Which of the following is the ability of the heart to supply oxygen to the muscles *?

CRF, the Obesity Paradox, and HF

CRF is a strong predictor of prognosis in healthy individuals and cohorts with CVD (Lee et al., 2012; Kodama et al., 2009; Lavie et al., 2013b). Many studies have established the prognostic significance of CRF and other variables of cardiopulmonary exercise testing in HF (Lavie et al., 2013b; Guazzi et al., 2016; Osman et al., 2000). The classic cut-off point for classifying HF patients into low- and high-risk groups have been the peak oxygen consumption (VO2) of 14 mL O2/kg min (Mancini et al., 1991).

Several studies have indicated a strong interaction between CRF and the obesity paradox in patients with CAD and HF (Lavie et al., 2013b; McAuley et al., 2012). We previously demonstrated in a cohort of 2066 patients with chronic HFrEF that patients with a high CRF (peak VO2 ≥ 14 mL/kg min) have a better prognosis and an obesity paradox does not affect this patient population (Lavie et al., 2013b). Contrarily, a strong obesity paradox was present in those with a poor CRF. The worse outcomes were observed in leaner individuals with a poor CRF (Fig. 10). Similar results were reported in other cohorts of HFrEF from the United States and Europe (Piepoli et al., 2016; Clark et al., 2015).

Cardiorespiratory Fitness

Although cardiorespiratory fitness (CRF) is determined by a number of nonmodifiable factors, such as gender, age, and genetic factors, it has also been considered in recent years an objective indicator of physical activity and used to assess the relationship between physical activity and health status [30,31]. Therefore, relationships observed between indicators of abdominal obesity and CRF may indirectly prove a relationship between physical activity and abdominal obesity. Of particular importance are the results of studies that made direct measurements of VAT. The earliest study on the subject reported CRF to show a significant correlation only with the amount of total abdominal adipose tissue and SAT, but not with VAT [32]. In another study, however, CRF was observed to negatively correlate with VAT in 13-year-old girls (r = −0.45) and boys (r = −0.43) [33]. Similar results were obtained in a study of white and black young people aged 8–17 years (r = −0.43 and r = −0.68, respectively) [34].

In 8-year-olds within the same BMI category, children with high CRF (assessed using a maximal multistage 20-m shuttle run test), had a significantly lower WC (P = 0.001) and a lower fat percentage in the abdominal region, as measured by DEXA (P < 0.001), compared to children with low CRF [35]. A similar relationship between CRF and WC in children and adolescents has been shown in many other studies [14,28,36–38], although some were no longer statistically significant after adjusting for the amount of fat [39]. CRF explained 9–26% of the variance of WC in children and adolescents of all ages [10,40]. A long-term study of children aged 6–12 years showed that the risk of continuation of abdominal obesity after 2 years was highest among those who had a high WC (1.9-fold) and low CRF (4.3-fold) at baseline [41]. Ortega and colleagues [37] also found that CRF appears to modify the relationship between objectively measured physical activity and abdominal obesity, and that the time devoted to intense activity is likely to be a key factor associated with abdominal obesity in children and adolescents with low fitness.

Aerobic endurance exercise for preventing CHD

Cardiorespiratory fitness is mainly increased by aerobic endurance exercise but in some less fit or diseased populations a small benefit can be achieved by muscular strength exercise (ACSM 2006b, Pollock et al 2000). It has been highlighted in the previous section that increased physical activity is beneficial in preventing CHD and CHD-related mortality. However, the debate continues on how much of the benefit is related to increased weekly energy expenditure with or without corresponding increases in cardiorespiratory fitness. The accuracy in measuring daily physical activity and daily energy expenditure is problematic (Tudor-Locke & Myers 2001), whereas measuring cardiorespiratory fitness can be done using a single test and is thus relatively easy. Perhaps it is due in part to the relative ease of accurately measuring fitness, compared to measuring physical activity, that increased fitness has been shown to have a statistically stronger and more beneficial association with reductions in CHD morbidity and mortality (Williams 2001). Figure 3.4 (Farrell et al 1998) illustrates the clear strength of cardiorespiratory fitness as an independent risk factor, compared with other cardiac disease risk factors. Figure 3.5 (Myers et al 2002) illustrates considerable differences between different levels of cardiorespiratory fitness and specifically CHD mortality. Myers et al (2004) reported up to a 50% reduction in all-cause and cardiovascular disease mortality in those with a higher level of cardiorespiratory fitness.

From the key evidence highlighted, it is apparent that there are two main avenues for preventing CHD through increased physical activity: that which aims to increase weekly energy expenditure within daily life and that which aims to increase cardiorespiratory fitness from more structured vigorous exercise. So far, from a scientific perspective, the latter has demonstrated a greater CHD prevention benefit. However, from a public health perspective, achieving such levels of participation in vigorous structured exercise appears to be an unattainable and/or unsustainable behaviour for large proportions of the population. Hence, public health initiatives have more recently focused on ways in which to reintroduce physical activity into the routine of daily life where experts feel there is a greater chance of successful behaviour change. The main problem is that physical activity has been literally manufactured ‘out of life’ in the techno-industrialized world through advances in transport and occupational technology and technology-based sedentary leisure pursuits (Paffenbarger et al 2001).

China provides an interesting example of changes in transport modes (Fig. 3.6). In 1986 in Beijing, 58%, 32% and 5% of urban travel was by bicycle, public transport and private car or employer's bus, respectively (Peng 2005). In the year 2000 this had changed to 38%, 27% and 23%, respectively, for these three same modes of urban transport. Bell et al (2002) have been able to show that such changes in transport, as a result of increased prosperity and a shift in the population living in rural to urban locations, are strongly associated with the sharp rises in obesity now prevalent in China (Wang et al 2007). In this vein, it is probably the rise in obesity as a consequence of decreases in active transport that leads to poorer cardiovascular health in such populations, and from this perspective, it is a ‘physically active transport’ policy and not a nationwide exercise training regimen that is required.

The mechanism of increased physical activity and fitness relates to the stability and progression/regression of coronary atherosclerotic plaque. In individuals who fail to expend more than 1000 kilocalories per week (equivalent to walking 1.5 miles per day) coronary disease showed a progression, whereas those who expended 1500 and 2000 kilocalories per week, halted and regressed their atherosclerosis, respectively (Hambrecht et al 1993).

13.3 Tests to Assess Endurance

Cardiorespiratory fitness is measured by VO2max which is one of the most often used tests to evaluate endurance capacity. VO2max is generally measured in laboratories using treadmill running, cycling, or rowing ergometers by progressively increasing intensity over a time period that exceeds 5 min. Heart rate, ventilation, and inhaled and exhaled oxygen and carbon dioxide differences are measured. The cardiac output and the arteriovenous oxygen difference multiplication factor gives the value of VO2max which, divided by body weight (mL/kg/min), which can be used to compare athlete results from the same or different sports and even the progress made over training sessions by an individual athlete. With the help of a portable mask, VO2max can be measured outdoors and in the competition setting, during running, skiing, cycling, kayaking, rowing, and even swimming.

Because of the importance of VO2max in health, since the value is negatively correlated with the incidence of a wide range of diseases, and in elite sport, since certain values are almost obligatory for success in endurance-associated sports, many methods have been developed to estimate VO2max.

The Cooper running test, 12 min of continuous running, is a good estimate of VO2max. Cooper’s equation, VO2max = running distance-504.9/44.73, is now well-established and used around the world.

In well-trained subjects, aged 21–51 years, the VO2max can be judged efficiently by the differences in the maximal and resting heart rates multiplied by 15.3 (Uth et al., 2004): VO2max = HRmax/HRrest × 15.3.

Another popular estimation of VO2max is the Rockport Fitness Walking Test, which uses 1.6 km (1 mile, 4 laps of a standard track) with the subjects walking as fast as possible, to estimate the VO2max using the following equation: VO2max = 132.853 − (0.0769 × body weight in pounds) − (0.3877 × age) + (6.315 × 0 if you are female or 1 if you are male) − (3.2649 × time to complete 1.600 m in minutes) − (0.1565 × number of heart beats in 10 s at the end of the 1-mile walk).

The bench step test, using a 42 cm-high bench, a stopwatch, and a metronome is another relatively straightforward test to estimate VO2max. The subject steps up and down, 1 ft at a time, onto the bench for 3 min, at a rate of 22 steps/min. For females and 24 for males. The number of heartbeats in the last minute is recorded using a heart rate monitor. Then, use the equation: VO2max = 111.33 − (0.42 × last minute heart rate) for males and VO2max = 65.81 − (0.1847 × last minute heart rate) for females, to estimate VO2max.

VO2max is important for cardiovascular and muscular endurance. However, the economy of the exercise is also very important. With the same VO2max, a competitor who can work at a higher percentage of VO2max in aerobic conditions has an advantage. Within a certain range, athletes who are able to work at a higher percentage of VO2max can easily compensate for a lower level of VO2max. Therefore, without question, one of the main goals of endurance training is to increase the intensity at which athletes reach the anaerobic threshold, which can be measured in the laboratory. The measurement allows one to determine heart rate and the intensity of the movement (running, cycling, rowing) at the point where the lactate levels increase in a steeper pattern, generally around 4 mmol/L (see Chapter 5).

The determination of lactate threshold can be done in the laboratory, using a treadmill or cycle ergometer, but a sport-specific field test could be more valuable. To measure lactate threshold, at least four intensities—low, moderate, high, and maximal intensity—must be selected in which heart rate and lactate levels are measured (Fig. 13.1). As an example, swimmers are asked to swim 200 m with low intensity, then their heart rate and blood lactate would be measured. This procedure would be repeated after moderate, high, and maximal intensities of swimming. The obtained results would allow estimation of the heart rate at the blood lactate level of 4 mmol/L. We can then use this value to set up the intensity based on the heart rate of a swimmer.

The Beep Test is widely used to assess endurance especially in ball games. In this test, participants must run between two lines 20 m apart and reach the lines before recorded signals beep. The test starts with a slow speed, which is gradually increased as the periods between beeps get shorter and shorter. If the line is reached before the beep sounds, the subject must wait until the beep sounds before continuing; and if participants do not reach the line (within 2 m) for two consecutive runs there is a warning, and on the third failure to reach the line in time, the test ends.

The Yo-Yo Test is similar to the Beep Test. The intermittent recovery 1 (IR-1) is created for recreational players starts at a speed of 10 km/h, while version 2 (IR-2) starts at 13 km/h and is designed for elite players. The Yo-Yo Test consists of 2 × 20 m shuttle runs at increasing speeds, interspersed with a 10-s period of active recovery (controlled by audio signals from a compact disc). The test is terminated when an individual is no longer able to maintain the required speed. The distance covered up to the end-point is represented in the test results (Iaia et al., 2008). VO2max can be judged by the distance of the Yo-Yo Test using the following formula:

Yo−Yo−IR−1:VO2max=distance inm×0.0084+36.4.

Yo−Yo−IR−2: VO2max=distance inm×0.0136+45.3.

However, Yo-Yo-IR tests have been shown to be a more sensitive measure of change in performance than has maximum oxygen uptake (Bangsbo et al., 2008).

The game-based performance test (GBPT) for team-handball was developed by Wagner et al. (2016) and consists of incremental treadmill running and a team-handball test game (TG) (2 × 20 min) peak oxygen uptake (), blood lactate concentration (BLC), heart rate (HR), sprinting time, time of offensive and defensive actions, as well as running intensities, ball velocity, and jump height tests. This test aims to evaluate the most of the important elements of team-handball. However, in order to be able to see the validity of this test, it must be applied widely and a correlation seen with real performance. In ball games and combat sports, coaches use objective (measured) and subjective scales (skillfulness, game-IQ, etc.) to evaluate players. Both are important.

Nonexercise prediction tests

The value of cardiorespiratory fitness as an indicator of all-cause mortality has been reported,61 and, as such, the need to estimate VO2max noninvasively has increased. Prediction equations that use nonexercise parameters such as age, body composition, gender, level of physical activity, and the subject’s perceived functional ability to walk, jog, or run given distances have emerged.62,63 The reliability of these newer nonexercise prediction tests shows promise. For example, George and colleagues63 found that a questionnaire-based regression equation predicted VO2max with a correlation of 0.85 in a sample of physically active college students. Similarly, Heil and colleagues62 developed an equation for men and women between the ages of 20 and 79 years and noted a correlation of 0.88 for the generalized equation (men and women together). The equation included percent body fat, age, gender, and an activity code derived from personal statements about activity level. Although this equation appears to be useful because of its wide age range, very few of the subjects were highly fit, and it may be best for a fairly sedentary population.

Malek and colleagues developed equations to predict VO2max from age, height, weight, and exercise frequency, intensity, and duration in aerobically trained women64 and men,65 but these are population specific. Overall, nonexercise prediction tests have one distinct advantage: they can be administered without the requirements of equipment, supervision, or any inconvenience to the subject. However, as with all regression equations, generalization to a population other than the one from which it was derived remains questionable.

Introduction

Physical inactivity and subsequent poor cardiorespiratory fitness are major health problems worldwide, particularly in developed countries. Physical activity has clear beneficial effects on health outcomes, including cardiovascular disease and all-cause mortality [1]. Globally, large prospective cohort studies have indicated that sedentary behavior is associated with poor health outcomes, including increased mortality [2–6]. Lee et al. [7] calculated the attributable risk for premature mortality and estimated that physical inactivity worldwide causes 9% of premature mortality, accounting for 5.3 million deaths worldwide in 2008.

Exercise favorably impacts multiple systems and health outcomes, and a graded relationship between exercise and the development of common chronic conditions including cardiovascular disease, diabetes, chronic lung disease, chronic kidney disease, and some cancer has been observed in the existing literature. Physical exercise has also consistently been identified as a central element of rehabilitation for many chronic diseases and has been successful in improving quality of life and reducing all-cause mortality [8].

Cancer is another chronic disease where significant research into preventive and therapeutic interventions has been conducted. In 2009, the American Cancer Society (ACS) estimated that there were nearly 1.5 million new cases of cancer diagnosed in the United States and more than 500,000 people who died from the disease [9]. In the last two decades, it has become clear that exercise plays a vital role in cancer prevention and control. There is growing evidence suggesting that exercise decreases the risk of many cancers, and data support the idea that exercise may extend survival for cancer survivors [9]. Our focus of the chapter is on the impact of exercise and obesity on the risk of developing cancer and the beneficial effects that exercise has after a diagnosis of cancer both during and after therapy.

Physical Fitness

There is an inverse relationship between cardiorespiratory fitness and both all-cause and cardiovascular mortality (Blair et al., 1989, 1996; Kokkinos et al., 2010). Put simply, fitter people tend to live longer than less fit people. Fitness can be improved by increasing exercise frequency, intensity, or duration among people of all ages and both sexes (Spina, 1999; Seals et al., 1984). Physical fitness is determined by many factors in addition to exercise including age, sex, body mass, and genetics (Bouchard and Rankinen, 2001). Physical fitness is far more responsive to exercise training than any of the traditional cardiovascular risk factors mentioned above. Additionally, routine physical activity attenuates the risk of cardiovascular disease and mortality more than that which can be explained by its impact on individual risk factors.

11 What are the five components of physical fitness?

1.

Cardiovascular fitness—also known as cardiorespiratory fitness, is the ability of the heart, lungs, and vascular system to deliver oxygen-rich blood to working muscles during sustained physical activity

Muscular strength—the amount of force a muscle or muscle group can exert against a resistance

Muscular endurance—the ability of a muscle or muscle group to repeat a movement many times or to hold a particular position for an extended period of time

Flexibility—the ability of a joint to move through its full range of motion, from a flexed to an extended position

Body composition—the amount of fat in the body compared with the amount of lean mass

Frequency

It is reported that deconditioned persons may improve cardiorespiratory fitness with only twice-weekly exercise.201 However, it is generally agreed that optimal training frequency appears to be achieved with 3–5 workouts per week. The additional benefits of more frequent training appear to be minimal, whereas the incidence of lower-extremity injuries increases abruptly. For those exercising at 60–80% HRR, an exercise frequency of 3 days per week is sufficient to improve or maintain VO2peak. When exercising at the lower end of the intensity continuum, exercising more than 3 days per week is not deleterious. Patients with extremely low functional capacities may benefit from multiple short (5 days per week) exercise sessions. Clearly the number of exercise sessions per week will vary depending on the patient's limitations, but also on the patient's and caregiver's lifestyles.

2 Sedentary Time, Physical Activity, and Fitness

The topic of sedentary behavior, low physical activity level, and low cardiorespiratory fitness is one that we have addressed in greater details recently.3a Professors Jeremy Morris (London bus drivers and conductors) and Ralph Paffenbarger (San Francisco Longshoremen and Harvard University Alumni studies) made the seminal observation that the level of physical activity on the job or during leisure time was inversely associated with mortality rates.4–9 These observations have been repeated multiple times in large studies focusing on middle-aged adults as well as older people.10,11 Prospective epidemiological studies have established over the last 60 years or so that the lower death rates resulting from a physically active lifestyle were seen for all-cause, cardiovascular, and cancer mortality. Regular exercise translates into multiple wide-ranging health benefits such that it has been defined by some as the equivalent of a “polypill” with favorable pleiotropic effects on all organs and systems.12

On the other hand, a number of studies reported in the last decade have highlighted the fact that sedentary behavior was also associated with mortality rates, with the most sedentary individuals exhibiting higher death rates. The first population study to focus on this question was a dose–response prospective study of participants of the 1981 Canada Fitness Survey, and it revealed a graded relationship between amount of sitting time and all-cause and cardiovascular mortality.13 When the groups with the highest and lowest amount of daily sitting time were compared, the reduction in risk of death associated with less sitting time was about 15–20%, a risk reduction effect that persisted after adjustment for leisure time physical activity and body mass index. This observation has been confirmed in subsequent cohort studies from around the world.

Sedentary behavior and physical activity level have strong influences on mortality rates but so does cardiorespiratory fitness. This was well illustrated by reports from the laboratory of Professor Steven Blair based on the Aerobic Center Longitudinal Study starting in the 1980s.14 The main findings from a series of papers published by Blair and colleagues are that low cardiorespiratory fitness, as estimated by time on a treadmill test to exhaustion, was associated with higher all-cause, cardiovascular, and cancer death rates and that this association was found to be present in overweight, diabetic, hypertensive, or hypercholesterolemic adults.14 Interestingly, the same trend is observed in older adults in whom the powerful risk reduction impact of cardiorespiratory fitness on mortality was observed among male veterans from 65 to 90 years of age.15

In summary, a high altitude review of the evidence accumulated thus far strongly suggests that low cardiorespiratory fitness, low physical activity level, and increasing sedentary behavior are powerful predictors of all-cause, cardiovascular, and perhaps cancer mortality. These observations have considerable implications for the research agenda on exercise molecular mechanisms. Much energy is currently devoted to discovering the signaling pathways and molecular regulation of gene expression in relevant tissues (especially skeletal muscle) in response to acute and chronic exposure to exercise, particularly aerobic and resistance exercise. In contrast, little attention is being paid to tissue and organ molecular profiling of low versus moderate versus high cardiorespiratory fitness with the aim of discovering some of the molecular mechanisms at play in the relation between fitness, disease prevention, and longevity. Although the basic notion of targeting cardiorespiratory fitness for molecular studies appears to be simple on the surface, it would be in fact a complex undertaking for a number of reasons. For instance, it should be rather easy to identify adults with targeted cardiorespiratory fitness levels among subjects of existing long-term prospective cohorts, but accessibility of tissues, beyond skin, muscle, adipose tissue, blood, feces, and urine poses a major problem. A thorough molecular exploration should ideally include not only these tissues but also heart, lung, liver pancreas, kidney, bone, and brain to name but the most obvious ones. The only reasonable way to overcome this critical limitation would be to perform the same molecular and cellular studies on animal models. In this regard, there is solid evidence that the relationship between cardiorespiratory fitness and mortality rates described in humans is also observed in rodents. In a recent study, it was reported that, in rats kept sedentary all their life, those with a high intrinsic cardiorespiratory fitness, as measured by the distance they could run on a treadmill, lived 28–45% longer than the rats with a low cardiorespiratory fitness.16

One critical topic to address would be that of untangling the intrinsic and acquired component of the cardiorespiratory fitness phenotype at the individual level. An adult has an intrinsic level of cardiorespiratory fitness which can be observed in a direct manner by measuring maximal oxygen uptake adjusted for body mass and body composition in people who have a life history of being sedentary. For instance, among 174 sedentary young adult males, 17–35 years of age, measured twice (on separate days) for VO2max at baseline in the HERITAGE Family Study, the mean value was 41 mL O2/kg/min with an SD of 8 mL (Fig. 2A). The distribution of VO2max scores was almost perfectly Gaussian, which implies that about 7% had a VO2max/kg of 29 mL or less (1.5 SD below the mean) and the same percentage exhibited a cardiorespiratory fitness level about 53 mL/kg and more, an extraordinary degree of heterogeneity in such a fundamental biological property among people who are confirmed sedentary with no significant amount of exercise training in their past. These data clearly show that there is a substantial fraction of sedentary adults who maintains a relatively high VO2max despite the fact that they do not engage in any exercise program. Actually, some sedentary young adults maintain a VO2max of 55 mL O2/kg/min and more, a level of cardiorespiratory fitness that is even out of reach to many exercisers.

The importance of cardiorespiratory fitness from a biological point of view and the complexity of its interpretation with regard to mortality rates are augmented by the fact that the sedens level of VO2max can be improved in most people by appropriate behavior, i.e., regular physical activity and especially exercise training. To illustrate this point, let us use again the same 174 young adult males of HERITAGE. They were trained for 20 weeks and achieved what we can call perfect adherence to the exercise training protocol. Maximal oxygen uptake was measured twice before the exercise program and twice again posttraining, i.e., 24 and 72 h after the last exercise session. The gains in VO2max (expressed in % of baseline) are illustrated in Fig. 2B. We note from the figure that the mean gain calculated from the increase in mL O2 was 16% with an SD of 9% with a distribution of scores clearly skewed to the right, i.e., skewed in the direction of the high gainers in response to the same exercise prescription. This extraordinary range of training responses occurred in spite of the fact that the program was fully standardized and that adherence to the exercise sessions, which were all performed in the laboratory under constant supervision, was deemed excellent. A substantial fraction of this group increased their indicator of cardiorespiratory fitness by 40% and more, whereas a large number gained 10% and less.

Personal characteristics, such as age and gender, are exerting major influences on intrinsic fitness level (sedens VO2max) and on the absolute response (delta mL O2) to an exercise program but not on the gains expressed in percentage of pretraining baseline level as the percentage VO2max gain is the same on average in men and women and does not vary across age groups.17–19 Ethnicity, defined here as blacks versus whites, is not contributing to either the intrinsic VO2max level adjusted for body mass and body composition or its trainability when expressed as a percentage of baseline level.17 The intrinsic cardiorespiratory fitness level adjusted for age, gender, body mass, and body composition is characterized by a heritability component of the order of 50%.20 Similarly, the trainability of VO2max, expressed in terms of gains in mL O2, has a heritability level of about 45%.19 Interestingly, there is no correlation between baseline, intrinsic fitness level and its trainability, with an r2 (× 100) of the order of 1%.17,19

The above observations raise many questions concerning the interpretation of the strong association between cardiorespiratory fitness level and mortality rate in prospective studies. They are too numerous to be all listed here but a number of examples will suffice to illustrate how critical the general topic of cardiorespiratory fitness, health, and longevity is to those with an interest in the study of the exercise biology and particularly the molecular basis of the causal relation between regular exercise and cardiorespiratory fitness. What are the biological differences between low and high fitness groups in molecular profiling at the level of the cardiovascular system, brain, lung, liver, kidneys, skeletal muscle, and adipose tissue? What are the molecular mechanisms accounting for the mortality rate difference between low and high cardiorespiratory fitness groups? Can the link between cardiorespiratory fitness and mortality rate in sedentary adults or in active adults be defined in terms of genomic, epigenomic, gene expression, and protein abundance differences in key tissues? What are the contributions to the fitness–mortality relationship of the sedentary levels of secreted myokines and adipokines, regulation of apoptosis, autophagy, stem cell populations, and subsets of miRNAs? An overarching question would be whether persons with a high intrinsic cardiorespiratory fitness level enjoy lower mortality rates comparable to those with more modest intrinsic fitness level but who are exercising regularly? If so, what are the molecular mechanisms driving these relationships to better health and longevity and are they identical in both groups?