Effect of Calorie Restriction on Doxorubicin Induced Cardiac

Dysfunction

Celina LuceroGenysie Van Duren

Potent Chemotherapy Effective against:

Solid tumors Leukemia breast cancer

Destroys cells by: Apoptosis DNA damage

Background: Doxorubicin (DOX)

Leukemia

DNA damage

Problem:

Attacks all metabolically active cells Damages cardiac tissue Creates reactive oxygen species and oxidative

stress Side Effects:

Cardiomyopathy Severe acute illnesses

“Red Death”

Background: DOX

Cardiac tissue

Form of dieting Proven to:

Extend lifespan Preserves cardiac function Lower body weight

Differing Effects: Acute= negative results Chronic= positive results

Background: Calorie Restriction (CR)

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

Introduction

Ekg: echocardiogram

Known facts:

DOX= effective…but dangerous CR= prolong heart functions

Combination? Both together= beneficial? Solve adverse effects of DOX Safer use with patients

Hypothesis/Purpose

Used Sprague-Dawley (Rattus norvegicus)

rats. Reliable and healthy subjects

Feeding: Normal first 2 weeks CR or AL treatments follow initial 2 weeks.

CR= 60% of AL intake

Methods

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

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

  Baseline Week 1 Week 2 Week 3 Week 4 Week 5

AL+SAL

N/A 355 (0) 301 (81) 306.3 (76.4) 312.3 (87.9) 331.7 (73.5)

AL+DOX

325 (0) 305.3 (82.9) 306 (85.9) 301.8 (83.5) 312.3 (78) 306.5 (80.4)

CR+SAL

304.3 (68.8) 289 (59.9) 285.3 (65.4) 290 (65) 271.7 (62.5) 251 (61.5)

CR+DOX

337.5 (3.5) 310.5 (2.1) 308.5 (6.7) 326.5 (6.4) 274.5 (.7) 279.5 (.7)

Results

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

Results

FS

AL + SAL AL + DOX CR + SALCR + DOX0.000.050.100.150.200.250.300.350.400.450.500.550.600.65

Vcfa

AL + SAL AL + DOX CR + SALCR + DOX0.00000.00010.00020.00030.00040.00050.00060.00070.00080.00090.00100.0011

*

mm

/sec

Vcfa at week 4. Speed at which the percentage change from FS happens adjusted to heart size.

Fractional shortening at week 4. Percentage of wall change during diastole to systole.

Perc

en

tage

*The black portion of the graph represents the standard error.

Diastole= relaxationSystole= contraction

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

Discussion

Top: M-mode Bottom: Doppler

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

Recommendations

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

Acknowledgments