Exercise Prevention of Cardiovascular Disease in Breast Cancer Survivors

Table 1

Potential mechanisms for exercise prevention of doxorubicin-related cardiovascular toxicity.

Myocardial target	Role of target	Direction of exercise-induced change^*	Direction of doxorubicin-induced change^*	Evidence of exercise prevention of doxorubicin-induced change
Mechanisms with evidence for their role in exercise prevention
Antioxidant to oxidative stress ratio	Prevention of oxidative damage	↑ [15]	↓ [13]	✓ [17–21, 52]; × [23]
Expression of myosin heavy chain isoform in rodents	Motor protein required for muscular contraction; in a healthy rodent heart there is a much higher concentration of the isoform	↑ [154]	↓ [155]	✓ [28, 35–37]; × [23]
Caspase 3 and 9 activity	Markers for apoptotic signaling	↓ [156]	↑ [14]	✓ [18, 23, 24, 26]
HSP 60 expression	Controls protein folding and unfolding in response to stress	↑ [18]	↑↑ [19]	✓ [17, 19]
Mitochondrial permeability transition pore opening	Regulation of calcium handling and apoptosis	↓ [157]	↑ [158]	✓ [26]
Ubiquitin-proteasome activation	Maintains protein function and quality control	↓ [159]	↑ [160]	✓ [24]
Endothelial progenitor cell level	Physiologic and pathologic vessel formation	↑ [54]	↓ [161]	✓ [55]
HSP72 expression	Controls protein folding and unfolding in response to stress	↑ [18, 162]	= [163]	✓ [23]; × [24, 40]
SERCA2a expression	Calcium recycling from the cytosol into the sarcoplasmic reticulum	↑ [164]	↓ [165]	✓ [166]; × [28, 29]
Mechanisms with evidence against their role in exercise prevention
HSP 70 expression	Controls protein folding and unfolding in response to stress	↑ [167]	↓ [168]	× [19]
AMPK activation	Senses and regulates energy homeostasis	↑ [169]	↓ [170]	× [166]
Cardiac progenitor cell level/heart mass	Physiological turnover of cardiomyocytes	↑ [171]	↓ [172]	× [29]
Expression of PGC-1	Transcription coactivator that regulates mitochondrial biogenesis and angiogenesis	= [32, 33]	↓ [173]	× [22, 34]
Potential mechanisms for exercise prevention lacking investigation
Neuregulin-1/ErbB4 signalling	Cardiac cell survival growth factor	↑ [60]	↓ [174]
Expression of GATA-4	Transcription factor involved in cardiac survival, hypertrophic growth of the heart	↑ [58]	↓ [175]

↑: increase; ↓: decrease; =: no change; ✓: evidence available in favor of this mechanism; ×: evidence available against this mechanism; : no evidence available.
HSP: heat shock protein; SERCA: sarcoplasmic reticulum calcium pump; AMPK: AMP-activated protein kinase; PGC: peroxisome proliferator-activated receptor- coactivator.
^*Note: Where possible reference cited provides evidence for the cardiomyocyte response, which may differ from other cell types.