excitation, calcium release and contraction become altered with age. Journal of Molecular and Cellular Cardiology. 2015;**83**:62‐72

[17] Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: Evidence for a pheno‐ type. The Journal of Gerontology: Series A Biological Sciences and Medical Sciences.

[18] Fedarko NS. The biology of aging and frailty. Clinics in Geriatric Medicine. 2011;**27**(1):27‐37 [19] Wang Z, Nakayama T. Inflammation, a link between obesity and cardiovascular disease.

[20] Zakynthinos E, Pappa N. Inflammatory biomarkers in coronary artery disease. Journal

[21] Yao X, Li H, Leng SX. Inflammation and immune system alterations in frailty. Clinics in

[22] Biala AK, Dhingra R, Kirshenbaum LA. Mitochondrial dynamics: Orchestrating the journey to advanced age. Journal of Molecular and Cellular Cardiology. 2015;**83**:37‐43

[23] Keller KM, Howlett SE. Sex differences in the biology and pathology of the aging heart.

[24] Liu CK, Lyass A, Larson MG, et al. Biomarkers of oxidative stress are associated with

[25] Morley JE, Malmstrom TK. Frailty, sarcopenia, and hormones. Endocrinology &

[26] Soysal P, Stubbs B, Lucato P, et al. Inflammation and frailty in the elderly: A systematic

[27] Michaud M, Balardy L, Moulis G, et al. Proinflammatory cytokines, aging, and age‐related diseases. Journal of the American Medical Directors Association. 2013;**14**(12):877‐882 [28] Hunter CA, Jones SA. IL‐6 as a keystone cytokine in health and disease. Nature

[29] Akki A, Yang H, Gupta A, et al. Skeletal muscle ATP kinetics are impaired in frail mice.

[30] Lavie CJ, De Schutter A, Alpert MA, Mehra MR, Milani RV, Ventura HO. Obesity para‐ dox, cachexia, frailty, and heart failure. Heart Failure Clinics. 2014;**10**(2):319‐326

[31] Niedernhofer LJ, Kirkland JL, Ladiges W. Molecular pathology endpoints useful for

[32] Lang PO, Mitchell WA, Lapenna A, Pitts D, Aspinall R. Immunological pathogenesis of main age‐related diseases and frailty: Role of Immunosenescence. European Geriatric

[33] Khan H, Kalogeropoulos AP, Georgiopoulou VV, et al. Frailty and risk for heart failure in older adults: The health, aging, and body composition study. American Heart Journal.

frailty: The Framingham Offspring Study. Age (Dordr). 2016;**38**(1):1

review and meta‐analysis. Ageing Research Reviews. 2016;**31**:1‐8

2001;**56**(3):M146‐M156

Mediators of Inflammation. 2010;**2010**:535918

214 Frailty and Sarcopenia - Onset, Development and Clinical Challenges

Canadian Journal of Cardiology. 2016;**32**(9):1065‐1073

Metabolism Clinics of North America. 2013;**42**(2):391‐405

aging studies. Ageing Research Reviews. 2016;**35**:241‐249

of Cardiology. 2009;**53**(3):317‐333

Geriatric Medicine. 2011;**27**(1):79‐87

Immunology. 2015;**16**(5):448‐457

Age (Dordr). 2014;**36**(1):21‐30

Medicine. 2010;**1**:112‐121

2013;**166**(5):887‐894

[61] Granziera S, Cohen AT, Nante G, Manzato E, Sergi G. Thromboembolic prevention in frail elderly patients with atrial fibrillation: A practical algorithm. Journal of the American Medical Directors Association. 2015;**16**(5):358‐364

[47] Won CW, Kim S. Use of frailty in deciding clinical treatment goals for chronic dis‐ ease in elderly patients in the community. Journal of the American Medical Directors

[48] Landi F, Russo A, Pahor M, et al. Serum high‐density lipoprotein cholesterol levels and

[49] Landi F, Russo A, Cesari M, Pahor M, Bernabei R, Onder G. HDL‐cholesterol and physi‐ cal performance: Results from the ageing and longevity study in the sirente geographic

[50] Ramsay SE, Arianayagam DS, Whincup PH, et al. Cardiovascular risk profile and frailty in a population‐based study of older British men. Heart. 2015;**101**(8):616‐622

[51] van den Kommer TN, Dik MG, Comijs HC, Fassbender K, Lütjohann D, Jonker C. Total cholesterol and oxysterols: Early markers for cognitive decline in elderly? Neurobiology

[52] Roubenoff R, Parise H, Payette HA, et al. Cytokines, insulin‐like growth factor 1, sarcope‐ nia, and mortality in very old community‐dwelling men and women: The Framingham

[53] Hwang AC, Liu LK, Lee WJ, et al. Association of frailty and cardiometabolic risk among community‐dwelling middle‐aged and older people: Results from the I‐Lan Longitudinal

[54] Carriere I, Pérès K, Ancelin ML, et al. Metabolic syndrome and disability: Findings from the prospective three‐city study. The Journal of Gerontology Series A Biological Sciences

[55] Wang X, Guo Z, Ding Z, et al. Endothelin‐1 upregulation mediates aging‐related cardiac

[56] Pulignano G, Del Sindaco D, Tinti MD, et al. Atrial fibrillation, cognitive impairment, frailty and disability in older heart failure patients. Journal of Cardiovascular Medicine

[57] Bibas L, Levi M, Touchette J, et al. Implications of frailty in elderly patients with electro‐ physiological conditions. JACC: Clinical Electrophysiology. 2016;**2**(3):288‐294

[58] Polidoro A, Stefanelli F, Ciacciarelli M, Pacelli A, Di Sanzo D, Alessandri C. Frailty in patients affected by atrial fibrillation. Archives of Gerontology and Geriatrics.

[59] Nguyen TN, Cumming RG, Hilmer SN. The impact of frailty on mortality, length of stay and re‐hospitalisation in older patients with atrial fibrillation. Heart, Lung and

[60] Veronese N, Cereda E, Stubbs B, et al. Risk of cardiovascular disease morbidity and mor‐ tality in frail and pre‐frail older adults: Results from a meta‐analysis and exploratory

meta‐regression analysis. Ageing Research Reviews. 2017;**35**:63‐73

fibrosis. Journal of Molecular and Cellular Cardiology. 2015;**80**:101‐109

mortality in frail, community‐living elderly. Gerontology. 2008;**54**(2):71‐78

area (ilSIRENTE Study). Age Ageing. 2007;**36**(5):514‐520

Heart Study. American Journal of Medicine. 2003;**115**(6):429‐435

Aging Study. Rejuvenation Research. 2015;**18**(6):564‐572

and Medical Sciences. 2014;**69**(1):79‐86

(Hagerstown). 2016;**17**(8):616‐623

Circulation. 2016;**25**(6):551‐557

2013;**57**(3):325‐327

Association. 2016;**17**(11):967‐969

216 Frailty and Sarcopenia - Onset, Development and Clinical Challenges

of Aging. 2009;**30**(4):534‐545

[89] Nadruz W, Kitzman D, Windham BG, et al. Cardiovascular dysfunction and frailty among older adults in the community: The ARIC study. The Journal of Gerontology Series A Biological Sciences and Medical Sciences. 2016;**72**:958‐964

[75] O'Neill DE, Knudtson ML, Kieser TM, Graham MM. Considerations in cardiac revascu‐ larization for the elderly patient: age isn't everything. Canadian Journal of Cardiology.

[76] Kang L, Zhang SY, Zhu WL, et al. Is frailty associated with short‐term outcomes for elderly patients with acute coronary syndrome? Journal of Geriatric Cardiology.

[77] Murali‐Krishnan R, Iqbal J, Rowe R, et al. Impact of frailty on outcomes after percutane‐ ous coronary intervention: A prospective cohort study. Open Heart. 2015;**2**(1):e000294

[78] Freiheit EA, Hogan DB, Patten SB, et al. Frailty trajectories after treatment for coronary artery disease in older patients. Circulation: Cardiovascular Quality and Outcomes.

[79] Singh M, Rihal CS, Lennon RJ, Spertus JA, Nair KS, Roger VL. Influence of frailty and health status on outcomes in patients with coronary disease undergoing percutaneous revascularization. Circulation: Cardiovascular Quality and Outcomes. 2011;**4**(5):496‐502

[80] Thukkani AK, Kinlay S. Endovascular intervention for peripheral artery disease.

[81] Suzuki J, Shimamura M, Suda H, et al. Current therapies and investigational drugs for

[82] Ochi M, Kohara K, Tabara Y, et al. Arterial stiffness is associated with low thigh muscle

[83] Lin CH, Chou CY, Liu CS, Huang CY, Li TC, Lin CC. Association between frailty and subclinical peripheral vascular disease in a community‐dwelling geriatric population: Taichung Community Health Study for Elders. Geriatrics & Gerontology International.

[84] Toosizadeh N, Stocker H, Thiede R, Mohler J, Mills JL, Najafi B. Alterations in gait parameters with peripheral artery disease: The importance of pre‐frailty as a confound‐

[85] Ehlert BA, Najafian A, Orion KC, Malas MB, Black JH, Abularrage CJ. Validation of a modified Frailty Index to predict mortality in vascular surgery patients. Journal of

[86] Arya S, Long CA, Brahmbhatt R, et al. Preoperative frailty increases risk of nonhome discharge after elective vascular surgery in home‐dwelling patients. Annals in Vascular

[87] Brahmbhatt R, Brewster LP, Shafii S, et al. Gender and frailty predict poor outcomes in infrainguinal vascular surgery. Journal of Surgical Research. 2016;**201**(1):156‐165

[88] Jha SR, Ha HS, Hickman LD, et al. Frailty in advanced heart failure: A systematic review.

peripheral arterial disease. Hypertension Research. 2016;**39**(4):183‐191

mass in middle‐aged to elderly men. Atherosclerosis. 2010;**212**(1):327‐332

2016;**32**(9):1132‐1139

218 Frailty and Sarcopenia - Onset, Development and Clinical Challenges

2015;**12**(6):662‐667

2016;**9**(3):230‐238

2015;**15**(3):261‐267

Surgery. 2016;**35**:19‐29

Circulation Research. 2015;**116**(9):1599‐1613

ing variable. Vascular Medicine. 2016;**21**(6):520‐527

Vascular Surgery. 2016;**63**(6):1595‐1601.e1592

Heart Failure Reviews. 2015;**20**(5):553‐560

### **Allogeneic Mesenchymal Stem Cells as a Treatment for Aging Frailty**

[103] Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC guideline for the man‐ agement of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Journal of

[104] Sepehri A, Beggs T, Hassan A, et al. The impact of frailty on outcomes after car‐ diac surgery: A systematic review. Journal of Thoracic and Cardiovascular Surgery.

[105] Lee DH, Buth KJ, Martin BJ, Yip AM, Hirsch GM. Frail patients are at increased risk for mortality and prolonged institutional care after cardiac surgery. Circulation.

[106] Chauhan D, Haik N, Merlo A, et al. Quantitative increase in frailty is associated with diminished survival after transcatheter aortic valve replacement. American Heart

[107] Dahya V, Xiao J, Prado CM, et al. Computed tomography‐derived skeletal muscle index: A novel predictor of frailty and hospital length of stay after transcatheter aortic

[108] Sorajja P, Mack M, Vemulapalli S, et al. Initial experience with commercial transcatheter mitral valve repair in the United States. Journal of American College of Cardiology.

[109] Morley JE, Vellas B, van Kan GA, et al. Frailty consensus: A call to action. Journal of

Thoracic and Cardiovascular Surgery. 2014;**148**(1):e1‐e132

valve replacement. American Heart Journal. 2016;**182**:21‐27

American Medical Directors Association. 2013;**14**(6):392‐397

2014;**148**(6):3110‐3117

220 Frailty and Sarcopenia - Onset, Development and Clinical Challenges

2010;**121**(8):973‐978

Journal. 2016;**182**:146‐154

2016;**67**(10):1129‐1140

Bryon A. Tompkins, Ana Marie Landin, Victoria Florea, Makoto Natsumeda, Angela C. Rieger, Wayne Balkan, Ivonne Hernandez Schulman and Joshua M. Hare

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.69194

#### **Abstract**

As life expectancy is projected to increase in the ensuing decades, individuals of older age continue to exceed the previous generation's lifespan. Advancing age is associated with a reduction in physical and mental functional capacity, and chronic inflammation is a major factor contributing to this decline. A heightened inflammatory state can lead to exhaustion, weakness, weight loss, slow gate speed, and an overall decrease in activity level. These phenotypes define the onset of the disease process known as frailty. Frailty is a growing epidemic, which severely undermines a person's ability to deal with outside stressors, and increases their rate of hospitalization, institutionalization, and mortality. Current interventions focus on preventative care by improving exercise capacity, strength, nutritional supplementation, diet, and mobility. However, a biological cure has heretofore remained elusive. Here, we introduce the novel therapeutic principle that mesenchymal stem cell (MSC) therapy may represent a safe, practical, and efficacious both the treatment and prevention of frailty in individuals of advancing age. To date, a phase I safety trial reveals an excellent safety profile and suggests that mesenchymal stem cells can ameliorate signs and symptoms of frailty. These early studies lay the groundwork for future large-scale clinical trials of this exciting and novel therapeutic concept that has the potential to expand health span in the aging population.

**Keywords:** mesenchymal stem cells, immunomodulation, frailty, tumor necrosis factor-alpha, regenerative medicine

© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **1. Introduction**

Projected life expectancy continues to grow worldwide owing to the advancement of new treatments and technologies for leading causes of death such as cardiovascular disease and cancer [1]. Meanwhile, frailty is gaining relevance as a significant clinical syndrome that is associated with increased risk of falls, depression, and disability, leading to higher mortality [2]. Frailty is defined by an age-related decline in reserve and function leading to a reduced ability to cope with acute or external stressors [3] and is characterized by easy tiring, decreased libido, mood disturbance, accelerated osteoporosis, diminished muscle strength, and susceptibility to disease. However, the pathophysiology underlying this syndrome is complex and not clearly understood [4].

Inflammation is a pathophysiologic change that is closely linked with frailty [5]. Aging is associated with immunosenescence or the dysregulation of the innate immune system, resulting in an increase of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β, further leading to a chronic low-grade inflammatory state [6]. Chronic inflammatory response inhibits the repair, turnover, and adaptation of many tissues, including skeletal muscle [6]. Regeneration of skeletal muscle involves the cross-talk of muscle cells with immune cells, where the pro-inflammatory phenotype of immune cells promotes migration of satellite cells to the injured area, activates satellite cells, and matures newly formed muscle fibers [7]. Muscular degeneration caused by the altered pro-inflammatory state in frail patients is referred to as sarcopenia, another critical physiologic component of frailty.

Aging also produces physiologic changes in the brain, contributing to the development of frailty. Neurons with high metabolic demands, such as the hippocampal pyramidal neurons, are an important mediator in the pathophysiology of cognitive decline and are a key component of the stress response [3]. Concomitant with changes in the immune system, microglial cells, which are the resident immune cells of the central nervous system, are also structurally and functionally altered with aging and undergo senescence, likely causing damage and neuronal death [8]. Accumulating evidence supports an association between frailty, cognitive impairment, and dementia [9, 10].

The brain and endocrine system are intrinsically linked through the hypothalamo-pituitary axis, controlling metabolism via a series of homeostatic hormones. Four major circulating hormones are affected by aging: first, the decrease of insulin-like growth factor 1 (IGF-1) is associated with lower strength and decreased mobility [11]. Second, decreased sex hormone (estradiol and testosterone) increases the release of luteinizing hormone and follicle-stimulating hormone [12]. Third, decreased activity of the adrenocortical cells produces the major sex steroid precursor dehydroepiandrosterone sulfate (DHEA-S), which is associated with a gradual rise in cortisol. DHEA-S directly maintains muscle mass and indirectly prevents the inflammatory pathways that contribute to muscle decline [13, 14]. Finally, the reduced level of 25(OH) vitamin D is associated with the development of osteoporosis [15].

Due to the complexity of multiple inter-related physiological systems that contribute to frailty, there is no gold standard for diagnosing the syndrome. There are currently two models for evaluating frailty: the phenotype model and the cumulative deficit model that forms the basis

Notes: MSCs home to sites of injury and to enhance repair of damaged tissue (heart, joints, muscle, and blood vessels) and exert their regenerative effects via paracrine signaling, mitochondrial transfer, direct cellular contact, and exosome excretion.

**Table 1.** The effect of MSCs on the phenotypes of frailty.

**1. Introduction**

222 Frailty and Sarcopenia - Onset, Development and Clinical Challenges

not clearly understood [4].

impairment, and dementia [9, 10].

Projected life expectancy continues to grow worldwide owing to the advancement of new treatments and technologies for leading causes of death such as cardiovascular disease and cancer [1]. Meanwhile, frailty is gaining relevance as a significant clinical syndrome that is associated with increased risk of falls, depression, and disability, leading to higher mortality [2]. Frailty is defined by an age-related decline in reserve and function leading to a reduced ability to cope with acute or external stressors [3] and is characterized by easy tiring, decreased libido, mood disturbance, accelerated osteoporosis, diminished muscle strength, and susceptibility to disease. However, the pathophysiology underlying this syndrome is complex and

Inflammation is a pathophysiologic change that is closely linked with frailty [5]. Aging is associated with immunosenescence or the dysregulation of the innate immune system, resulting in an increase of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β, further leading to a chronic low-grade inflammatory state [6]. Chronic inflammatory response inhibits the repair, turnover, and adaptation of many tissues, including skeletal muscle [6]. Regeneration of skeletal muscle involves the cross-talk of muscle cells with immune cells, where the pro-inflammatory phenotype of immune cells promotes migration of satellite cells to the injured area, activates satellite cells, and matures newly formed muscle fibers [7]. Muscular degeneration caused by the altered pro-inflammatory state in frail

patients is referred to as sarcopenia, another critical physiologic component of frailty.

Aging also produces physiologic changes in the brain, contributing to the development of frailty. Neurons with high metabolic demands, such as the hippocampal pyramidal neurons, are an important mediator in the pathophysiology of cognitive decline and are a key component of the stress response [3]. Concomitant with changes in the immune system, microglial cells, which are the resident immune cells of the central nervous system, are also structurally and functionally altered with aging and undergo senescence, likely causing damage and neuronal death [8]. Accumulating evidence supports an association between frailty, cognitive

The brain and endocrine system are intrinsically linked through the hypothalamo-pituitary axis, controlling metabolism via a series of homeostatic hormones. Four major circulating hormones are affected by aging: first, the decrease of insulin-like growth factor 1 (IGF-1) is associated with lower strength and decreased mobility [11]. Second, decreased sex hormone (estradiol and testosterone) increases the release of luteinizing hormone and follicle-stimulating hormone [12]. Third, decreased activity of the adrenocortical cells produces the major sex steroid precursor dehydroepiandrosterone sulfate (DHEA-S), which is associated with a gradual rise in cortisol. DHEA-S directly maintains muscle mass and indirectly prevents the inflammatory pathways that contribute to muscle decline [13, 14]. Finally, the reduced level

Due to the complexity of multiple inter-related physiological systems that contribute to frailty, there is no gold standard for diagnosing the syndrome. There are currently two models for evaluating frailty: the phenotype model and the cumulative deficit model that forms the basis

of 25(OH) vitamin D is associated with the development of osteoporosis [15].

of the Canadian Study of Health and Aging (CSHA) frailty index [16]. The phenotype model defines frailty as meeting three or more of five criteria: weight loss (>5% of body weight in the previous year), exhaustion (positive response to questions regarding effort required for activity), weakness (decreased grip strength), slow gait speed (>6–7 seconds for walking 15 feet), decreased physical activity, or low energy expenditure (kcal spent per week: males expending <383 kcal, females expending <270 kcal) (**Table 1**) [17]. This model is simple and easy to use; however, it fails to include factors such as cognitive impairment and highly prevalent conditions associated with functional decline and disability [3].

The cumulative deficit model is based on the accumulation of illnesses, functional and cognitive declines, and social situations that are added together to calculate frailty [16]. This model utilizes 20 or more medically and functionally related questions and 92 baseline variables. The deficit model fashioned the origin of the CSHA frailty index [3]. The frailty index measures a number of age-associated health deficits (signs, symptoms, and laboratory values) [18], which is calculated by dividing each 'deficit' by the total number tested [3]. The higher the number of deficits, the higher the score, with '1' being the maximum index, which indicates a poorer prognosis. Specifically, Rockwood and Mitnitski noted that an index >0.7 indicates a high risk of mortality [19]. In an effort to simplify this index, the same authors proposed the CSHA clinical frailty score, a 7-point rapid screening tool that was highly correlated with the frailty index; with 7 being the maximum score, indicating "severe frailty" [20]. The clinical frailty score is currently widely used in clinical practice [21].

#### **2. Epidemiology**

Universal characteristics that are associated with an increased prevalence of frailty include: chronological age, female sex, racial, and ethnic minority, those in supportive residential settings, and lower income [22]. The prevalence among community-dwelling people over 65 years of age ranges from 4 to 17% in studies with varying geographic features [23, 24]. There are similar trends in Japan, the country with the highest life expectancy in the world. The reason for longevity in Japan is multifactorial. The universal health insurance system, the high population density with close access to hospitals, fish-based diets, awareness of healthy aging in the general public, and lower prevalence of lung cancer despite a higher population of smokers are some contributors [25]. Interestingly, a meta-analyses of frail Japanese patients using the phenotype model demonstrated that the age-stratified-weighted prevalence of frailty was lower in younger age groups (1.9% in 65–69 years, 3.8% in 70–74 years), the same in the 75–79-year age groups (10.0%), but higher in older age groups (20.4% in 80–84 years, 35.1% in ≥85 years) when compared to Western countries [25]. One explanation is that non-Japanese frail older individuals die younger, while Japanese frail older individuals survive longer, leading to a higher prevalence of frailty in their 80s.

#### **3. Intervention and preventive care**

While there is no cure for frailty, exercise is considered the most effective intervention to improve quality of life and functionality in frail adults. Improvements in muscle strength and mobility [26, 27] are among the most successful changes reported. Several studies have demonstrated an improvement in muscle strength in older persons with resistance exercise [28–30]. A longitudinal study of aging showed that physical activity is associated with a slower progression in functional limitations in older adults over a follow-up period of 6 months [31]. A randomized, placebo-controlled trial compared resistance exercise training, multinutrient supplementation, both interventions, and neither intervention (control group) in frail adults over a period of 10 weeks. The study suggested that high-intensity resistance exercise training improved muscle strength, gait velocity, and stair-climbing power. However, nutritional supplementation did not reduce muscle weakness or physical frailty [28]. Similarly, the LIFE-P (lifestyle interventions and independence for Elders pilot) exploratory study demonstrated that regular physical activity reduces frailty prevalence at a 12-month follow-up time point [32].

Another approach to delay frailty is the use of nutritional supplements, which increase protein and caloric daily intake. Administration of leucine-enriched essential amino acids can increase muscle synthesis through stimulation of the mechanistic target of rapamycin (mTOR) signaling pathway [33]. The PROT-AGE study [34] reviewed the dietary protein intake in older healthy people (>65 years). They found that the optimal protein intake in older persons with sarcopenia is 1.0–1.2 g/kg body weight per day, and higher protein intake >1.2 g/kg body weight per day for those who are exercising. The PROVIDE trial [35] assessed protein supplements enriched in leucine and vitamin D in sarcopenic older adults at high risk for disability. The study demonstrated that the group receiving high quantity protein supplements gained significantly more muscle mass and improved their chair stand ability relative to the control group.

The randomized Controlled Trial of Community-based Nutritional, Physical and Cognitive Training Intervention Programmes for At Risk Frail Elderly (FIT) compared the effects of 6-month interventions with either nutritional supplementation, cognitive training, physical activity, the combination treatments, or no intervention (control) in prefrail and frail adults [36]. Frailty score and status were measured at 3, 6 and 12 months. While these parameters were reduced in all groups, including the controls, the other four groups were significantly improved compared to the controls, at all three time points. However, none of the interventions improved the secondary endpoints, which included: hospitalizations, falls, and performance of activities of daily living [36]. Recent studies suggest that vitamin D plays a role in the pathogenesis and management of frailty [37, 38]. One such study demonstrated that daily doses of ≥800 IU of vitamin D has beneficial effects on balance and muscle strength [39]; while another reported an improvement in balance with a single large dose of vitamin D [40]. While an analysis of 53 trials showed that vitamin D supplementation alone does not prevent fractures in older adults [41], supplementation of vitamin D in combination with calcium can prevent disabling hip fractures among others [41].

While diet and exercise have been thoroughly evaluated, hormone therapy has also been tested. Testosterone undecanoate plus a high-calorie supplement (2108–2416 kJ/day) was compared with a control group (placebo plus a low-calorie supplement (142–191 kJ/day)) in a randomized controlled trial. The results showed that there were no significant differences in frailty scores at either 6- or 12-month follow-up between the groups [42]. While testosterone treatment improves muscle strength, it also increases incidence of adverse cardiovascular events [43]. Estrogen in combination with progestin therapy in postmenopausal women increases the risk of incident breast cancer after 5.6- or 7.1-years of follow-up [44, 45]. Likewise, the benefits of dehydroepiandrosterone sulfate (DHEA-S) supplementation in frail patients have not been demonstrated. Older subjects who received DHEA for 2 years exhibited no beneficial effects on body composition, physical performance, or quality of life [46]. Similarly, 1 year of treatment with insulin-like growth factor 1 (IGF-1) did not alter bone mineral density, fat mass, muscle strength, blood lipid parameters, and measures of postprandial glucose disposal in postmenopausal women [47].

Frailty is increasingly recognized as a clinical state of vulnerability with increased risk of adverse health outcomes. The pathogenesis that underlies this syndrome is multifactorial and elusive, and there is not yet a gold standard for diagnosis or treatment. Exercise and nutritional supplementations are currently the key interventions for frailty. Although helpful, none of them have been proven to treat the disease process. Therefore, an alternative approach to treating frail adults needs to be investigated. Here, we focus on a novel intervention, allogeneic mesenchymal stem cells (allo-MSCs) as a potential therapy for the treatment of frailty. While the mechanism is as yet unclear, we propose that the beneficial effects of MSCs for frailty are due, in large part, to a combination of their immunomodulatory, antifibrotic, and pro-regenerative effects.

#### **4. Regenerative medicine**

ranges from 4 to 17% in studies with varying geographic features [23, 24]. There are similar trends in Japan, the country with the highest life expectancy in the world. The reason for longevity in Japan is multifactorial. The universal health insurance system, the high population density with close access to hospitals, fish-based diets, awareness of healthy aging in the general public, and lower prevalence of lung cancer despite a higher population of smokers are some contributors [25]. Interestingly, a meta-analyses of frail Japanese patients using the phenotype model demonstrated that the age-stratified-weighted prevalence of frailty was lower in younger age groups (1.9% in 65–69 years, 3.8% in 70–74 years), the same in the 75–79-year age groups (10.0%), but higher in older age groups (20.4% in 80–84 years, 35.1% in ≥85 years) when compared to Western countries [25]. One explanation is that non-Japanese frail older individuals die younger, while Japanese frail older individuals survive longer, leading to a higher prevalence of frailty in their 80s.

While there is no cure for frailty, exercise is considered the most effective intervention to improve quality of life and functionality in frail adults. Improvements in muscle strength and mobility [26, 27] are among the most successful changes reported. Several studies have demonstrated an improvement in muscle strength in older persons with resistance exercise [28–30]. A longitudinal study of aging showed that physical activity is associated with a slower progression in functional limitations in older adults over a follow-up period of 6 months [31]. A randomized, placebo-controlled trial compared resistance exercise training, multinutrient supplementation, both interventions, and neither intervention (control group) in frail adults over a period of 10 weeks. The study suggested that high-intensity resistance exercise training improved muscle strength, gait velocity, and stair-climbing power. However, nutritional supplementation did not reduce muscle weakness or physical frailty [28]. Similarly, the LIFE-P (lifestyle interventions and independence for Elders pilot) exploratory study demonstrated that regular physical activity reduces frailty prevalence at a 12-month follow-up time point [32].

Another approach to delay frailty is the use of nutritional supplements, which increase protein and caloric daily intake. Administration of leucine-enriched essential amino acids can increase muscle synthesis through stimulation of the mechanistic target of rapamycin (mTOR) signaling pathway [33]. The PROT-AGE study [34] reviewed the dietary protein intake in older healthy people (>65 years). They found that the optimal protein intake in older persons with sarcopenia is 1.0–1.2 g/kg body weight per day, and higher protein intake >1.2 g/kg body weight per day for those who are exercising. The PROVIDE trial [35] assessed protein supplements enriched in leucine and vitamin D in sarcopenic older adults at high risk for disability. The study demonstrated that the group receiving high quantity protein supplements gained significantly more muscle mass and improved their chair stand ability relative to the control

The randomized Controlled Trial of Community-based Nutritional, Physical and Cognitive Training Intervention Programmes for At Risk Frail Elderly (FIT) compared the effects of 6-month interventions with either nutritional supplementation, cognitive training, physical activity, the combination treatments, or no intervention (control) in prefrail and frail

**3. Intervention and preventive care**

224 Frailty and Sarcopenia - Onset, Development and Clinical Challenges

group.

Frailty is a multifactorial condition triggered by genetic and environmental factors. As previously described, there is a direct association between frailty and the loss of proliferative homeostasis, neurodegeneration, DNA/mitochondrial mutations, free radical accumulation, a rise in pro-inflammatory markers, and increased immunosenescence. Stem cell depletion is a key mechanism postulated to contribute to frailty and its epigenetic dysregulation [48–50]. Thus, the repletion of stem cells is an appealing approach to treat this multifactorial dysregulation and MSCs are a particularly attractive candidate. MSCs are a multipotent, self-renewing somatic progenitor cell type that exhibits immunoprivileged properties [51–53] and are relatively easy to collect (bone marrow harvest), isolate, and expand [54, 55].

MSCs home to sites of injury, upregulate endogenous stem cells, and reduce inflammation and organ dysfunction [56–61]. With respect to age-related diseases, MSCs have demonstrated improvements in ischemic and nonischemic cardiomyopathies [62–64], stroke [65], systemic inflammation [66], and Parkinson's, among others [67]. Although not completely understood, the beneficial effects of stem cells are likely due primarily to paracrine signaling [68, 69] including microvesicle/exosome release [70, 71] and secondarily to direct cellular contact including gap junction formation [72] and mitochondrial exchange via tunneling nanotubes [73, 60].

MSC effects at the molecular level are secondary to the secretion of growth factors, chemokines, and metalloproteinases, including vascular endothelial growth factor (VEGF), angiopoetin-1, fibroblast growth factor, placental growth factor, stem cell-derived factor (SDF), plasminogen activator [74], hepatocyte growth factor/scatter factor (HGF/SF) [75], secreted frizzled-related protein 2 (Sfrp2), hypoxic-induced Akt-regulated stem cell factor (HASF) and IGF-1 and -2 [76]. These molecules stimulate the Akt pathway [77], promote vasculogenesis [56], and protect native cells under hypoxic conditions [68]. In the heart, injection of MSCs produces antifibrotic, anti-inflammatory, and proangiogenic [57–59] effects and upregulates the proliferation of endogenous cardiac stem cells [60, 61], while improving the preservation of function of the cells surrounding the sites of injection.

MSCs mediate metabolic changes and stimulate resident cell activation after injury. *In vitro* studies have shown that MSC-conditioned culture media stimulates resident cardiac stem cells to proliferate, differentiate, and migrate [53, 78] via IGF-1. HASF and Sfrp2 prevent cardiomyocyte apoptosis, promote cardiac stem cell differentiation, and reduce fibrosis after myocardial infarction (MI) [79–81].

The absence of major histocompatibility complex (MHC) class II antigens underlies the lack of allo-MSCs to stimulate a major immune response [82] and has generated an interest in their systemic and local application without the need for immunosuppression [62]. In the clinical setting, multiple trials have evaluated and proven the safety and efficacy of MSC therapy [63, 64, 83–85]. Several disease processes have been studied in humans: autoimmune diseases, organ transplantation, and as a therapeutic agent after solid organ injury.

#### **5. Immune biomarkers in aging and frailty**

Aging and frailty are associated with a dramatic impairment of the ability of the immune system to provide protection from new pathogens. Older frail individual has serious complications that cause adverse health outcomes including acute illness, heightened inflammatory state, and immune dysregulation, which cause a severe impairment in both innate and adaptive immunity and greater susceptibility to infectious diseases, comorbidities, and increased mortality [86, 87]. The accumulation of reactive oxygen species (ROS) in the aging process leads, in part, to chronic activation of Toll-like receptors (TLRs), which in turn leads to an increase in the inflammatory process [88–90]. In frailty, the immune phenotype is dysregulated due to incrementing chronic inflammation known as inflammaging and includes increased IL-6, C-reactive peptide (CRP), and TNF-α [87]. Inflammaging plays an important role in the suppression of the immune system and the remodeling of the immune phenotype (**Figure 1**). The remodeling of the immune phenotype in aging is known as immunosenescence and is marked by several immune biomarkers described below.

a key mechanism postulated to contribute to frailty and its epigenetic dysregulation [48–50]. Thus, the repletion of stem cells is an appealing approach to treat this multifactorial dysregulation and MSCs are a particularly attractive candidate. MSCs are a multipotent, self-renewing somatic progenitor cell type that exhibits immunoprivileged properties [51–53] and are

MSCs home to sites of injury, upregulate endogenous stem cells, and reduce inflammation and organ dysfunction [56–61]. With respect to age-related diseases, MSCs have demonstrated improvements in ischemic and nonischemic cardiomyopathies [62–64], stroke [65], systemic inflammation [66], and Parkinson's, among others [67]. Although not completely understood, the beneficial effects of stem cells are likely due primarily to paracrine signaling [68, 69] including microvesicle/exosome release [70, 71] and secondarily to direct cellular contact including gap junction formation [72] and mitochondrial exchange via tunneling nanotubes [73, 60].

MSC effects at the molecular level are secondary to the secretion of growth factors, chemokines, and metalloproteinases, including vascular endothelial growth factor (VEGF), angiopoetin-1, fibroblast growth factor, placental growth factor, stem cell-derived factor (SDF), plasminogen activator [74], hepatocyte growth factor/scatter factor (HGF/SF) [75], secreted frizzled-related protein 2 (Sfrp2), hypoxic-induced Akt-regulated stem cell factor (HASF) and IGF-1 and -2 [76]. These molecules stimulate the Akt pathway [77], promote vasculogenesis [56], and protect native cells under hypoxic conditions [68]. In the heart, injection of MSCs produces antifibrotic, anti-inflammatory, and proangiogenic [57–59] effects and upregulates the proliferation of endogenous cardiac stem cells [60, 61], while improving the preservation

MSCs mediate metabolic changes and stimulate resident cell activation after injury. *In vitro* studies have shown that MSC-conditioned culture media stimulates resident cardiac stem cells to proliferate, differentiate, and migrate [53, 78] via IGF-1. HASF and Sfrp2 prevent cardiomyocyte apoptosis, promote cardiac stem cell differentiation, and reduce fibrosis after

The absence of major histocompatibility complex (MHC) class II antigens underlies the lack of allo-MSCs to stimulate a major immune response [82] and has generated an interest in their systemic and local application without the need for immunosuppression [62]. In the clinical setting, multiple trials have evaluated and proven the safety and efficacy of MSC therapy [63, 64, 83–85]. Several disease processes have been studied in humans: autoimmune diseases,

Aging and frailty are associated with a dramatic impairment of the ability of the immune system to provide protection from new pathogens. Older frail individual has serious complications that cause adverse health outcomes including acute illness, heightened inflammatory state, and immune dysregulation, which cause a severe impairment in both innate and adaptive immunity and greater susceptibility to infectious diseases, comorbidities, and

organ transplantation, and as a therapeutic agent after solid organ injury.

relatively easy to collect (bone marrow harvest), isolate, and expand [54, 55].

226 Frailty and Sarcopenia - Onset, Development and Clinical Challenges

of function of the cells surrounding the sites of injection.

**5. Immune biomarkers in aging and frailty**

myocardial infarction (MI) [79–81].

The immune risk phenotype (IRP), which is the ratio of CD4+ to CD8+ T cells, decreases to <1 in aging and frailty, has been linked to increased risk of mortality [91, 92]. The decreased IRP associated with aging and frailty is due to an expansion of the CD8+ compartment in comparison to the CD4+ compartment. In spite of the expansion of the CD8+ T-cell compartment, the effector T cells in frail individuals have diminished function mostly due to antigen experienced CD8+ T cells re-expressing the naïve marker CD45RA, also known as TEMRA T cells [87]. This expansion of the TEMRA T cell population is exacerbated by factors such as chronic activation due to Cytomegalovirus (CMV) exposure known to be present in >60% of the US population [93]. Finally, the ability to produce protective antibodies upon new antigenic exposure is also severely impaired in aging and frailty due to a remodeling of the B cell compartment. In addition, there is an intrinsic defect in B cells in aging, which causes a decrease in the enzyme, activation-induced cytidine deaminase (AID) leading to diminished ability to switch antibody isotype, which has been correlated to increased TNF-α [94]. The inflammaging process depletes the B cell compartment of switched memory B cells, which are a predictive biomarker for protective vaccine response. In addition, the refractory/ exhausted B cell compartment is expanded filling up the B cell niche with unresponsive cells [86, 94, 95].

**Figure 1.** The role of stressors, aging, and inflammation in frailty and the effects of mesenchymal stem cells. As individuals grow older, several stressors (poor nutrition, diseases, oxidative stress, and environmental factors) increase the inflammaging process leading to frailty. Mesenchymal stem cells (MSCs) secrete several factors that block or reverse the inflammaging process and ultimately reverses the effects of frailty.

### **6. The role of MSCs in inflammaging and immune modulation**

Human bone marrow-derived MSCs downregulate the expression of pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and monocyte chemoattractant protein-1 (**Figure 2**) [96, 32]. Other immunomodulatory properties include the inhibition of dendritic cells, natural killer cells [97–99], and T/B cell proliferation via the downregulation of the molecules programmed death-1 (PD-1) transforming growth factor-β, HGF, nitric oxide, indoleamine 2,3-dioxygenase, and prostaglandin-E2 release [52, 68]. Interestingly, MSCs are able to transform pro-inflammatory macrophages (M1) into anti-inflammatory macrophages (M2) by upregulating IGF-1 and IL-10 [100], thereby promoting angiogenesis and cardiomyocyte recovery [101, 102]. Most importantly, MSCs suppress T cell activation, which is crucial due to the high incidence of CMV virus among the US population, causing chronic activation of T cells leading to an exhausted immune phenotype [103].

Ground-breaking immune-modulatory results in the Randomized Comparison of Allogeneic Versus Autologous Mesenchymal Stem Cells for Nonischemic Dilated Cardiomyopathy: POSEIDON-DCM study demonstrated that 6 months post-TESI, allogeneic human mesenchymal stem cells (hMSCs) were more efficient than auto-hMSCs in reducing serum levels of TNF-α, increased switched memory B cells, decreased exhausted B cells concomitant with a decrease in the percentage of B cells expressing TNF-α, decreased T cell activation and decreased TEMRA T cells [62]. This reversal on the effects of chronic inflammation on these immune biomarkers opens up the feasibility of using allo-hMSC as a treatment to reverse the process of inflammaging and immunosenescence.

Together, these findings are indicative of the safety of MSC therapy in a variety of disease processes. Furthermore, given that MSCs are known to elicit immunomodulatory, neoangiogenic,

**Figure 2.** MSCs serve as an anti-inflammatory treatment. (A) Depiction of systemic inflammation (white asterisks'). (B). The anti-inflammatory effects of MSCs. Reproduced from Golpanian et al., with permission from the publisher.

endogenous cellular proliferative, and antifibrotic effects post-MI in both animal models and clinical trials alike, we anticipate that MSC therapy will act in a similar manner and prove beneficial in older individuals with frailty.

#### **7. CRATUS phase I and II**

**6. The role of MSCs in inflammaging and immune modulation**

Human bone marrow-derived MSCs downregulate the expression of pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and monocyte chemoattractant protein-1 (**Figure 2**) [96, 32]. Other immunomodulatory properties include the inhibition of dendritic cells, natural killer cells [97–99], and T/B cell proliferation via the downregulation of the molecules programmed death-1 (PD-1) transforming growth factor-β, HGF, nitric oxide, indoleamine 2,3-dioxygenase, and prostaglandin-E2 release [52, 68]. Interestingly, MSCs are able to transform pro-inflammatory macrophages (M1) into anti-inflammatory macrophages (M2) by upregulating IGF-1 and IL-10 [100], thereby promoting angiogenesis and cardiomyocyte recovery [101, 102]. Most importantly, MSCs suppress T cell activation, which is crucial due to the high incidence of CMV virus among the US population, causing chronic activation of T cells leading to an exhausted immune phenotype [103].

Ground-breaking immune-modulatory results in the Randomized Comparison of Allogeneic Versus Autologous Mesenchymal Stem Cells for Nonischemic Dilated Cardiomyopathy: POSEIDON-DCM study demonstrated that 6 months post-TESI, allogeneic human mesenchymal stem cells (hMSCs) were more efficient than auto-hMSCs in reducing serum levels of TNF-α, increased switched memory B cells, decreased exhausted B cells concomitant with a decrease in the percentage of B cells expressing TNF-α, decreased T cell activation and decreased TEMRA T cells [62]. This reversal on the effects of chronic inflammation on these immune biomarkers opens up the feasibility of using allo-hMSC as a treatment to reverse the

Together, these findings are indicative of the safety of MSC therapy in a variety of disease processes. Furthermore, given that MSCs are known to elicit immunomodulatory, neoangiogenic,

**MSCs**

**Reduces Inflammation:** TNF-α, IL-1β, IL-6

**Figure 2.** MSCs serve as an anti-inflammatory treatment. (A) Depiction of systemic inflammation (white asterisks'). (B). The anti-inflammatory effects of MSCs. Reproduced from Golpanian et al., with permission from the publisher.

process of inflammaging and immunosenescence.

228 Frailty and Sarcopenia - Onset, Development and Clinical Challenges

The therapeutic interventions available to frail older individuals focus on improving the functionality of a precipitously declining quality of life. With the understanding that deteriorating endogenous stem cell function is a key mechanism behind this disease process, the allogeneic human mesenchymal stem cells (allo-hMSC) in patients with aging FRAilTy via intravenous delivery (CRATUS) trial (**Figure 3**) was established to reverse the untoward effects of frailty. Conducted at the University of Miami Miller School of Medicine, the pilot phase was designed to establish an optimal dose, and tested the hypothesis that allo-hMSCs were safe, well tolerated, and reduced the signs and symptoms of the disease [104]. The study was conducted in a nonrandomized, nonblinded, escalating dosage via peripheral intravenous infusion in 15 frail subjects [104]. Donors were healthy males and females between the ages of 20 and 45 [104]. Three groups of five patients each received either 20 million (M)-, 100M-, or 200M-cells [104]. Patients were followed out to 1-year postinfusion. The pilot phase revealed the two most salient doses (100M- and 200M-cells) [55] and was followed by

**Figure 3.** Schematic of the CRATUS pilot and randomized phases.

phase II, a randomized, double-blinded, placebo-controlled trial that further tested the safety and efficacy of allo-hMSCs in frail older individuals.

#### **7.1. Results of the phase I study**

The 15 subjects in the pilot phase had an average age of 78.4 ± 4.7 years [55]. Eight patients were categorized as vulnerable to frailty with a CSHA score of 4 and the others were mild, with a score of 6 (*n* = 6) and moderate with a score of 7 (*n* = 1) [55]. Most importantly, the primary endpoint, treatment-emergent serious adverse events (TE-SAE) at 1-month postinfusion, was met with no adverse reactions in any group [55].