Aerobic Exercise and Cardiac Function of Murines Exposed to Doxorubicin: a Meta-Analysis

Matos, Mariana Inocêncio; Rubini, Ercole da Cruz; Meirelles, Frederico de Oliveira; Silva, Elirez Bezerra da

doi:10.36660/abc.20190260

Mariana Inocêncio Matos Mailing Address: Mariana Matos • Universidade do Estado do Rio de Janeiro - Programa de Pós-Graduação em Ciências do Exercício e do Esporte - Rua São Francisco Xavier, 524, 9º andar. Postal Code 20550-900, Rio de Janeiro, RJ – Brazil. E-mail: mariana.i.matos@gmail.com

Universidade do Estado do Rio de Janeiro - Programa de Pós-Graduação em Ciências do Exercício e do Esporte, Rio de Janeiro, RJ - Brazil

Universidade do Estado do Rio de Janeiro - Grupo de Pesquisa em Ciências do Exercício e da Saúde, Rio de Janeiro, RJ - Brazil

https://orcid.org/0000-0002-2717-062X

Ercole da Cruz Rubini

Universidade do Estado do Rio de Janeiro - Programa de Pós-Graduação em Ciências do Exercício e do Esporte, Rio de Janeiro, RJ - Brazil

Universidade do Estado do Rio de Janeiro - Grupo de Pesquisa em Ciências do Exercício e da Saúde, Rio de Janeiro, RJ - Brazil

Universidade Estácio de Sá, Rio de Janeiro, RJ – Brazil

Frederico de Oliveira Meirelles

Universidade do Estado do Rio de Janeiro - Programa de Pós-Graduação em Ciências do Exercício e do Esporte, Rio de Janeiro, RJ - Brazil

Universidade do Estado do Rio de Janeiro - Grupo de Pesquisa em Ciências do Exercício e da Saúde, Rio de Janeiro, RJ - Brazil

Universidade Estácio de Sá, Rio de Janeiro, RJ – Brazil

https://orcid.org/0000-0001-6075-2106

Elirez Bezerra da Silva

Universidade do Estado do Rio de Janeiro - Programa de Pós-Graduação em Ciências do Exercício e do Esporte, Rio de Janeiro, RJ - Brazil

Universidade do Estado do Rio de Janeiro - Grupo de Pesquisa em Ciências do Exercício e da Saúde, Rio de Janeiro, RJ - Brazil

https://orcid.org/0000-0002-5989-6556

Mailing Address: Mariana Matos • Universidade do Estado do Rio de Janeiro - Programa de Pós-Graduação em Ciências do Exercício e do Esporte - Rua São Francisco Xavier, 524, 9º andar. Postal Code 20550-900, Rio de Janeiro, RJ – Brazil. E-mail: mariana.i.matos@gmail.com

Author Contributions

Conception and design of the research, Analysis and interpretation of the data and Critical revision of the manuscript for intellectual content: Matos MI, Rubini EC, Meireles FO, Silva EB; Acquisition of data: Matos M; Statistical analysis: Silva EB; Writing of the manuscript: Matos MI, Rubini EC, Meireles FO.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Author (year)	Type of exercise	Intervention protocol	DOX injection	Left ventricular fractional shortening (FS%)
				Control + DOX		Aerobic exercise + DOX
				n	${\bar{X}}_{SD}$	n	${\bar{X}}_{SD}$
Hayward et al. (2012)¹⁸18. Hayward R, Lien CY, Jensen BT, Hydock DS, Schneider CM. Exercise training mitigates anthracycline induced chronic cardiotoxicity in a juvenile rat model. Pediatr Blood Cancer. 2012;59(1):149-54.	Aerobic Running wheel	Free access 24h/day Total: 10 weeks	2 mg/kg for 7 days Total = 14 mg/kg during exercise	15	52 ± 38	17	61 ± 29
Hydock et al. (2012) _(a)¹⁹19. Hydock DS, Lien CY, Jensen BT, Parry TL, Schneider CM, Hayward R. Rehabilitative exercise in a rat model of doxorubicin cardiotoxicity. Exp Biol Med. 2012;237(12):1483-92.	Aerobic Running wheel	Free access 24h/day Total: 10 weeks	1 mg/kg for 15 days Total = 15 mg/kg during exercise	15	45 ± 3	9	46 ± 4
Hydock et al. (2012) _(b)¹⁹19. Hydock DS, Lien CY, Jensen BT, Parry TL, Schneider CM, Hayward R. Rehabilitative exercise in a rat model of doxorubicin cardiotoxicity. Exp Biol Med. 2012;237(12):1483-92.	Aerobic Running wheel	Free access 24h/day Total: 10 weeks	2.5 mg/kg weekly for 6 weeks Total = 15 mg/kg during exercise	10	52 ± 5	10	61 ± 4
Calvé et al. (2012) _(a)²⁰20. Calvé A, Haddad R, Barama SN, Meilleur M, Sebag IA, Chalifour LE. Cardiac response to doxorubicin and dexrazoxane in intact and ovariectomized young female rats at rest and after swim training. Am J Physiol Heart Circ Physiol. 2012;302(10):H2048-57.	Aerobic Swimming	1h/day Total: 4 weeks	3 mg/kg on the 26th day of life pre-exercise	8	53.1 ± 3.8	8	49.5 ± 2.2
Calvé et al. (2012)_(b)²⁰20. Calvé A, Haddad R, Barama SN, Meilleur M, Sebag IA, Chalifour LE. Cardiac response to doxorubicin and dexrazoxane in intact and ovariectomized young female rats at rest and after swim training. Am J Physiol Heart Circ Physiol. 2012;302(10):H2048-57.	Aerobic Swimming	1h/day Total: 4 weeks	3 mg/kg on the 26th day of life pre-exercise	8	47 ± 2.1	8	51.6 ± 1.7
Dolinsky et al. (2013)²¹21. Dolinsky VW, Rogan KJ, Sung MM, Zordoky BN, Haykowsky MJ, Young ME, et al. Both aerobic exercise and resveratrol supplementation attenuate doxorubicin-induced cardiac injury in mice. Am J Physiol Endocrinol Metab. 2013;305(2):E243-53.	Aerobic Treadmill	10-18 m/min 5 days/week Total: 8 weeks	8 mg/kg per week for 4 weeks Total = 32 mg/kg pre-exercise	8	23.8 ± 1.0	8	28.0 ± 0.7
Jensen et al. (2013) _(a)²²22. Jensen BT, Lien CY, Hydock DS, Schneider CM, Hayward R. Exercise mitigates cardiac doxorubicin accumulation and preserves function in the rat. J Cardiovasc Pharmacol. 2013;62(3):263-9.	Aerobic Treadmill	13-30 min/m 5⁰-18⁰ 20-60 min/day 5 days/week Total: 10 weeks	10 mg/kg single dose post exercise	8	50.47 ± 2.77	4	61.60 ± 7.28
Jensen et al. (2013) _(b)²²22. Jensen BT, Lien CY, Hydock DS, Schneider CM, Hayward R. Exercise mitigates cardiac doxorubicin accumulation and preserves function in the rat. J Cardiovasc Pharmacol. 2013;62(3):263-9.	Aerobic Running wheel	Free access 24h/day Total: 10 weeks	10 mg/kg single dose post exercise	8	50.47 ± 2.77	7	58.3 ± 4.33
Parry et al. (2015)²³23. Parry TL, Hayward R. Exercise training does not affect anthracycline antitumor efficacy while attenuating cardiac dysfunction. Am J Physiol Regul Integr Comp Physiol. 2015;309(6):R675-83.	Aerobic Running wheel	Free access 24h/day Total: 11 weeks	12 mg/kg single dose post exercise	6	59 ± 6^† † measurement done on the 5th day after DOX injection;	4	63 ± 4^† † measurement done on the 5th day after DOX injection;
Lien et al. (2015) _(a)²⁴24. Lien CY, Jensen BT, Hydock, DS, Hayward R. Short-term exercise training attenuates acute doxorubicin cardiotoxicity. J Physiol Biochem. 2015;71(4):669-78.	Aerobic Treadmill	18-24 m/min Total: 5 days	10 mg/kg single dose post exercise	10	48 ± 4	10	56 ± 4
Lien et al. (2015) _(b)²⁴24. Lien CY, Jensen BT, Hydock, DS, Hayward R. Short-term exercise training attenuates acute doxorubicin cardiotoxicity. J Physiol Biochem. 2015;71(4):669-78.	Aerobic Running wheel	Free access 24h/day Total: 5 days	10 mg/kg single dose post exercise	10	48 ± 4	10	51 ± 5
Lien et al. (2015) _(c)²⁴24. Lien CY, Jensen BT, Hydock, DS, Hayward R. Short-term exercise training attenuates acute doxorubicin cardiotoxicity. J Physiol Biochem. 2015;71(4):669-78.	Aerobic Treadmill	18-24 m/min Total: 5 days	15 mg/kg single dose post exercise	13	39 ± 6	13	48 ± 5
Lien et al. (2015) _(d)²⁴24. Lien CY, Jensen BT, Hydock, DS, Hayward R. Short-term exercise training attenuates acute doxorubicin cardiotoxicity. J Physiol Biochem. 2015;71(4):669-78.	Aerobic Running wheel	Free access 24h/day Total: 5 days	15 mg/kg single dose post exercise	13	39 ± 6	12	45 ± 3

Author (year)	Type of exercise	Intervention protocol	DOX injection	Left ventricular developed pressure (LVDP), mm Hg
				Control + DOX		Aerobic exercise + DOX
				n	${\bar{X}}_{SD}$	n	${\bar{X}}_{SD}$
Chicco et al. (2005)²⁵25. Chicco JA, Schneider CM, Hayward R. Voluntary exercise protects against acute doxorubicin cardiotoxicity in the isolated perfused rat heart. Am J Physiol Regul Integr Comp Physiol. 2005;289:424-31.	Aerobic Running wheel	Free access 24 h/day Total: 8 weeks	10 μM single dose post exercise	7	30.5 ± 1.4	7	50.1 ± 7.7
Chicco et al. (2006)²⁶26. Chicco AJ, Schneider CM, Hayward R. Exercise training attenuates acute doxorubicin-induced cardiac dysfunction. J Cardiovasc Pharmacol. 2006;47(2):182-9.	Aerobic Treadmill	15-27 m/min 0°-5° 20-60 min/day 5 days/week Total: 12 weeks	15 mg/kg single dose post exercise	15	46 ± 9	15	84 ± 7
Hayward et al. (2012)¹⁸18. Hayward R, Lien CY, Jensen BT, Hydock DS, Schneider CM. Exercise training mitigates anthracycline induced chronic cardiotoxicity in a juvenile rat model. Pediatr Blood Cancer. 2012;59(1):149-54.	Aerobic Running wheel	Free access 24 h/day Total: 10 weeks	2 mg/kg for 7 days Total = 14 mg/kg during exercise	22	91 ± 15^† † measurement done with 300 beats per minute;	22	121 ± 12^† † measurement done with 300 beats per minute;
Jensen et al. (2013)_(a)²²22. Jensen BT, Lien CY, Hydock DS, Schneider CM, Hayward R. Exercise mitigates cardiac doxorubicin accumulation and preserves function in the rat. J Cardiovasc Pharmacol. 2013;62(3):263-9.	Aerobic Treadmill	13-30 min/m 5º-18 m 20-60 min/day 5 days/week Total: 10 weeks	10 mg/kg single dose post exercise	14	70 ± 3^†† †† measurement done on the 9th day after DOX injection.	10	93 ± 3^†† †† measurement done on the 9th day after DOX injection.
Jensen et al. (2013)_(b)²²22. Jensen BT, Lien CY, Hydock DS, Schneider CM, Hayward R. Exercise mitigates cardiac doxorubicin accumulation and preserves function in the rat. J Cardiovasc Pharmacol. 2013;62(3):263-9.	Aerobic Running wheel	Free access 24 h/day Total: 10 weeks	10 mg/kg single dose post exercise	14	70 ± 3^†† †† measurement done on the 9th day after DOX injection.	10	89 ± 2^†† †† measurement done on the 9th day after DOX injection.

Author (year)	Randomization	Concealment of randomization	Blinding of participants^* * The items referring to randomization and blinding of the sample were considered as low risk of bias even when not stated in the randomized controlled trial, given that studies of murine models neutralize these biases.	Blinding of evaluators^* * The items referring to randomization and blinding of the sample were considered as low risk of bias even when not stated in the randomized controlled trial, given that studies of murine models neutralize these biases.	Incomplete outcomes	Selective outcome reporting	Other sources of bias	Risk of bias
Chicco et al. (2005)	Low	Low	Low	Low	Low	Low	Low	Low
Chicco et al. (2006)	Low	Low	Low	Low	Low	Low	Low	Low
Hayward et al. (2012)	Low	Low	Low	Low	Low	Low	Low	Low
Hydock et al. (2012)	Low	Low	Low	Low	Low	Low	Low	Low
Calvé et al. (2012)	Low	Low	Low	Low	Low	Low	Low	Low
Jensen et al. (2013)	Low	Low	Low	Low	Low	Low	Low	Low
Dolionsky et al. (2013)²¹21. Dolinsky VW, Rogan KJ, Sung MM, Zordoky BN, Haykowsky MJ, Young ME, et al. Both aerobic exercise and resveratrol supplementation attenuate doxorubicin-induced cardiac injury in mice. Am J Physiol Endocrinol Metab. 2013;305(2):E243-53.	Low	Low	Low	Low	Low	Low	Low	Low
Parry et al. (2015)²³23. Parry TL, Hayward R. Exercise training does not affect anthracycline antitumor efficacy while attenuating cardiac dysfunction. Am J Physiol Regul Integr Comp Physiol. 2015;309(6):R675-83.	Low	Low	Low	Low	Low	Low	Low	Low
Lien et al. (2015)²⁴24. Lien CY, Jensen BT, Hydock, DS, Hayward R. Short-term exercise training attenuates acute doxorubicin cardiotoxicity. J Physiol Biochem. 2015;71(4):669-78.	Low	Low	Low	Low	Low	Low	Low	Low

Certainty assessment							No. of patients		Effect		Certainty	Importance
No. of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Aerobic exercise	Control	Relative (95% CI)	Absolute (95% CI)	Certainty	Importance
Fractional shortening (assessed with echocardiography and Doppler)
13	randomized trials	not serious	not serious	very seriousᵃ	not serious	none	230	222	–	mean 5.33% higher (3.4 to 7.26)	⨁⨁◯◯ Low	Critical
Left ventricular developed pressure (assessed with pressure transducer)
5	randomized trials	not serious	not serious	very seriousᵃ	not serious	none	153	166	–	mean 24.84 mm Hg higher (20.84 to 28.84)	⨁⨁◯◯ Low	Critical

[1] Mailing Address: Mariana Matos • Universidade do Estado do Rio de Janeiro - Programa de Pós-Graduação em Ciências do Exercício e do Esporte - Rua São Francisco Xavier, 524, 9º andar. Postal Code 20550-900, Rio de Janeiro, RJ – Brazil. E-mail: mariana.i.matos@gmail.com

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Aerobic Exercise and Cardiac Function of Murines Exposed to Doxorubicin: a Meta-Analysis

Abstract

Background:

Objectives:

Method:

Results:

Conclusion: