Effect of Calorie Restriction on Doxorubicin Induced Cardiac Dysfunction

Effect of Calorie Restriction on Doxorubicin Induced Cardiac Dysfunction Celina Lucero Genysie Van Duren

Background: Doxorubicin (DOX) • Potent Chemotherapy • Effective against: • Solid tumors • Leukemia • breast cancer • Destroys cells by: • Apoptosis • DNA damage Leukemia DNA damage

Background: DOX • Problem: • Attacks all metabolically active cells • Damages cardiac tissue • Creates reactive oxygen species and oxidative stress • Side Effects: • Cardiomyopathy • Severe acute illnesses • “Red Death” Cardiac tissue

Background: Calorie Restriction (CR) • Form of dieting • Proven to: • Extend lifespan • Preserves cardiac function • Lower body weight • Differing Effects: • Acute= negative results • Chronic= positive results

Introduction • Used rats: • Split into 4 groups- • Ad Lib (AL)+Saline (SAL), AL+DOX, CR+SAL, and CR+DOX • Done over 4 weeks • Echocardiographs monitor heart: • M-mode= left ventricle • Doppler= mitral and aortic valves Ekg: echocardiogram

Hypothesis/Purpose • Known facts: • DOX= effective…but dangerous • CR= prolong heart functions • Combination? • Both together= beneficial? • Solve adverse effects of DOX • Safer use with patients

Methods • Used Sprague-Dawley(Rattusnorvegicus) rats. • Reliable and healthy subjects • Feeding: • Normal first 2 weeks • CR or AL treatments follow initial 2 weeks. • CR= 60% of AL intake

Methods • Timeline Instructions • At 10 wks animals (males and females) assigned to feeding and activity regimens. • After a 2 week acclamation the DOX treatment will start • On weeks 2-9 the animals will receive either saline or DOX at 2.5 mg/kg for a total dose of 20 mg/kg

Results • Body Mass: • General decrease. CR= more • No significant differences • M-mode: • Variables generally the same • Corrected velocity of circumferential shortening (Vcfa) was only significant difference. • Between CR+DOX and AL+DOX • Doppler: • Variables generally the same • No significant differences

Results Table 1.Body Weight Averages Average body weights (g) over the course of the experiment. Number in parenthesis represent the standard deviation (StDev).

Results Percentage * mm/sec Fractional shortening at week 4. Percentage of wall change during diastole to systole. Vcfa at week 4. Speed at which the percentage change from FS happens adjusted to heart size. *The black portion of the graph represents the standard error. Diastole= relaxation Systole= contraction

Discussion • Body Mass: • CR= more weight loss • DOX did not effect weight • DOX normally lowers weight • M-mode: • Little thinning in LV walls • Previous study= profound thinning in LV walls • Doppler: • No significant differences • Fatalities: • Two rats in DOX group Top: M-mode Bottom: Doppler

Recommendations • Time Constraints: • Chronic CR proven to be better • Rats did not have enough time. • Only 7.5 mg/kg of DOX injected cumulatively • Previous studies= larger amount DOX • Again longer period of time • Rats not exposed to DOX long enough • Subjects: • Small sample size, decreased power

Acknowledgments • Thank you for everything! • Mentors: • Stephanie Greufe • Reid Hayward • Advisor: • Nick Horianopoulos • FSI Director: • Lori Ball • Sponsors: • Kinder Morgan Foundation • Xcel Energy Foundation • Frank and Gloria Walsh Science Foundation • Suncor Energy

Effect of Calorie Restriction on Doxorubicin Induced Cardiac Dysfunction