Breast cancer (BC) survival rates have improved during the past two decades and as a result older BC survivors are at increased risk of developing heart failure (HF). Although the HF phenotype common to BC survivors has received little attention, BC survivors have a number of risk factors associated with HF and preserved ejection fraction (HFPEF) including older age, hypertension, obesity, metabolic syndrome and sedentary lifestyle. Moreover, not unlike HFPEF, BC survivors with preserved left ventricular ejection fraction (BCPEF) have reduced exercise tolerance measured objectively as decreased peak oxygen uptake (peak VO2). This review summarizes the literature regarding the mechanisms of exercise intolerance and the role of exercise training to improve peak VO2 in BCPEF.

INTRODUCTION

Breast cancer (BC) is the most frequently diagnosed malignancy among women and the second leading cause of cancer mortality in the United States [1]. As a result of advances in prevention, early detection and treatment, BC death rate has decreased by 36% between 1989 and 2012 [2]. A consequence of this success is that older BC survivors are at increased risk of developing heart failure (HF) [311] due, in part, to the direct cardiotoxic effects of anti-cancer therapy and indirect effects of an unfavourable lifestyle [12,13].

Traditionally, studies examining the cardiotoxic effects of anti-cancer therapy have primarily focused on left ventricular (LV) systolic dysfunction and the development of HF symptoms [14]; however, more than half of HF patients have preserved LV ejection fraction (HFPEF) [15,16]. BC survivors also have a number of risk factors associated with HFPEF including older age, hypertension, obesity, metabolic syndrome and sedentary lifestyle [12,1719]. Importantly, a consequence of a sedentary lifestyle (and reduced exercise tolerance) is that it is an independent risk factor for HFPEF [20]. Accordingly, older BC survivors may be at increased risk for developing HFPEF which may have important clinical implications as medication and device therapies do not improve survival in these patients [15,16].

The aim of this brief review is to: (1) highlight the mechanisms of exercise intolerance in BC survivors with preserved LV ejection fraction (BCPEF), and (2) discuss the role of exercise training to improve exercise tolerance as indexed via peak exercise oxygen consumption (peak VO2).

Determinants of exercise intolerance in BCPEF

A number of investigators have measured peak VO2 in BCPEF and age-matched non-cancer controls (n=190 survivors, mean age: 54 years; mean time post chemotherapy: 3.3 years; mean ejection fraction: 61%) [2125]. As shown in Figure 1, peak VO2 is on average 5.5 ml/kg·min (19%) lower in BCPEF compared with age-matched non-cancer controls. The mechanism(s) for the reduced exercise tolerance is not entirely clear, but may be due to impaired cardiac function, peripheral vascular dysfunction, decreased skeletal muscle oxygen utilization or some combination of these factors.

Peak VO2 in BCPEF and non-cancer controls

Figure 1
Peak VO2 in BCPEF and non-cancer controls
Figure 1
Peak VO2 in BCPEF and non-cancer controls

Role of impaired cardiac function

An early study by Jones et al. [21] compared the acute haemodynamic responses during peak upright cycle exercise in 47 post-menopausal BC survivors (mean age: 59 years; mean time post chemotherapy: 34 months; mean resting LV ejection fraction: 64%) and 11 age- and sex-matched healthy control subjects. The decreased peak VO2 in BCPEF was due to a lower peak cardiac output attributed to a blunted increase in stroke volume as peak heart rate and arteriovenous oxygen difference were not different between groups (Table 1, Figure 2) [21]. Importantly, since oxygen extraction is directly proportionate to muscle oxygen diffusional conductance and inversely related to cardiac output [26], the finding that peak arteriovenous oxygen difference is similar between BCPEF and non-cancer controls despite a longer transit time for muscle oxygen extraction (due to lower cardiac output) suggests that impaired (micro)vascular function and/or skeletal muscle abnormalities may also limit peak VO2.

Table 1
Acute haemodynamic responses during aerobic exercise in BCPEF and HFPEF compared with healthy control subjects

* Khouri et al. [24] measured post exercise data at 82% peak heart rate and reserve function was calculated as post exercise minus rest for BCPEF compared with control. Calculated as the difference between 75% peak power output minus rest for BCPEF compared with control from published data from Koelwyn et al. [25]. NM, not measured.

VariableBCPEF compared with healthy controlHFPEF compared with healthy control
Cardiac output 
 Peak* ⇓ [21,24⇔ [44] ⇓ [4547
 Reserve (peak exercise minus rest)* ⇓ [21,24⇓ [45,46
Heart rate 
 Peak ⇔ [21,24,25⇓ [4447
 Reserve ⇓ [21⇓ [45,46
Stroke volume 
 Peak* ⇓ [21,24⇔ [44,45] ⇓ [47
 Reserve* ⇔ [24,25⇔ [45] ⇓ [46
End-diastolic volume 
 Peak* ⇔ [24⇔ [47] ⇓ [45
 Reserve ⇔ [25⇔ [45,46
End-systolic volume 
 Peak NM ⇔ [45
 Reserve ⇓ [25⇓ [45,46
End-systolic elastance 
 Peak NM NM 
 Reserve ⇓ [25⇓ [48
Ejection fraction 
 Peak* ⇔ [24⇔ [45] ⇓ [47
 Reserve*† ⇔ [24] ⇓ [25⇓ [45,46
Arteriovenous oxygen difference 
 Peak ⇔ [21⇔ [46]⇓ [44,45,47
 Reserve NM ⇔ [46] ⇓ [45
Systemic vascular resistance 
 Peak ⇔ [21⇔ [45
 Reserve NM ⇔ [45
VariableBCPEF compared with healthy controlHFPEF compared with healthy control
Cardiac output 
 Peak* ⇓ [21,24⇔ [44] ⇓ [4547
 Reserve (peak exercise minus rest)* ⇓ [21,24⇓ [45,46
Heart rate 
 Peak ⇔ [21,24,25⇓ [4447
 Reserve ⇓ [21⇓ [45,46
Stroke volume 
 Peak* ⇓ [21,24⇔ [44,45] ⇓ [47
 Reserve* ⇔ [24,25⇔ [45] ⇓ [46
End-diastolic volume 
 Peak* ⇔ [24⇔ [47] ⇓ [45
 Reserve ⇔ [25⇔ [45,46
End-systolic volume 
 Peak NM ⇔ [45
 Reserve ⇓ [25⇓ [45,46
End-systolic elastance 
 Peak NM NM 
 Reserve ⇓ [25⇓ [48
Ejection fraction 
 Peak* ⇔ [24⇔ [45] ⇓ [47
 Reserve*† ⇔ [24] ⇓ [25⇓ [45,46
Arteriovenous oxygen difference 
 Peak ⇔ [21⇔ [46]⇓ [44,45,47
 Reserve NM ⇔ [46] ⇓ [45
Systemic vascular resistance 
 Peak ⇔ [21⇔ [45
 Reserve NM ⇔ [45

Peak and post exercise heart rate (A), stroke volume (B), and cardiac output (C) in BCPEF and healthy controls

Figure 2
Peak and post exercise heart rate (A), stroke volume (B), and cardiac output (C) in BCPEF and healthy controls
Figure 2
Peak and post exercise heart rate (A), stroke volume (B), and cardiac output (C) in BCPEF and healthy controls

Khouri et al. [24] measured peak VO2 during treadmill exercise, as well as LV volumes and cardiac output (using 2D echocardiography) at rest and post-exercise (82% peak heart rate) in 57 women with early stage BC (mean age: 51 years; mean time post chemotherapy: 26 months; mean LV ejection fraction: 55%) and 20 sex-matched healthy controls. Peak VO2 was 20% lower in BCPEF compared with healthy controls with no significant difference between groups for maximal heart rate. Post exercise stroke volume and cardiac index were significantly lower whereas post exercise end-diastolic volume, ejection fraction and ejection fraction reserve (post exercise minus rest) were not significantly different between groups [24] (Table 1, Figure 2). Finally, in both uni- and multi-variate analysis, cardiac index reserve was significantly related to peak VO2 [24].

More recently, Koelwyn et al. [25] compared LV volumes and ventricular-arterial coupling (at rest, 25%, 50%, 75% peak power output) and peak VO2 during cycle exercise, using 2D echocardiography, in 30 older BC survivors (mean age: 61 years; time post chemotherapy: 6.5 years; mean LV ejection fraction: 60%) and 30 age-matched controls. Peak VO2, sub-maximal exercise end-diastolic volume, stroke volume and effective arterial elastance (a measure of arterial afterload) were not different between groups (Table 1) [25]. In contrast, sub-maximal exercise ejection fraction was significantly lower in BCPEF secondary to decreased end-systolic elastance (an indirect measure of LV contractility) [25].

Role of impaired peripheral vascular function

Jones et al. compared brachial artery flow-mediated dilation (FMD) in response to cuff ischemia (an endothelial dependent-stimulus) in 26 HER2+ BC survivors (mean age: 48 years; mean time post chemotherapy completion: 20 months; mean ejection fraction: 64%) and 10 age-matched healthy controls [22]. The authors reported that brachial artery FMD was not significantly different between groups, and was not related to peak VO2 [22]. Koelwyn et al. [25] confirmed and extended these findings by demonstrating that brachial artery FMD, carotid-femoral and carotid-radial pulse wave velocity, and carotid compliance were not significantly different between BCPEF and healthy controls. Taken together, the few studies performed to date suggest large conduit artery endothelial function and arterial stiffness are not impaired in BCPEF.

It is important to note however that endothelial function and arterial stiffness represent a mere fraction of available vascular end-points. Moreover, these resting measurements do not provide exercise specific insight into skeletal muscle blood flow regulation. In particular regulation of the downstream resistance vessels which play a primary role in the control of microvascular tone and thus the precise delivery of oxygen and nutrients to the active skeletal muscle tissue (e.g. functional sympatholysis or exercise hyperaemia) may be more informative when trying to understand mechanisms responsible for exercise intolerance in BCPEF [2730]. More work is therefore needed to fill this important knowledge gap.

Role of skeletal muscle dysfunction

Since a majority of the oxygen consumed during exercise occurs in the active muscles [31], the decline in peak VO2 in BCPEF may be due to a reduction in the quantity or quality of skeletal muscle. Villasenor et al. [32] have shown that decreased muscle mass (sarcopenia) is a prevalent condition, and an independent predictor of poor prognosis in older non-metastatic BC survivors. Toth et al. [33], using the vastus lateralis muscle biopsy technique in 19 cancer patients (BC, n=6) before or during cancer treatment, reported reduced (≈20%) single muscle fibre cross-sectional area for both slow-twitch myosin heavy chain (MHC) I and fast-twitch MHC IIA in both weight-stable cancer patients and those with a history of weight loss. Moreover, the distance walked in 6 min was positively related to MHC I/IIA fibre ratio [33]. Finally, decreased exercise tolerance may also be the result of peripheral muscle weakness as peak VO2 is related to leg strength in older BC survivors [34].

Beyond these fibre typing and morphological studies however, the composition of skeletal muscle in BCPEF remains to be elucidated. Work performed from Kitzman et al. has elegantly shown a fundamental shift in skeletal muscle oxidative capacity (reduced capillary-to-fibre type ratio, decreased oxidative fibres and oxidative capacity) in HFPEF, and that these changes contribute significantly to exercise intolerance [35,36]. Whether similar changes contribute in BCPEF is an important topic of future investigation.

In summary, not unlike the findings in clinically stable HFPEF patients [26] (Table 1), studies performed to date suggest that the reduced peak VO2 in BCPEF is due both to central and peripheral abnormalities that result in reduced oxygen delivery and/or utilization by the active muscles.

Improvement in peak VO2 with exercise training in BCPEF

Several meta-analyses reported that exercise training during or after cancer treatment improves peak VO2, physical functioning, fatigue and quality of life [37,38]. Despite these benefits, the mechanisms of the training-mediated increase in peak VO2 in BCPEF are not well known.

Haykowsky et al. compared the effects of aerobic exercise training on peak VO2, resting and dobutamine stress LV volumes and ejection fraction during the first 4 months of adjuvant trastuzumab in 17 women with HER2+ BC (mean age: 53 years; mean rest and peak dobutamine stress LV ejection fraction: 64% and 79% respectively). Compared with baseline, exercise training did not change peak VO2 (19.8 compared with 21.7 ml/kg·min, P=0.2) or peak heart rate. Moreover, LV end-diastolic and end-systolic volumes were significantly higher at rest and during dobutamine stress whereas resting LV ejection fraction was significantly lower after 4 months [39].

Jones and colleagues examined the effect of 12 weeks of moderate to high-intensity aerobic training (n=10, mean age: 51 years, mean ejection fraction: 54%) compared with no-training (n=10, mean age: 46 years; mean ejection fraction: 53%) on peak VO2, resting LV volumes and systolic function, brachial artery endothelial function in women with operable BC during neoadjuvant chemotherapy [40,41]. Aerobic training significantly increased peak VO2 (between group mean change: 4.1 ml/kg·min) and oxygen pulse without a change in resting LV volumes, cardiac output, ejection fraction or brachial artery FMD [40,41].

Giallauria et al. recently compared 1 year of moderate-intensity cycle training and dietary program (n=25, mean age: 52 years; peak VO2: 12.6 ml/kg·min) compared with no-training (general lifestyle recommendations in accordance with the DIANA protocol, n=26, mean age: 54 years; mean peak VO2: 12.8 ml/kg·min) on peak VO2 and vascular function in women with early stage invasive BC (diagnosed within past 5 years) [42]. One year of training resulted in a significant increase in peak VO2 (15%), oxygen pulse (11%) and reactive hyperaemia index (19%) with no significant change in the control group [42].

Although the mechanisms for the increased oxygen pulse (product of stroke volume and arterial-venous oxygen difference) were not studied, the finding that exercise training does not improve resting cardiac function or large conduit artery endothelial function during chemotherapy [40,41] or LV systolic function during peak dobutamine stress during biologic therapy [39] suggests that the increased oxygen pulse may be due to favourable changes in microvascular and/or skeletal muscle function that result in increased oxygen extraction by the active muscles. Notably, our group has shown that the increased peak VO2 in clinically stable older HFPEF patients after 16 weeks of aerobic training is due to ‘non-cardiac’ peripheral skeletal muscle adaptations that result in increased arterial-venous oxygen difference [26,43].

CONCLUSION

BC survival rates have improved during the past two decades and as a result older BC survivors are at increased risk of developing HF [311]. Although the HF phenotype common to BC survivors has received little attention, these individuals have many risk factors associated with HFPEF [12,1719]. Moreover, many BC survivors adhere to a sedentary lifestyle which is an independent risk factor for HFPEF [20]. The few studies performed to date suggest that the marked exercise intolerance found in BCPEF appears to be due to central and peripheral abnormalities that result in reduced oxygen delivery and/or utilization by the active muscles (Table 1). Regular exercise is associated with favourable improvement in peak VO2 in BCPEF; however, the mechanisms responsible for this improvement are unknown. Given that BCPEF may be at increased risk for HFPEF coupled with the finding that exercise training is the only proven therapy that improves peak VO2 in clinically stable HFPEF patients [26], future studies are required to determine the mechanism of exercise intolerance and improvement with exercise training in BCPEF.

FUNDING

Professor Haykowsky is funded by the Moritz Chair in Geriatrics in the College of Nursing and Health Innovation at University of Texas at Arlington.

Abbreviations

     
  • BC

    breast cancer

  •  
  • BCPEF

    breast cancer survivors with preserved left ventricular ejection fraction

  •  
  • FMD

    flow-mediated dilation

  •  
  • HF

    heart failure

  •  
  • HFPEF

    heart failure and preserved ejection fraction

  •  
  • LV

    left ventricular

  •  
  • MHC

    myosin heavy chain

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