Muscular strength (MusS) has been increasingly utilized to stratify cardiovascular (CV) and metabolic risks in healthy individuals and in those with acute and chronic conditions and aging-associated cardiometabolic abnormalities.1 Importantly, the assessment of MusS may be convenient and relatively inexpensive. Its assessment is required for the evaluation and identification of nutritional status and body composition abnormalities such as frailty, sarcopenia, and sarcopenic obesity; known contributors to reduced quality of life and increased hospitalization; morbidity and mortality; and several cardiometabolic diseases.1–8 MusS has also been associated with cardiometabolic risk factors,1 ultimately proposing MusS as a potential therapeutic target using nonpharmacologic strategies, such as exercise training, increased physical activity, and dietary changes.
This review discusses the role of MusS on cardiovascular disease (CVD) risk factors, CVD, CVD-related mortality, and all-cause mortality. We then review the role of resistance exercise training (RT) on the risk of CVD risk factors, CVD, and CVD-related mortality, and all-cause mortality, and finally discuss the role of MusS in identifying nutritional status abnormalities such as frailty and sarcopenia, major risk factors for CVD and all-cause mortality.
ASSESSMENT OF MUSCULAR STRENGTH USING HANDGRIP STRENGTH
MusS can be conveniently, reliably, and safely estimated by measuring handgrip strength (HGS) using a dynamometer.9–12 HGS can be used alone, or in combination with other tests,9 and even though HGS does not provide a measure of whole body MusS, it is well correlated with measures of MusS obtained from the arm, leg, and trunk.10 Thus, it is a simple, highly reproducible, and inexpensive tool that can be easily implemented in clinical practice. The HGS procedure requires a maximal isometric contraction of the forearm, performed in either the standing or sitting positions, without the elbows being supported.11 In populations, such as those critically ill, that are unable to maintain their elbows unsupported during HGS, elbows may be supported in a bed or armchair, to still obtain reasonable accuracy in the assessment of MusS.12 Individuals are instructed to squeeze the dynamometer for 3-5 sec and the maximal value of three measurements is recorded. Several age- and sex-adjusted cut-off values have been developed to classify the level of individual MusS.
MUSCULAR STRENGTH AND CVD
The role of MusS on the incidence of CVD and CVD-related mortality has been investigated extensively in the recent years.1,13 An analysis of 38 588 men suggested that dynapenia in youth can predict the risk of CVD and CVD-related events in adults.14 Individuals with greater MusS in youth, measured using a standardized score of three isometric MusS tests (HGS, elbow flexion, and knee extension), had a 12% relative risk (RR) reduction for CVD as adults, but without a significant association with CVD-related mortality.14 Although dynapenia was not associated with incident CVD, it was associated with a 31% RR increase for CVD mortality14; these results were independent of estimated cardiorespiratory fitness (CRF).14 This is essential to clarify as most studies, even those with extremely large sample size, do not adjust their findings for CRF, making it difficult to distinguish whether the associations between MusS and clinical outcomes are mediated by CRF.
In a large analysis of 1 160 082 healthy young adults (mean 18 yr) on the risk of CVD, particularly coronary heart disease (CHD) and cerebrovascular diseases, after a 25-yr follow-up (mean 44 yr),15 MusS assessed with HGS was associated with significantly lower risk for CHD and intracerebral infarction.15 In a very recent analysis of the Aerobics Center Longitudinal Study (ACLS) in 8116 men, the middle tertile of MusS was associated with a substantial reduction also for the risk of sudden cardiac death, even after adjustments for major comorbidities and aerobic physical activity level.16 Moreover, reduced MusS has been recently associated with greater risk for heart failure (HF).17 In an analysis of the UK Biobank data of 374 493 participants, during a mean follow-up of 4.1 yr, every 5-kg increase of HGS was associated with a 19% RR reduction in developing HF, even after adjustment for several potential confounders (Figure 1).17
Although MusS remains a very strong prognostic determinant of health, preserving muscular fitness over the course of the lifespan would be also desirable. A recent retrospective analysis of 1104 active adult men aged 21-66 yr using an assessment that combines both MusS and muscular fitness, such as push-up capacity, found that greater push-up capacity was associated with a marked lower risk for CVD.18 Specifically, those individuals able to complete >40 push-ups presented an impressive 96% RR reduction for CVD compared with those who were unable to complete >10 push-ups.18 Of note, the study also presented important limitations, particularly, the different categories of push-up capacity also presented several significant differences in more typical CVD risk factors, which prevented allowing for a conclusion if push-up capacity was an independent predictor for future CVD.18
In patients with established cardiometabolic diseases, the role of MusS on CVD and CVD-related mortality has not been extensively investigated. In patients with pre-diabetes and diabetes, every 1-kg increase of HGS was associated with a progressive reduction in CVD events, in both men and women, even after adjustments for anthropometrics and age (Figure 2).19 Particularly, a 12% and a 30% RR reduction for CVD-related mortality for each 1-kg increase of HGS was found in men and women, respectively.19 Moreover, the higher quintiles for HGS were associated with marked reductions of the composite CVD outcome (ie, CVD-related mortality, myocardial infarction, and stroke) compared with the lower quintiles, but without a statistically significant difference between the fourth and fifth quintiles of HGS. Importantly, no assessments of CRF and physical fitness were performed to determine whether the effects of MusS were independent of CRF.19
MusS remains a strong risk factor in primary prevention; however, its association with clinical outcomes in patients with established CVD is only recently being investigated. In a study including 1314 patients with established CHD, hospitalized for acute coronary syndrome or coronary artery bypass grafting, a greater MusS (ie, quadriceps isometric strength) was associated with reduced risk for CVD-related mortality.20 Specifically, for every 10% increase in MusS, an impressive 34% RR reduction for CVD mortality was observed, even after adjustment for key prognostic factors.20
MUSCULAR STRENGTH AND ALL-CAUSE MORTALITY
MusS has also been investigated with regard to its effects on all-cause mortality in health and disease.21–23 Over 30 yr ago, an analysis of 82 older women admitted to the hospital to the geriatric unit found that an HGS cut-off of ≥5 kg was associated with a more favorable prognosis.6 The study was clearly limited by the small sample size; however, similar findings were replicated over the years. In a study investigating the effects of HGS in predicting survival in older adults (>75 yr), dynapenia was associated with an 86% RR increase for all-cause mortality.7 In the study discussed previously of 38 588 healthy younger men, in addition to being associated with CVD prevalence and CVD-related mortality, MusS was also associated with all-cause mortality.14 Those individuals with low MusS in youth presented an 18% RR increase for all-cause mortality; however, no significant associations were found in those with greater MusS.14
In a recent meta-analysis of almost 2 million men and women, greater MusS, defined using HGS, was associated with a 31% RR reduction for all-cause mortality. Interestingly, the beneficial effects of HGS were more pronounced in women (40% RR reduction) compared with men (31% RR reduction), suggesting that perhaps MusS could exert even stronger protective effects in women.24
In an analysis of 1071 men followed up for 40 yr, both the baseline low levels of MusS, as well as a decline overtime of MusS, were associated with a significant increase in all-cause mortality.8 Particularly, in men <60 yr, the progressive loss of MusS was a greater predictor for all-cause mortality; in fact, the survivors presented a decline of about 0.2 kg/yr of HGS, while those who died presented a significantly greater loss of 1.5 kg/yr. In those individuals >60 yr, reduced baseline MusS level was the predominant factor driving the association with reduced survival.8 Importantly, these associations persisted even after adjustments of skeletal muscle mass estimated using 24-hr creatinine excretion.8
While older data suggested that MusS is dependent on lean mass (LM), due to the strong correlation between these two variables,25 a more recent study suggests that MusS and LM affect clinical outcomes independent of each other. To support this concept, an analysis of the Health, Aging and Body Composition Study including 2292 participants, well distributed between men and women, aged 70-79 yr, found that MusS (ie, quadriceps strength and HGS) was strongly associated with mortality (Figure 3), while LM assessed with both computerized tomography scan and dual-energy x-ray absorptiometry was not.26 Another study of 197 374 men and women ≥ 65 yr confirmed such findings, with increased mortality in those with lower HGS, independent of anthropometrics, such as muscle area and body mass index.27 Indeed, in the aging population, reductions in MusS precede loss of muscle mass.26 Furthermore, reductions in force per unit muscle area have been reported in both aging28 and disease populations.29 Therefore, MusS, independent of muscle mass, may be a therapeutic target for improving outcomes in patient populations.
Additional studies have found that frailty is associated with poor outcomes in patients with established CVD; however, they also investigated whether the assessment of MusS alone could outperform the overall assessment of frailty. In 309 inpatients ≥70 yr with ≥2-vessel CHD, frailty was associated with poor prognosis, defined as all-cause mortality at 6 mo.30 When the different items used to assess frailty were studied individually, dynapenia and low gait speed outperformed the comprehensive frailty scores being used.30 In the study discussed earlier of 1314 individuals with CHD, a greater MusS was also associated with a lower risk for all-cause mortality.20
In patients with HF, in which the role of body composition and MusS has been mostly investigated with regard to their contribution to reduced CRF,2,31–34 MusS has also been shown to predict clinical events. In 122 patients with severe HF with reduced ejection fraction, a greater MusS has been associated with improved long-term survival, and its ability to predict outcomes was even superior to measures of CRF (ie, peak oxygen uptake).35 The role of MusS in predicting clinical outcomes in patients with HF with preserved ejection fraction remains speculative.
MUSCULAR STRENGTH AND CVD RISK FACTORS
MusS has been associated with several CVD risk factors and chronic diseases associated with increased CVD risk, including metabolic syndrome (MetS), type 2 diabetes mellitus (T2DM), hypertension (HTN), and obesity. An analysis of the ACLS, including 8570 healthy men between 25 and 80 yr of age, investigated the association of MusS with risk of having MetS.36 MusS was divided in quartiles, and after adjustments for comorbidities and maximal treadmill time, the highest quartile of MusS presented a 24% RR reduction for incident MetS compared with the lowest quartile.36 Similar results were further confirmed in other studies,37 including in Asian individuals.38,39
With regard to T2DM, an analysis of the Health, Aging, and Body Composition study found that both men and women with T2DM had significantly reduced MusS compared with non-T2DM individuals.40 Greater duration of T2DM (≥6 yr) and poor glycemic control (glycated hemoglobin ≥8%) were associated with a further reduction of MusS.40 An additional study of 1840 older adults 70-79 yr of age found that the progressive reduction of MusS, typical of the physiologic aging process, occurs at an accelerated rate in patients with T2DM.41 These results were confirmed in later studies.42,43
Dynapenia has also been associated with increased risk for HTN; however, the evidence is conflicting on whether MusS is an independent risk factor for HTN. In 4147 men (20-82 yr) followed up for a mean of 19 yr, in individuals with pre-HTN, the middle and high tertiles of MusS were associated with a significantly lower risk for incident HTN, while MusS was not predictive for HTN in normotensive individuals.44 It is important to note that, after statistical adjustments for CRF, MusS was no longer significantly associated with the risk for HTN, even in those individuals with pre-HTN.44 Another study presenting conflicting data investigated 4597 individuals participating in the National Health and Nutrition Examination Survey45 reported HGS was positively associated with diastolic blood pressure in both men and women.45 In men, greater MusS was associated with a greater 31% RR increase for HTN; however, no associations were found in women.45
Obesity is a major risk factor for CVD46,47 and the relationship between its risk and MusS has been investigated only in a few studies. A study of 606 individuals from the Physical Activity Longitudinal Study found that, after a follow-up of 20 yr, lower MusS was associated with a 78% RR increase to gain ≥10 kg.48 Of note, the weight gain and height at follow-up were self-reported,48 clearly requiring more study to confirm these findings. In a study using a more accurate assessment of body composition using underwater weighing or 7-site skinfold measurements, the authors reported similar findings in men (women were not enrolled).49 Specifically, the highest quintile of MusS was associated with a 70% RR reduction to present an excess body fat, defined as being ≥25% body fat, compared with the lowest quintile.49 Low-grade systemic inflammation, also a known risk factor for CVD, has also been negatively associated with MusS.50
RESISTANCE TRAINING AND CVD RISK
The most effective tool to improve MusS in both young and older adults remains RT.1,51–55 Furthermore, RT can modulate both typical CVD risk factors56–60 and CRF,61 and recent analyses suggest potential benefits also on CVD and all-cause mortality.62,63 Whether the benefits on clinical outcomes are due to the beneficial effects on MusS, however, remains unclear.
In an analysis of 7418 individuals followed up for a mean of 4 yr, RT was associated with a lower risk for MetS.57 Meeting the RT guidelines was associated with a significant 17% RR reduction for MetS.57 Importantly, larger amounts of RT were not predictive for further reduction of MetS risk.57 Recently, RT has been also associated with lower risk for hypercholesterolemia.56 Similar to what was noted for the risk of MetS, meeting the guidelines for RT was associated with a 13% RR reduction risk to develop hypercholesterolemia.56 Importantly, both studies used the self-reported level of RT,56,57 clearly requiring validation in prospective clinical trials. RT has also been associated with reduced blood pressure64,65 as well as improved glycemic control.66,67
An analysis of the ACLS including 12 591 participants found that even low levels of RT were associated with reduced risk for CVD and all-cause mortality, even when conducting <1 hr/wk of RT, independent of aerobic exercise,62 whereas there appeared to be a loss of benefit at very high levels of RT. The beneficial effects, however, of low doses of RT were at least partially mediated by a reduction in body mass index. Another analysis that included women enrolled in the Women's Health Study also found that RT was associated with beneficial effects; however, very high levels of RT (>150 min/wk) did not confer additional benefits.63
MUSCULAR STRENGTH TO IDENTIFY NUTRITIONAL STATUS ABNORMALITIES ASSOCIATED WITH INCREASED CV RISK
HGS has been growingly utilized to identify nutritional status abnormalities, such as frailty and sarcopenia. Both conditions are associated with increased risk for CVD and all-cause mortality in apparently healthy individuals as well as in those with acute and chronic diseases.
Frailty reflects a state of decreased physiologic reserve and increased vulnerability to stressors.68 Frailty is associated with poor prognosis in a number of acute and chronic conditions, highly prevalent in older adults, but also increasing in younger populations. Importantly, frailty is associated with increased risk to develop CVD and markedly reduced survival. Frailty has been consistently associated with a >2-fold RR for CVD in primary prevention, but also in those with established CVD.30 A study of 3135 community-dwelling older men, investigating the causes of death in frail individuals, found that about 35% of deaths were attributed to CVD,69 highlighting the high CV risk that frailty poses, particularly in older adults. Another recent systematic review and meta-analysis of 19 studies found that, in addition to the increased CV risk,69 frailty was associated with an increased risk of all–cause mortality, even when different diagnostic criteria for frailty were utilized.70 Another study also found that, in addition to baseline frailty status, changes in frailty status at 1 yr strongly predict survival at 6 yr.71
The identification of frailty and its monitoring over time typically requires a comprehensive measure of MusS associated with an assessment of functional capacity and muscular fitness, and a history of unintentional weight loss, with the Fried definition of frailty remaining the most commonly used in both research and clinical practice.9 Fried and colleagues9 first described the phenotype of frailty in 5317 individuals ≥65 yr, finding an overall prevalence of about 7%. Importantly, the presence of frailty was independently associated with worse quality of life and increased risk of falls, all-cause mortality, and hospitalizations.9 Following this important analysis, the identification of frailty and the validation of the Fried criteria were performed in other studies,72,73 confirming the high prevalence of the condition and the related poor outcomes associated with frailty.
More recently, a meta-analysis investigating the prevalence of frailty found a variable value with an overall pooled prevalence among all studies of 18%.74 Such data suggested a greater number of individuals with frailty compared with that described previously,9 further emphasizing the importance of using MusS to identify frailty in older adults for potential interventions.
Similar to frailty, sarcopenia has been growingly associated with increased CV risk and all-cause mortality in apparently healthy individuals as well as in those with established diseases.2,4 In a study of 4425 older adults, mean 70 yr, in addition to finding a high prevalence of sarcopenia of 37%, the presence of sarcopenia corresponded with worse prognosis.75 Presence of sarcopenia was associated with an increased risk for CVD-related mortality in women, but not in men, while in both women and men sarcopenia was associated with an increased risk for all-cause mortality by a 32% RR increase.75 Importantly, such association could not be explained by differences in body mass index nor waist circumference.75 In a very recent analysis investigating the role of sarcopenia on CV risk, individuals with sarcopenia were significantly more likely to present a high CV risk score (ie, >10%) using the American College of Cardiology/American Heart Association guidelines.76 Furthermore, sarcopenia remains a major contributor to reduced quality of life and exercise intolerance in apparently healthy individuals as well as in those with established CVD.2,4,31
Because sarcopenia is a strong negative prognosticator for CVD and all-cause mortality, its early identification would allow for potential interventions, ultimately reducing sarcopenia-associated morbidity and mortality. As described later, reduced MusS assessed with HGS remains a key diagnostic criterion for sarcopenia.2,3 Importantly, sarcopenia was initially described as a physiologic process characterized by LM loss due to aging77; however, more recent data suggest that sarcopenia can also be present in younger individuals, particularly in those with extremely limited physical activity and increased adiposity.2,5
The definition of sarcopenia has evolved over the years. While in the past the definition of sarcopenia required the reduction of LM, particularly of appendicular LM (ie, LM of arms and legs),77 the most recent definition of sarcopenia requires a reduction in HGS as key criteria: <27 kg for men and <16 kg for women.2,3 A reduction of HGS alone suggests a probable presence of sarcopenia; however, it does not allow clinicians and researchers to make a conclusive diagnosis, requiring at least one of the following additional criteria: (1) a reduction of total appendicular LM (<20 kg for men and <15 for women) or appendicular LM index (<7 kg/m2 for men and <6 kg/m2 for women); and (2) low physical performance (gait speed ≤0.8 m/s, short physical performance battery ≤8 points, Timed-Up and Go test ≥20 sec, or 400-m walk test that cannot be completed or completed with ≥6 min). When one of these two criteria is met, in addition to reduced HGS, the diagnosis of sarcopenia is confirmed; when all three criteria are met sarcopenia is then considered severe.2,3
The term “sarcopenia” is often used interchangeably with cachexia; however, the latter is typically associated with unintentional weight loss in the 6-12 mo prior to its assessment, with concomitant LM and fat mass losses.78 Both conditions are characterized by reduced CRF and MusS; however, recent data suggest that sarcopenia may be associated with greater impairments in CRF and MusS than cachexia, at least in patients with concomitant HF.2,32,79
NUTRITIONAL STRATEGIES INCLUDING WEIGHT LOSS AND MUSCULAR STRENGTH
The role of RT to improve MusS has been largely investigated showing a dose-response effect of RT on muscle hypertrophy80 as well as MusS,81 and ultimately improvements in CV risk, as discussed previously. Little is known on the effects of dietary interventions to increase MusS in patients with dynapenia. Few dietary interventions have shown, however, promising results on measures of MusS.82,83
Aging remains the strongest predictor for reduced LM and overall MusS; interestingly, the physiologic reduction in LM accompanied by a lower MusS seems to be caused by an impaired synthesis or protein rather than increased degradation in response to protein intake,84 at least in absence of other comorbidities characterized by the presence of a chronic catabolic state due to an increase in resting energy expenditure.2 Therefore, nutritional strategies aimed at increasing LM and MusS to a lower degree have attempted to increase the reduced protein synthesis.85
Among macronutrients, proteins have by far received the most attention with regard to their effects on LM hypertrophy and MusS.82,83 More recently, fatty acids, particularly unsaturated fatty acids, have also been explored regarding their ability to modulate the immune system and possibly reduce the level of low-grade systemic inflammation,82,83,86 although the evidence with regard to their effects on MusS remains conflicting.87 The type of protein used has been inconsistent in the literature; in fact, different strategies have been utilized: from whey protein to specific amino acids, making it hard to generalize and compare the results from different studies.88
With regard to whey protein, which contains a high amount of essential amino acids, which supposedly promote protein synthesis, in a randomized controlled trial, 80 older adults (70-85 yr) enrolled in a 6-mo intervention with supplementation of 40 g of whey protein split in 2 doses/d experienced a significant increase in MusS compared with an isocaloric amount of maltodextrin (ie, carbohydrates).89 Of note, both interventions were implemented in addition to RT, suggesting that whey protein supplementation may further increase the beneficial effects of RT. Recently, another randomized trial in older women >60 yr found that supplementation with 35 g of whey protein in addition to RT was associated with increased MusS.90 Importantly, the study also investigated whether timing of ingestion (pre-training vs post-training) would affect MusS; however, independent of time of ingestion, whey protein supplementation was beneficial without significant differences between pre-training and post-training ingestion.90 Furthermore, supplementation with vitamin D, creatine, and other pharmacologic interventions has been investigated over the years, with conflicting evidence due to the large variability of dose of supplementation used and population investigated and discussed at length elsewhere.91–100
A major concern of most dietary intervention studies relies on the fact the clinical trials were typically of short duration and of limited sample size, ultimately preventing the determination of the effects on clinical outcomes. Considering the major role of MusS in modifying CV risk, however, we could speculate that dietary interventions resulting in improved MusS have the potential to improve clinical outcomes. Importantly, most studies used dietary interventions in the form of food or specific supplement as an adjunct to exercise training; therefore, the results should not be generalized to those who are not enrolled in a structured exercise training program.
Weight loss is often recommended in patients with overweight or obesity to improve CVD risk factors.47 The role of weight loss on MusS is, however, less known. Weight loss induced by caloric restriction is associated with a concomitant reduction in fat mass and LM, and unless it is paralleled by exercise training, weight loss can result in a reduction in MusS.101,102 In those individuals who achieve a large weight loss (ie, >10% of body weight), however, exercise training may not be sufficient to preserve MusS,103 highlighting the need to develop novel strategies, including novel regimens of exercise training and perhaps novel nutritional and/or pharmacologic intervention to mitigate the progressive reduction in MusS.104
MusS is a strong modifiable risk factor for several CVDs, but also CVD-related mortality and all-cause mortality. Except for the risk of HTN, where the evidence is conflicting, MusS seems to exert protective effects on several CV and metabolic conditions (ie, MetS, T2DM, and obesity). Importantly, such effects seem to be, for the most part, independent of the amount of LM, CRF, and physical activity. The studies discussed herein, however, cannot prove whether dynapenia is a mediator or perhaps only a marker of overall worse nutritional status able to identify those with frailty and sarcopenia among others, which, in turn, confer a greater risk for cardiometabolic diseases. In other words, is this relationship causal or merely association? Further study is clearly warranted to determine whether therapeutics, including targeting nutrition and RT, aimed at increasing MusS, with and without changes in LM, can, in fact, affect major clinical outcomes, and whether this can be implemented to improve cardiac rehabilitation outcomes in patients with established CVD, especially CHD and HF.
Dr Carbone is supported by a Career Development Award 19CDA34660318 from the American Heart Association. Dr Kirkman is supported by a Career Development Award 19CDA34740002 from the American Heart Association. Dr Rodriguez-Miguelez is supported by a Career Development Award 18CDA34110323 from the American Heart Association.
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