Reduced lean body mass: a potential modifiable contributor to the pathophysiology of heart failure

A thorough understanding of the circulatory system as a functional unit implies integrative thinking. Virtually every organ and tissue in the human body can influence and be influenced by salient cardiovascular variables. Yet, the fundamental aim of cardiovascular pathophysiology is not merely descriptive. Causal relationships in complex living organisms may largely vary in the magnitude of the effect size, from trivial (or redundant) to crucial. The discernment of primary factors that predominantly explain and limit the functions of the circulatory system intellectually empowers us to modify outcomes as desired. In the present article, we will focus on the potential role of lean body mass (LBM), a variable plausibly amenable to change, in heart failure (HF). Body composition is typically categorized into three mass components: bone, fat, and lean body mass (LBM). The latter comprises the bulk of muscles, organs, and fluids, representing the largest fraction (55%–95%) of body mass in healthy non-obese individuals, as determined via dual-energy X-ray absorptiometry (DXA). Within LBM, the prevailing tissue is the skeletal muscle. The concept of LBM was indeed originally conceived to represent the ‘active’ mass of the body. In fact, LBM strongly determines resting metabolic rate, approximately entailing +25 kcal/day per +1 kg of LBM. Hence, the relationship between LBM and the maximal metabolic capacity of the human body, as represented by peak O2 consumption (VO2peak), could reasonably be foreseen. This is not the case, however, according to experimental studies in men, which overwhelmingly constitute the basis of our knowledge in human physiology.1 LBM is not a limiting factor of VO2peak, and thus no relationship is expected in healthy men.1 They may attain VO2peak with only ∼50% of total muscle mass being activated, e.g. with leg exercise alone2—a statement not applicable to heart failure (HF) patients, who require simultaneous arm and leg exercise to reach VO2peak.3 The preceding statement in healthy individuals may seem paradoxical since the activation of muscle fibers is known to elicit the following concatenation: skeletal muscle vasodilation, decreased total peripheral resistance (TPR) and cardiac afterload, increased stroke volume, and cardiac output, ultimately leading to enhanced O2 delivery and consumption. The larger the muscle mass activated, the greater the O2 delivery and consumption—it could be reasonably hypothesized. Yet, the evidence demonstrates that the addition of arm to leg exercise does not increase VO2peak in men.2 Despite more muscle mass is recruited with simultaneous arm and leg exercise, TPR and cardiac afterload are not further reduced, and consequently peak cardiac output (Qpeak) and O2 delivery are not substantially augmented, compared with leg exercise alone.2 Beyond a certain threshold of muscle mass activation, skeletal muscle vasodilation is partly restrained by the sympathetic system in men, preserving the high-pressure gradient required for efficient blood flow distribution during exercise.2 Therefore, men generally have a ‘massive surplus’ of skeletal muscle relative to their capacity to circulate the available blood volume. The question arises as to whether the physiology of cardiac and aerobic capacities in men can be extrapolated to women. The female sex is characterized by markedly low LBM in absolute and relative (to body mass) units, resulting in a clear LBM gap between sexes.1,4 We explored the aforementioned question in a sample (n ≥ 60) of healthy women and men matched by age, physical activity, and VO2peak.1,4 Strong positive relationships between LBM, Qpeak, and VO2peak were found in women, and none was observed in men.1 Moreover, LBM was exclusively associated in women with key structural and functional attributes of the circulatory system that determine Qpeak and VO2peak.4 These mainly included positive relationships between LBM and the internal dimension and relaxation properties of the left ventricle (LV), as well as a negative relationship between LBM and TPR at peak exercise. Importantly, these associations were independent of body fat percentage and established cardiovascular risk factors (body mass index, blood pressure, heart rate, total cholesterol, glucose).4 Furthermore, repeated analyses including fat body mass instead of LBM yielded fewer and weaker relationships with cardiovascular variables.4 Collectively considered, the tenet of larger LBM equating to proportionally enhanced central and peripheral cardiovascular capacity is fulfilled in women. These findings concur with early evidence of concurrent increases in LBM and VO2peak (and presumably Qpeak) in response to resistance training in women but not in men. While further experimental studies are required to provide conclusive evidence, LBM might be a limiting factor of and therefore a fundamental target to improve the overarching function of the circulatory system in the female population—perhaps additionally comprising men with low (female-like) LBM.1,4 Numerous phenotypic alterations may take a predominant role in the development and progression of a multifaceted disease such as HF. Low LBM might be a salient trait with broad-spectrum pathophysiological implications, notably in HF with preserved ejection fraction (HFpEF).5 While still speculative, women could be predisposed to prevail among HFpEF patients owing, among other factors, to their limited (and limiting) LBM. The systemic vasodilatory capacity of female HFpEF patients might be inherently restrained in proportion to the sex-specific LBM,1 implying the shrinkage of stroke volume, cardiac reserve, and aerobic exercise capacity.1,4 Namely, low LBM is hypothesized to curtail the main functional attributes of the circulatory system (Figure 1). In addition, a circulatory system perpetually irrigating less ‘active’ mass and thereby less capable of reducing TPR must generate higher pressure gradients for a given systemic blood flow at rest and during exercise.1 Incipient hypertensive modifications in the heart and vessels of women with low LBM may thus be expected, particularly considering the typical long-lived nature of cardiovascular disease in women, paving the way toward advanced LV concentric and vascular remodeling prevalently observed in older HFpEF patients. Ultimately, severe exercise intolerance, the prominent chronic HFpEF symptom, could be the natural consequence of a ubiquitous limiting factor (low LBM), which could also hinder the benefits of established pharmacotherapy in HF. Unless the hypothesized limiting factor is enhanced, the prognosis of HFpEF might not be greatly improved. Hypothesized mechanistic link between lean body mass (LBM) and cardiac and aerobic capacities. Reduced LBM, notably in women, entailing a curtailment of skeletal muscle mass exceeding the threshold to become a limiting factor, may restrain the overall muscle contraction-induced vasodilatory capacity to decrease total peripheral resistance (TPRpeak) and cardiac afterload at peak exercise, proportionally limiting peak cardiac output (Qpeak) and O2 consumption (VO2peak). MAPpeak, mean arterial pressure at peak exercise Theoretical constructs in physiology are useful as long as they serve as working hypotheses that evoke new questions, opening lines of feasible and plausibly relevant research. To this end, we should first ponder the specific evidence currently available. In this regard, the role of LBM as a potential pathophysiological factor in HFpEF has been sparsely investigated. A decade ago, the positive relationship between LBM (measured by DXA) and VO2peak in HFpEF patients mainly including women (n = 41) was reported.6 However, the same research group noted no association between the cross-sectional area of upper leg skeletal muscles (measured by magnetic resonance imaging) and VO2peak in a smaller HFpEF group (n = 23).7 Whether the mass rather than the cross-sectional area of skeletal muscle is associated with VO2peak remains to be elucidated. Notwithstanding, in a larger sample of HFpEF patients (n = 85), LBM was positively related to LV diastolic function (E/e’, a primary determinant of LV filling and Qpeak) and VO2peak.8 Provided that LBM independently circumscribes the upper limit of cardiac and aerobic capacities in a large fraction of HFpEF patients, the elementary and pragmatic question ensues: can LBM be increased, or at least its atrophy prevented, in this population? Scarce evidence on this question indicates that the addition of resistance training—i.e. the lifestyle intervention eliciting the greatest impact on skeletal muscle mass— to a caloric restriction program does not attenuate the loss of LBM in obese HFpEF patients, albeit muscle strength is increased.9 Of note, the prescribed intensity and number of repetitions (collectively reflecting the ‘dose’) of resistance training are typically low in studies including HF patients,10 which may involve insufficient stimuli for muscle growth. Indeed, a higher dose of resistance training leads to robust LBM gains in the general elderly population. Nonetheless, little is known regarding LBM adaptations in patients with HF. In patients with HF and reduced ejection fraction (HFrEF), low-dose resistance training is known to induce large increments (15%–25%) in VO2peak, without negatively affecting blood pressure or arterial stiffness,10 yet its effects on LBM or surrogates have been seldom determined and remain inconclusive.10 Assuming minor or null LBM increments might be possibly elicited via low-dose resistance training in HFpEF patients, would the foreseen neuromuscular adaptations leading to increased strength (via augmented recruitment of muscle fibers) improve the functional capacity of the circulatory system? Certainly, much remains to be ascertained on this topic, albeit no remarkable methodological challenge is hindering a prompt resolution of the herein exposed knowledge gap, with the compelling prospect of a substantial clinical impact. The authors apologize for not including a more comprehensive list of references due to the article format’s restrictions. Candela Diaz-Canestro, PhD; Hung-Fat Tse, MD, PhD; Kai-Hang Yiu, MD, PhD; and David Montero, PhD Early Career Scheme (106210224 to D.M.) and Seed Fund (104006024 to D.M.).

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