Sarcopenic Obesity and the Pathogenesis of Exercise Intolerance in Heart Failure With Preserved Ejection Fraction

Abstract

Heart failure with preserved ejection fraction (HFpEF) is the most common form of heart failure (HF) in older adults. The primary chronic symptom in patients with HFpEF, even when well compensated, is severe exercise intolerance. Cardiac and peripheral functions contribute equally to exercise intolerance in HFpEF, though the latter has been the focus of fewer studies. Of note, multiple studies with exercise training have shown that exercise intolerance can improve significantly in the absence of improvements in exercise cardiac output, indicating a role of peripheral, non-cardiac adaptations. In addition, clinical drug trials performed to date in HFpEF, all of which have focused on influencing cardiovascular function, have not been positive on primary clinical outcomes and most have not improved exercise capacity. Mounting evidence indicates that sarcopenic obesity, characterized by the coexistence of excess fat mass and decreased muscle mass, could contribute to the pathophysiology of exercise intolerance in older HFpEF patients and may provide avenues for novel treatments.

Introduction

Heart failure (HF) with preserved ejection fraction (HFpEF) is the most common form of HF in older adults, particularly women, and is increasing in prevalence as the population ages [1]. The prevalence of HFpEF is rising, with morbidity, mortality, and healthcare costs on par with HF with a reduced ejection fraction (HFrEF) [1–4]. The primary symptom in patients with HFpEF, even when well compensated, is severe exercise intolerance, and is associated with their reduced quality of life [5–11]. However, HFpEF pathophysiology is poorly understood; most drug trials in HFpEF focused on improving cardiovascular function have not resulted in an increase in exercise tolerance [12,13], the key symptom in this common, important disorder among the elderly.

Our data and those of others’ indicate that in older HFpEF patients, abnormalities in skeletal muscle and increased adiposity are major contributors to exercise intolerance [10,14,15]. Often overlooked regarding HFpEF is that approximately 85% of elderly patients with the disorder are overweight or obese and that the HFpEF epidemic has largely paralleled the obesity epidemic [16**]. Furthermore, normal aging is associated with characteristic changes in body composition, including decreases in lean body mass and muscle strength, and increases in adiposity [17–19]. Sarcopenic obesity, the coexistence of excess fat mass and decreased muscle mass, is a concern in the aged society. In this review, we will focus on relationship between the sarcopenic obesity on pathophysiology of exercise intolerance in elderly HFpEF patients.

Pathophysiology of Exercise Intolerance in HFpEF

Exercise intolerance can be objectively measured as reduced peak exercise oxygen consumption (V_O2) by expired gas analysis, a technique that is valid and reproducible, including in elderly patients with HFpEF [20]. According to the Fick equation, V_O2 is equal to the product of cardiac output (CO) and arterial–venous oxygen content difference (A-V_O2 Diff); therefore, the reduced peak V_O2 in patients with HFpEF may be caused by decreased CO or by decreased oxygen delivery to or impaired oxygen utilization by the exercising skeletal muscles.

The cause of decreased peak VO2 in elderly HFpEF patients has been attributed to reduced peak CO secondary to blunted chronotropic, lusitropic, inotropic, and vasodilator reserve [6,7], to reductions in both peak CO and A-VO2 Diff [8*,9,11], or primarily to reduced peak A-V_O2 Diff secondary to impaired skeletal muscle oxidative metabolism [5]. Haykowsky and colleagues found that compared with age-matched healthy controls [8*], the change in A-V_O2 Diff from rest to peak exercise was the strongest independent predictor of the reduced peak V_O2 in HFpEF patients [8*]. Furthermore, in a separate study, these investigators found that improved peak A-V_O2 Diff accounted for the most of the improvement in peak V_O2 following exercise training [21*]. This is supported by the work of Fujimoto et al who showed that exercise training in HFpEF patients was not associated with any significant change in CO [22]. Recently Dhakal et al., found that directly measured AV_O2 diff was the major determinant of exercise capacity in HFpEF and that these patients have abnormally low peripheral oxygen extraction during exercise compared to HFrEF subjects and normal controls [23].

Findings of another study indicate that improvements in peak V_O2 with exercise training in HFpEF are not associated with altered endothelial function or arterial stiffness, suggesting that skeletal muscle hypoperfusion, skeletal muscle atrophy, and/or abnormal muscle metabolism play an important role in the severe exercise intolerance experienced by HFpEF patients and its improvement with exercise training [21*]. Supporting this is the results of a recent meta-analysis of 6 randomized controlled trials of exercise training in patients with HFpEF revealed exercise training improved peak V_O2 and quality of life without any significant change in resting diastolic or systolic function [24*]. This may explain why drug trials in HFpEF to date, focused on influencing cardiovascular function have not improved exercise intolerance [12;13].

Aging, Obesity, and HFpEF

Aging is a systemic process affecting all organ systems and associated with significant alterations in body composition. Typically fat mass increases with age and peaks around age 60–75 years [17], whereas muscle mass and strength starts to decline progressively with a more accelerated loss after the age of 60 [18]. Visceral fat and intramuscular fat tend to increase, while subcutaneous fat in other regions of the body (abdomen, thigh, calves) decreases [19]. This change in body composition is worsened by concomitant disorders such as HF [25]. Recent studies have suggested underlying aging changes are important contributors to the HFpEF epidemic [14,26]. Obesity is one of the strongest risk factors for development of HFpEF, particularly among older women; overweight / obesity is present in about 85% of older HFpEF patients [27]. In obese older adults, the presence of excess fat mass and the age-related decrease of lean body mass exaggerate the above mentioned alterations [28]. Both regional and total adipose tissue has adverse consequents on organ function, overall system function, and outcomes. In addition to its effects on cardiovascular function, increased adiposity markedly impairs physical function and skeletal muscle composition and function.

Sarcopenic Obesity

Sarcopenic obesity, the coexistence of excess fat mass and decreased muscle mass, is not just a combination of two conditions, but is more related to cardio-metabolic and functional abnormalities, and is a concern in the aged society [29,30]. According to Baumgartner et al. criteria; sarcopenic-obesity characterizes individuals having 1) an appendicular skeletal muscle index (legs and arms muscle mass/height (m2) <2 standard deviation in comparison to a young adult reference group aged between 20 and 30 years old and 2) a percentage of body fat above the 60th percentile for the same gender and age [31].

Sarcopenic Obesity-Pathophysiology and Consequences

Aging is associated with a decline in a variety of neural, hormonal and environmental trophic signals to muscle. Physical inactivity, hormonal changes, pro-inflammatory state, malnutrition, loss of alpha-motor units in the central nervous system, and altered gene expression accelerate the loss of muscle mass and mass-specific strength [32].

Inflammation

Aging is associated with a systemic pro inflammatory state, and associated with increased levels of cytokines such as interleukin (IL)-6 and tumor necrosis factor (TNF)-α [33,34]. Furthermore, adipose tissue is an active metabolic tissue that secretes hormones and proteins. In adipose tissue, either adipocytes directly or infiltrating macrophages produces pro-inflammatory cytokines, such as IL-6 and TNF-α [35]. These cytokines have direct catabolic effects on skeletal muscle: TNF-α impairs muscle protein synthesis [36,37] and increases muscle protein degradation [38,39] while IL-6 increases muscle protein degradation [40]. It has also been demonstrated that TNF-α impairs endothelial function with a decreased blood and nutrient supply to skeletal muscle, thus reducing exercise endurance. Recently, the transforming growth factor- β related cytokine myostatin was identified as an important mediator of cardiac-induced muscle wasting in HFrEF [41]. Of note, genetically modified mice with enhanced myostatin expression in the myocardium showed skeletal muscle rarefaction, indicating that cardiac myostatin elaboration is sufficient to induce skeletal muscle wasting [41]. Thus, a pro-inflammatory state may be one of the key factors in creating a vicious cycle of decreased muscle strength among older adults.

Oxidative Stress

Aging is associated with a chronic state of oxidative stress, which activates profibrotic signaling pathways [42,43], and one of the major contributing factors to skeletal muscle decline [44]. Skeletal muscle continues to produce reactive oxygen species (ROS) during contractile activity. These phenomena happen together with age-related decline of the muscle enzymatic scavenger systems, thus producing an alteration of mitochondrial DNA and abnormalities in the electron transport system [45].

Altered endocrine function

A recent study showed that sarcopenic obesity is associated with decreased growth hormone (GH) secretion and has lower testosterone [46,47]. Low levels of these anabolic hormones have been reported positively associated with low muscle strength [48,49]. It is known that insulin like growth factor (IGF-1) plays an important role in muscle growth and repair [50]. Clinical and experimental studies showed that low testosterone resulting in lower protein synthesis and a loss of muscle mass [51].

Obesity

Obesity has multiple adverse consequences for skeletal muscle, including inflammation, oxidative stress, and insulin resistance (IR). Along with visceral fat accumulation, loss of skeletal muscle, which is the largest insulin-responsive target tissue, produces IR. Adding to this, increases in visceral fat may lead to higher secretion of pro-inflammatory adipokines that further promote IR as well as potentially direct catabolic effects on muscles [52,53]. Moreover, it has been hypothesized that muscle fat infiltration causes IR in obese individuals [53]. IR promotes muscle catabolism, mitochondrial dysfunction, and impairs protein synthesis in skeletal muscle.

Fatty infiltration of skeletal muscle is associated with reduced strength [54,55] and functional status [56], muscle dysfunction [55] and decreased contractility and motor unit recruitment [55], and interference in normal cellular signaling [57]. Furthermore, increased intermuscular fat is associated with reduced mitochondrial mass, biogenesis, and oxidative metabolism [58]. Increased adiposity is often associated with high circulating free fatty acids, which inhibit GH production and decrease plasma IGF-I [59,60]. Thus, a vicious circle between skeletal muscle loss and fat gain changes in body composition may lead to more sarcopenia and then to further metabolic problems and inflammation [61]. In addition, Paulus and Tschope recently proposed that co morbidities and especially obesity induce a systemic inflammatory state, which induces oxidative stress in the coronary microvascular endothelium [62**].Obesity is associated with several impairments in the microcirculation, including rarefaction and impaired endothelial function[63].

Lack of physical activity

Sedentary life-style is an important risk factor for obesity [64]. Obese persons also tend to be less physically active and this might contribute to the loss of muscle mass and strength at any age [65,66]. Furthermore, muscle atrophy leads to reduction in metabolic rate both at rest and during physical activity, thus further aggravating the sedentary state, all of which can cause obesity. However, the adverse effects of obesity on pathogenesis and outcomes appear to not be merely due to deconditioning.

Sarcopenic Obesity and Exercise Intolerance

Sarcopenic obesity can lead to multiple alterations in skeletal muscle; decreased muscle quality, with reduced relative number of type II fibers [67,68] and decreased capillary density [69], decreased muscle mass and strength, increased muscle catabolism and impaired muscle protein synthesis, increased accumulation of intermuscular fat [70], and alterations in mitochondrial mass, biogenesis and oxidative metabolism with mitochondrial dysfunction [71,72]; all associated with reduced strength [73], endurance, peak VO2, and mobility [74–76]. Both decreased muscle mass and decreased oxidative capacity of skeletal muscle with aging contribute to the observed 1% annual decline in maximal aerobic capacity [77]. In healthy persons, peak VO2 declines at the rate of 3 to 8% per decade after the age of 30 years, but adjustment for muscle mass substantially mitigates this decline.

These skeletal muscle abnormalities, an imbalance between increased muscle catabolism and attenuated muscle anabolism, likely are significant contributors to the genesis of symptoms of exercise limitation. These alterations influence both peripheral and ventilatory muscles, are present at rest, and deteriorate during exercise. This suggests that loss of muscle mass is a significant contributor to associated inflammation and may play an important role in the age-related process that leads to sarcopenia. These findings mirror the role of skeletal muscle abnormalities in HFpEF, which is closely associated with aging.

Sarcopenic Obesity and Exercise Intolerance in HFpEF

It is noteworthy that abnormalities in skeletal muscle mass and function are frequently present in patients with mild or moderate chronic HFrEF and likely may contribute to fatigue and exercise intolerance [78]. Of note, in animal models of HFrEF, these occur independent of physical activity, indicating that they are not merely due to deconditioning that likely also occurs in symptomatic HF. The multinational SICA-HF study shows that muscle wasting is a frequent co-morbidity among patients with chronic HFrEF and associated with worse exercise capacity in treadmill performance and in walking exercise tests [79].

As most of these studies have been performed in patients with HFrEF, the specific changes of skeletal muscle in patients with HFpEF are less clear. Progressive decline in muscle mass, strength and function that occurs with normal human aging is associated with increased frailty and HFpEF [25,80]. Rather than being simply a result of deconditioning, recent data suggest that frailty and muscular abnormalities may directly contribute to the HFpEF syndrome, a finding similar to HFrEF, where skeletal muscle abnormalities appears to be independent of physical activity and deconditioning [81]. Non-cardiac co-morbidities are highly prevalent in HFpEF [82*] and these co-morbidities can produce systemic pro inflammatory state [62**] and further accelerate the process of muscle wasting as seen in HFrEF.

Using dual energy x-ray absorptiometry, Haykowsky and colleagues found percent body fat and percent leg fat were significantly increased, whereas percent body lean and leg lean mass were significantly reduced in older HFpEF patients versus healthy controls [83*]. Moreover, the slope of the relation of peak VO2 with percent leg lean mass was markedly reduced in the HFpEF versus healthy control group [83*]. This suggests abnormalities of skeletal muscle mass and quality contribute to exercise intolerance in HFpEF. These investigators extended these results by directly characterizing thigh muscle composition using phase-contrast MRI, which showed abnormal fat infiltration into the thigh skeletal muscle and that this was associated with reduced peak exercise VO2 in HFpEF [84**] indicating presence of abnormal skeletal muscle composition.

Increased intermuscular fat may contribute to reduced peak VO2 in patients with HFpEF by way of a number of mechanisms as described previously. Heinonen et al, [85] using positron emission tomography, found that adipose tissue blood flow adjacent to the active muscles increased sevenfold during continuous isometric knee-extension exercise in non-obese younger healthy sedentary women. Thus, increased thigh intermuscular fat in older patients with HFpEF may “steal” blood that would normally be delivered to the active muscles during exercise and, thereby, reduces perfusive oxygen delivery to the thigh muscle. Adipose within skeletal muscle is also metabolically active, and can potentially impair oxidative metabolism and mitochondrial function. Together, these findings support the concept that altered skeletal muscle composition contributes to exercise intolerance in older patients with HFpEF.

Kitzman et al. also showed that compared with healthy subjects, older HFpEF patients had a shift in skeletal muscle fiber type distribution with a reduced percentage of slow twitch type I fibers and reduced type I-to-type-II fiber ratio and reduced capillary-to-fiber ratio [86**]. Furthermore, both capillary-to-fiber ratio and percentage of type I fibers were significant, independent predictors of peak VO2 (Figure 1) [86**]. Several investigators have reported that HFrEF patients have decreased oxidative type I fibers compared with healthy control subjects [87–89], and that this is related to peak V_O2 [90]. Compared with type II fibers, type I fibers, which were found to be reduced in HFpEF, have greater oxidative capacity and mitochondrial density and contribute disproportionately to the ability to perform sustained aerobic exercise. Recently, Bowen et al showed that in a Dahl salt-sensitive rats, HFpEF is associated with significant molecular, mitochondrial, and histological alterations in the diaphragm and soleus. [91**]. Importantly, exercise training was able to prevent skeletal muscle contractile dysfunction in both the diaphragm and soleus, and this was associated with preserved mitochondrial function. Collectively, therefore, these findings have important implications for better understanding the pathophysiology of HFpEF [86**, 91**].

Figure 1.

Relationship of capillary-to-fiber ratio (A) and percentage of type I muscle fibers (B) with peak O₂ uptake (VO₂) in older patients with heart failure with preserved ejection fraction (■) and age-matched healthy control subjects (▲).

From Kitzman DW, Nicklas B, Kraus WE, Lyles MF, Eggebeen J, Morgan TM et al. Skeletal muscle abnormalities and exercise intolerance in older patients with heart failure and preserved ejection fraction. Am J Physiol Heart Circ Physiol 2014;306:H1364-70, with permission from The American Physiological Society.

In aging and in HF, muscle blood flow (perfusive and diffusive O2 delivery) assumes an important role in limiting VO2 kinetics [92]. Therefore, the reduced capillary-to-fiber ratio in HFpEF patients, also known to be associated with sarcopenic obesity, would be expected to result in a decreased diffusive capacity for O2 transport to active skeletal muscle during exercise and limit exercise capacity [93]. Potential causes for the skeletal muscle abnormalities in HFpEF might include neuroendocrine activation, sympathetic overdrive, oxidative stress, inflammation, abnormal Ca2+ cycling and excitation-contraction coupling, and deconditioning [90]. Of note, the reduced microvascular density in skeletal muscle in older HFpEF patients parallels a similar finding in cardiac muscle as reported by Mohammed et al [94**]. This suggests the possibility of a common systemic factor that serves as a trigger for HFpEF, and adds further support to HFpEF as a likely systemic disorder [95*].

Loss of skeletal muscle mass and increased adiposity in old HFpEF patients are concerning because this can exacerbate physical inactivity. Even if they are not primarily caused by physical inactivity, many of these changes are further worsened by sedentary behaviors, so the symptoms and limitation are propagated as the older person limits their physical exertions. This may be another example of vicious cycles which of characteristerizes geriatric syndromes [96].

Future Perspectives

Understanding and addressing the role of sarcopenic obesity in HFpEF presents a major opportunity, because drug trials in HFpEF to date, focused on influencing cardiovascular function, have not improved exercise intolerance. Thus, a focus on sarcopenic obesity in HFpEF, while contrary to the traditional paradigm, could yield novel, potentially modifiable therapeutic targets.

Aerobic and resistance exercise programs

There is strong evidence that exercise training in patients with sarcopenic obesity in older adults improves physical function [97]. The results of the Lifestyle Interventions and Independence for Elders Pilot (LIFE-P) study [98] demonstrated that an intervention of structured physical activity improves physical performance scores in a group of 70- to 89-year-old participants. In as little as 12 weeks, resistance training two or three days a week can result in muscle hypertrophy and increased cross-sectional area of both type I and type II fibers essential for both muscular endurance and strength [99]. Davidson et al, conducted a 6-month investigation to determine the independent and combined effects of resistance and aerobic training on functional limitations in abdominally obese older men and women [100]. The greatest loss in fat mass occurred in the combined training, and gain in skeletal muscle occurred in the resistance training and combined training groups at 6 months. Hence, functional improvements are enhanced with the addition of resistance training to exercise programs.

In patients with HFrEF, exercise interventions, primarily aerobic exercise training, have resulted in beneficial molecular and functional changes in skeletal muscle including improved oxidative function and higher mitochondrial number and density [16,87–90,101,102], increased IGF-1 expression [103] and reduced local oxidative stress and inflammation [104]. These molecular changes correlate with increased exercise performance manifested by longer exercise duration and higher peak VO2, as well as improved endothelial function [103,105]. As most of these studies have been performed in patients with HFrEF, the specific effect of exercise interventions in patients with HFpEF are unclear.

Exercise Therapy in HFpEF

Kitzman and colleagues reported the first single-center, medically supervised, randomized controlled trial comparing the effects of 16 weeks of endurance exercise training versus attention control in 53 older (mean age = 70 years) patients with HFpEF. The exercise training increased peak VO2, ventilatory anaerobic threshold, 6-minute walk distance, and physical quality-of-life scores [15]. Similar results for these end-points were seen in a multicenter study of 64 HFpEF patients randomized to 3 months of combined exercise training and strength training [106]. In a second, separate, randomized, attention-controlled, single- blind trial of 4 months upper and lower extremity endurance exercise training reported by Kitzman et al. exercise training resulted in a significant increase in peak VO2 without altering carotid arterial stiffness or brachial artery flow mediated dilation [107].

Taken together, exercise training with or without resistance training appears to be an effective non-pharmacologic therapy in clinically stable patients with HFpEF to improve exercise tolerance and possibly quality of life. Future studies should build on these data to understand optimal modality of exercise and ways to enhance the favorable response further..

Dietary intervention

Protein supplementation, in combination with resistance exercise, enhances muscle protein synthesis and improves body composition by increasing lean mass in relation to fat mass [108]. Supplementation with leucine, which appears to be the most potent branched-chain amino acid for stimulation of protein synthesis, has also been proposed for the prevention of sarcopenia [109]. To date, evidence is relatively sparse about the comparison of macronutrient manipulation and conventional caloric restriction in terms of weight loss and effects on body composition and especially on the phenotype of sarcopenic obesity, and is absent regarding older heart failure patients.

Caloric restriction

Intentional weight loss via caloric restriction has the potential to reduce excess adipose and improve many of the related abnormalities above. However, weight loss is controversial in patients with HF. Many studies suggest that overweight and obesity in established HF is associated with improved survival, whereas underweight and normal weights are associated with worsened survival. More recently, a U-shaped curve relating survival to body weight has shown excess mortality at the extremes, morbid obesity and cachexia. These trends are seen in HFpEF as well [110]. In small studies with variable controls, bariatric surgery appears to improve symptoms of HF in patients with morbid obesity and HF and potentially prevent overt HF. However, dietary weight loss in HF patients remains controversial, and no studies have reported examining this.

However, in non-HF patients, improvements in body composition and physical function have been reported consistently in patients without HF, including older persons and women. A meta-analysis of 18 randomized controlled trials of exercise studies with or without diet components indicated that 3–18 month programs that included aerobic and strengthening exercise (2–3 days per week) with caloric restriction (typically 750 kcal deficit/day), induced the greatest change in functional performance measures compared with exercise or diet alone [111]. Importantly, caloric restriction results in significant loss of skeletal muscle along with adipose, which could have adverse long term consequences in HF. Few studies showed compared to diet or the aerobic exercise [112], the combination of diet–exercise improvements in physical performance test and peak VO2. Thus, while there is promise for multimodal exercise coupled with diet for counteracting sarocpenic obesity and improving mobility, physical function and exercise capacity in older, obese adults in general, this is untested in HF [97].

Hormonal therapy

Studies of Rudman et al. showed that GH administration results in increased lean body mass and decreased fat-to-muscle ratio in older subjects [113]. Administration of these hormones to aged animals restores cellular protein synthesis, increases lean body mass, decreases adiposity, improves endothelial function, improves endurance and contractile function. Likewise, in patients with HIV-associated lipodystrophy, GH administration also increased lean mass and decreased adiposity [114]. Finally, in a recent randomized trial in patients with HFrEF, GH replacement increased peak VO2 and exercise duration, and improved quality of life [115]. The pleiotropic actions of GH and IGF-I exerted in the heart, skeletal muscle, and vascular bed could account for the effects of GH on enhancing exercise capacity.

A meta-analysis of modestly sized randomized, placebo-controlled trials showed that testosterone supplementation in patients with HFrEF is associated with an increase of ≈54 m on the 6min walk test, as well as improvements in peak VO2 and NYHA class [116].

Therapeutically, injection of a myostatin-blocking antibody in mice with preexisting HF preserved muscle mass [117]. Thus, myostatin inhibition might be a medically relevant avenue for the treatment of muscle wasting in HF. This needs to be verified in larger cohorts of patients with HF. However, a number of clinical trials that target myostatin in older patients with sarcopenia associated with other chronic disorders are ongoing. The results of these may inform future trials in older patients with HFpEF.

Conclusion

HFpEF is a true geriatric syndrome, with complex, multi-factorial pathophysiology and clinical heterogeneities. In addition to cardiac dysfunction, abnormalities in peripheral function including vascular, skeletal muscle, and adipose tissue may contribute substantially to pathogenesis and outcomes. A revised paradigm that incorporates the full range of abnormalities and targets non-cardiac as well as cardiac mechanisms, and searches for common linkages between these, may lead to improved understanding and advances in treatment. Clinical trials aimed specifically at addressing sarcopenia and excess adiposity in patients with HFpEF could help to ameliorate physical functional impairments and disability in patients with this important and increasingly prevalent syndrome in older patients.