See Also: Caloric Restriction or Aerobic Exercise Training on Peak Oxygen Consumption and Quality of Life in Obese Older Patients With HFpEF

Fitness, as measured by maximal oxygen uptake, correlates with clinical outcomes in patients with heart failure (HF), and is commonly used as a surrogate outcome variable in HF studies. Low fitness has been linked to heightened risk of cardiac mortality, HF re-hospitalization, and all-cause mortality in patients with heart failure and a reduced ejection fraction (HFrEF).^1,2 Fitness has similar prognostic capabilities in patients with heart failure with preserved ejection fraction (HFpEF) and improving fitness has been linked to increased quality of life and exercise capacity.^3-5 A number of exercise training and a few drug intervention HFpEF studies have used improvements in fitness as a primary outcome variable.^6,7

The recent study by Kitzman et al,⁸ builds on the group's prior work of exercise training in HFpEF by incorporating caloric restriction as adjunctive therapy to exercise. HFpEF patients randomized to receive both exercise training and caloric restriction had improvements in fitness that were additive beyond groups assigned to exercise or caloric restriction alone. The study is an elegant approach to a vexing issue in HFpEF, namely improving functional capacity with the aim to avoid subsequent morbidity and mortality. The effect size of peak VO₂ increase seen in the exercise and caloric restriction group was 2.5 ml/kg/min, in line with prior studies with exercising training which typically result in a 2.5-3.0 ml/kg/min improvement.^4,5

However, interpreting changes in fitness scaled to body mass can be difficult in the setting of caloric restriction and its associated weight loss. Fitness is typically scaled to kilograms of body mass to account for differences in absolute peak VO₂ arising from differences in body size. To better understand why this is practical, it is important to remember the determinants of peak VO₂.⁹ By the Fick equation: Peak VO₂ = Cardiac output x (Arterio-venous oxygen difference), and therefore represents the maximal rate of flux of oxygen from the environment to the mitochondria, or the integrated systemic cardiorespiratory capacity. Differences in fitness between persons of different fitness levels are driven predominantly by differences in cardiac output (e.g. increased stroke volume) but also are affected by differences in arterio-venous oxygen gradients in the exercising muscle (quantified as lean muscle mass). Scaling peak VO₂ to body weight presumes to account for the anthropomorphic related differences in cardiac output and lean mass.¹⁰ Thus, a large man will likely have a larger peak VO₂ when measured in liters/minute compared to a smaller man, but after adjusting for body mass, relative VO₂ expressed in ml/kg/min should be similar between these two individuals, assuming equivalent degrees of fitness.

While scaling to body mass has the advantage of adjusting for differences amongst individuals, scaling within the same person before and after a weight loss intervention can pose a difficult conundrum in evaluating changes in fitness. As noted above, fitness levels depend predominantly on cardiac output, but changes in lean muscle mass can also affect fitness. Caloric restriction or other strategies to promote weight loss in the absence of exercise training will lead mostly to loss of fat mass, but can also lead to a reduction in lean muscle mass without changing cardiac output or stroke volume. Fat mass has no contribution to aerobic power and is essentially extra weight that must be carried by the body during exercise. The "engines" responsible for generating aerobic power or fitness, are 1) cardiac output which delivers oxygen and nutrient rich blood to 2) aerobically respiring mitochondria in skeletal muscle. Losing fat mass does not affect "engine" power, but rather gets rid of the "extra baggage." In contrast, exercise training can improve aerobic power by increasing lean muscle mass, improving oxygen extraction in myofibrils, and increasing peak stroke volume during exercise. Thus, improving fitness can be an arduous and time intensive task and, unfortunately, cannot be circumvented by liposuction.

In the present study, HFpEF subjects assigned to caloric restriction lost on average 5 kg of fat mass and 2 kg of lean mass. Subjects randomized to exercise lost 2 kg of fat mass and 1 kg of lean mass. There was no change in resting cardiac index and presumably stroke volume although it is not reported. Not surprisingly, there was no change in absolute VO₂ in the caloric restriction group versus controls (1537 ml/min vs 1519 ml/min; p=0.44). Therefore, the size of their engine remained the same (i.e., true cardiorespiratory fitness was unchanged), even though it became easier to move the newly smaller body uphill and through space (imagine placing the same V6 engine from a large SUV into a subcompact car).

However, this is not to say that weight loss did not have other beneficial effects. Subjects randomized to caloric restriction were more likely to have reduction in New York Heart Association class with a concomitant increase in exercise time. High sensitivity C-reactive protein decreased as well as reductions in total cholesterol and low-density lipo-protein. Interestingly, Minnesota Living with Heart Failure quality of life scores were not affected by exercise or caloric restriction.

Given the high prevalence of obesity in HFpEF patients, strategies to improve weight loss are essential to improve "non-cardiac" factors that worsen the syndrome and impair work performance. Improved insulin sensitivity should lessen microvascular dysfunction, dyslipidemia, and inflammation. Weight loss may help to improve obstructive sleep apnea as well as to restore functional capacity by reducing joint pain when ambulating. With the lack of evidence-based therapies for HFpEF, weight loss is a readily available intervention that has the potential to positively influence the numerous co-morbidities that are common in HFpEF.

References

1. Myers J, Arena R, Cahalin LP, Labate V, Guazzi M. Cardiopulmonary Exercise Testing in Heart Failure. Curr Probl Cardiol 2015;40:322-72.
2. Mancini DM, Eisen H, Kussmaul W, Mull R, Edmunds LH, Jr., Wilson JR. Value of peak exercise oxygen consumption for optimal timing of cardiac transplantation in ambulatory patients with heart failure. Circulation 1991;83:778-86.
3. Shafiq A, Brawner CA, Aldred HA, et al. Prognostic value of cardiopulmonary exercise testing in heart failure with preserved ejection fraction. The Henry Ford HospITal CardioPulmonary EXercise Testing (FIT-CPX) project. Am Heart J 2016;174:167-72.
4. Kitzman DW, Brubaker PH, Morgan TM, Stewart KP, Little WC. Exercise training in older patients with heart failure and preserved ejection fraction: a randomized, controlled, single-blind trial. Circ Heart Fail 2010;3:659-67.
5. Edelmann F, Gelbrich G, Dungen HD, et al. Exercise training improves exercise capacity and diastolic function in patients with heart failure with preserved ejection fraction: results of the Ex-DHF (Exercise training in Diastolic Heart Failure) pilot study. J Am Coll Cardiol 2011;58:1780-91.
6. Redfield MM, Chen HH, Borlaug BA, et al. Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA 2013;309:1268-77.
7. Kosmala W, Holland DJ, Rojek A, Wright L, Przewlocka-Kosmala M, Marwick TH. Effect of If-channel inhibition on hemodynamic status and exercise tolerance in heart failure with preserved ejection fraction: a randomized trial. J Am Coll Cardiol 2013;62:1330-8.
8. Kitzman DW, Brubaker P, Morgan T et al. Effect of Caloric Restriction or Aerobic Exercise Training on Peak Oxygen Consumption and Quality of Life in Obese Older Patients With Heart Failure With Preserved Ejection Fraction: A Randomized Clinical Trial. JAMA 2016;315:36-46.
9. Levine BD. .VO₂max: what do we know, and what do we still need to know? J Physiol 2008;586:25-34.
10. Carrick-Ranson G, Hastings JL, Bhella PS, et al. The effect of age-related differences in body size and composition on cardiovascular determinants of VO₂max. J Gerontol A Biol Sci Med Sci 2013;68:608-16.

Keywords: Arthralgia, Body Weight, C-Reactive Protein, Caloric Restriction, Cardiac Output, Cholesterol, Dyslipidemias, Heart Failure, Inflammation, Insulin Resistance, Lipectomy, Mitochondria, Muscle, Skeletal, Myofibrils, Obesity, Prevalence, Quality of Life, Sleep Apnea, Obstructive, Stroke Volume, Weight Loss, Geriatrics

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